Triagem neonatal por espectrometria de massas em tandem (MS/MS) para a detecção da Homocistinúria Clássica (HCU) / Newborn screening by tandem mass spectrometry (MS/MS) for the detection of Classical Homocystinuria (HCU)

INTRODUÇÃO: a HCU representa o distúrbio maisfrequente do metabolismo da metionina. No entanto, os dados disponíveis sugerem que essa condição pode ser classificada na categoria de doença ultrarrara no Brasil. As anormalidades bioquímicas resultantes da doença (hipermetioninemia, hiperhomocisteinemia e diminuição de cisteína) levam a comprometimento ocular (subluxação do cristalino ou ectopia lentis, miopia, glaucoma, descolamento de retina, entre outros), comprometimento do sistema esquelético (escoliose, pectus excavatum, osteoporose, membros longos, hábito marfanóide), vascular (tromboembolismo, flush malar, livedo reticularis) e atraso no desenvolvimento ou deficiência intelectual, entre outros. O tratamento para HCU tem como principal objetivo a diminuição da homocisteína total e está descrito em PCDT. O método baseado em MS/MS tem sido a base para a detecção de HCU em programas de triagem neonatal em vários países, a partir de amostras de sangue impregnado em papel filtro. PERGUNTA DE PESQUISA: a triagem neonatal (em sangue seco, colhido em papel-filtro) por MS/MS, para a detecção da HCU, em recém-nascidos (RN) assintomáticos, é custo-efetiva e reduz a mortalidade e as complicações de curto e longo prazo naqueles RN nos quais a doença é detectada, em comparação ao diagnóstico dessa doença em indivíduos com suspeita clínica ou manifestações clínicas? EVIDÊNCIAS CLÍNICAS: em uma busca sistemática da literatura científica, realizada em 22 de setembro de 2022, foram encontradas 548 referências nas plataformas MEDLINE (via Pubmed), EMBASE (via Elsevier), Cochrane Library, LILACS (via BVS) e PROSPERO. Foram identificados 7 estudos observacionais que atendiam aos critérios de inclusão deste PTC. Considerando os 4 desfechos primários avaliados, não foram encontrados estudos sobre apenas um deles (Internações hospitalares decorrentes da doença ou de suas complicações). Os estudos incluídos descrevem maior frequência de óbitos por complicações da doença. Com relação à incidência de complicações ou condições resultantes da doença, independente da necessidade de admissão hospitalar, também há uniformidade entre os resultados dos estudos incluídos, sendo a mesma inferior no grupo que recebeu a intervenção. As complicações que apresentaram benefício pela intervenção foram alterações oftalmológicas, prejuízos no desenvolvimento cognitivo/deficiência intelectual, alterações neuropsiquiátricas e escoliose. A Qualidade de Vida dos pacientes com HCU também parece ser prejudicada pelo diagnóstico tardio. Os resultados sugerem, portanto, que os indivíduos com HCU seriam beneficiados com a inclusão da triagem neonatal para a detecção dessa doença, com uma certeza de evidência muito baixa. AVALIAÇÃO ECONÔMICA: propôs-se uma análise de custo-utilidade construída com base nas diretrizes metodológicas publicadas pelo Ministério da Saúde, na perspectiva do SUS, tendo como população alvo todos os RN no país. Recentemente a CONITEC emitiu um parecer no qual recomenda a incorporação da MS/MS para a triagem neonatal da Deficiência de Acil-CoA Desidrogenase de Cadeia Média (em inglês, MCADD) e da fenilcetonúria (PKU); como a triagem para HCU seria neste mesmo equipamento e com o uso do mesmo kit reagente utilizado nestas duas doenças (MCADD e PKU), não haverá gasto adicional com a primeira etapa da triagem (1ª amostra) quando todos os RN são testados. O custo adicional, com a possível inclusão da HCU na triagem neonatal, advém da necessidade de repetir o teste em MS/MS, através de uma 2ª coleta, quando a 1ª coleta for alterada. Os pacientes com diagnóstico de HCU devem ser tratados, seguindo-se o PCDT específico para esta doença. O valor obtido ao se calcular o custo incremental da adoção da estratégia de triagem neonatal de HCU dividido pelo incremento na efetividade (na forma de utilidade) é R$ 2.818,95/19,80, resultando em uma Razão de Custo-efetividade Incremental (RCEI) de R$ 142,39/QALY. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: A análise de impacto orçamentário (AIO) desenvolvida considerou então os custos necessários para realizar a 2ª coleta da triagem (a 2ª testagem da triagem). Os cálculos indicaram que ao longo de 5 anos, o valor gasto seria de R$ 2.850,00, uma média anual de R$ 575,00. CONSIDERAÇÕES FINAIS: a triagem neonatal (em sangue seco, colhido em papel-filtro) com MS/MS para a detecção de HCU reduz a mortalidade e as complicações de curto e longo prazo para aqueles nos quais a doença é detectada, sem produzir efeitos adversos ou riscos inaceitáveis na população rastreada, em comparação ao diagnóstico em fase sintomática. Esses resultados são baseados em evidências de certeza muito baixa, conforme revelado pela avaliação GRADE. Por fim, tão importante quanto a inclusão da triagem neonatal com MS/MS para a detecção de HCU é a correta orientação por equipe especializada do tratamento adequado a fim de evitar as complicações da doença. Os laboratórios responsáveis pela triagem neonatal deverão determinar adequadamente os seus pontos-de-corte para metionina e razão metionina/fenilalanina, de forma a tornar adequada a sensibilidade do teste. O custo incremental da adoção da estratégia de triagem neonatal de HCU dividido pelo incremento na efetividade (na forma de utilidade) é R$ 2.818,95/19,80, resultando em uma Razão de Custo-efetividade Incremental (RCEI) de R$ 142,39/QALY. Em síntese, os resultados encontrados mostram que há um incremento relevante em anos de vida associados à melhor qualidade de vida, por um custo incremental relativamente baixo. Ao longo de 5 anos, o valor gasto com a incorporação da triagem neonatal para HCU no SUS seria de cerca de 2,8 milhões de reais, uma média anual de aproximadamente 560 mil reais. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Diante do exposto, os membros do Plenário da Conitec, presentes na 114ª Reunião Ordinária, realizada no dia 09 de novembro de 2022, deliberaram por unanimidade que a matéria fosse disponibilizada em consulta pública com recomendação preliminar favorável à incorporação, no SUS, da triagem neonatal por espectrometria de massas em tandem (MS/MS) para a detecção da Homocistinúria Clássica (HCU). Para esta recomendação os membros do Plenário concordaram que foram apresentados resultados favoráveis para um número pequeno de crianças, com impacto orçamentário e razão de custo-efetividade baixos sob o aspecto do limiar de custoefetividade proposto para doenças raras. CONSULTA PÚBLICA: A consulta pública n° 96 ficou vigente no período entre 19/12/2022 e 09/01/2023. Foram recebidas duas contribuições, sendo ambas pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Todas as contribuições (n=2; 100%) concordaram com a recomendação preliminar da Conitec de incorporar a Triagem neonatal por MS/MS para detecção da HCU no SUS. RECOMENDAÇÃO FINAL DA CONITEC: os membros do Comitê de Produtos e Procedimentos da Conitec, em sua 117ª Reunião Ordinária, realizada no dia 29 de março de 2023, deliberaram por unanimidade, recomendar a incorporação da triagem neonatal por espectrometria de massas em tandem (MS/MS) para a detecção da Homocistinúria Clássica (HCU), conforme Protocolo Clínico do Ministério da Saúde. Não foram apresentados elementos, durante a consulta pública, que pudessem alterar a recomendação preliminar. Foi assinado o registo de deliberação nº 813/2023. DECISÃO: Incorporar, no âmbito do Sistema Único de Saúde - SUS, a triagem neonatal por espectrometria de massas em tandem (MS/MS) para a detecção da Homocistinúria Clássica (HCU), conforme Protocolo Clínico do Ministério da Saúde, publicada no Diário Oficial da União nº 89, seção 1, página 222, em 11 de maio de 2023.

Screening methods for neonatal hyperbilirubinemia: benefits, limitations, requirements, and novel developments.

Severe neonatal hyperbilirubinemia (SNH) is a serious condition that occurs worldwide. Timely recognition with bilirubin determination is key in the management of SNH. Visual assessment of jaundice is unreliable. Fortunately, transcutaneous bilirubin measurement for screening newborn infants is routinely available in many hospitals and outpatient settings. Despite a few limitations, the use of transcutaneous devices facilitates early recognition and appropriate management of neonatal jaundice. Unfortunately, however, advanced and often costly screening modalities are not accessible to everyone, while there is an urgent need for inexpensive yet accurate instruments to assess total serum bilirubin (TSB). In the near future, novel icterometers, and in particular optical bilirubin estimates obtained with a smartphone camera and processed with a smartphone application (app), seem promising methods for screening for SNH. If proven reliable, these methods may empower outpatient health workers as well as parents at home to detect jaundice using a simple portable device. Successful implementation of ubiquitous bilirubin screening may contribute substantially to the reduction of the worldwide burden of SNH. The benefits of non-invasive bilirubin screening notwithstanding, any bilirubin determination obtained through non-invasive screening must be confirmed by a diagnostic method before treatment. IMPACT: Key message: Screening methods for neonatal hyperbilirubinemia facilitate early recognition and timely treatment of severe neonatal hyperbilirubinemia (SNH). Any bilirubin screening result obtained must be confirmed by a diagnostic method. What does this article add to the existing literature? Data on optical bilirubin estimation are summarized. Niche research strategies for prevention of SNH are presented. Impact: Transcutaneous screening for neonatal hyperbilirubinemia contributes to the prevention of SNH. A smartphone application with optical bilirubin estimation seems a promising low-cost screening method, especially in low-resource settings or at home.

Virus containment box for retinopathy of prematurity screening and laser.

PURPOSE: Health care workers are susceptible to contracting infection with COVID-19 by aerosol transmission. This is a risk while examining and/or treating an un-sedated neonate in retinopathy of prematurity (ROP) screening and treatment. But screening for neonates for ROP and treating with laser, when required, should not be delayed to avoid the blindness. We describe a cost-effective method of containing aerosols generated during such a procedure in an un-sedated baby. METHODS: An acrylic transparent containment box was prepared to accommodate an average-sized infant. The box had four walls and a roof. The floor was open to place the container box over the baby. The walls have two types of openings, large ones to allow passage of hands to examine the baby, small ones to enable passage of oxygen tubing when required. A simulation was created to examine the impact of aerosol spray on examining healthcare personnel. RESULTS: The cost of the acrylic box was negligible. It could be assembled locally with available acrylic sheets and craftsmen. It was not difficult to examine the baby inside the box, and the simulation demonstrated that it protected the health personnel from the aerosol contamination. CONCLUSION: The described method is likely to increase healthcare personnel's confidence not to delay or deny ROP screening and laser treatment and save the babies from blindness.

Intra- and inter-rater reliability of a biophotogrammetric assessment protocol for preterm infants / Confiabilidade intra e interexaminador do protocolo de avaliação biofotogramétrica em prematuros

ABSTRACT Objective: To measure the intra- and inter-rater reliability of a biophotogrammetric assessment protocol for thoracoabdominal motion in preterm infants. Methods: This is an analytical cross-sectional study. Footage of 40 preterm infants was made in two views (lateral and anterior). The babies were placed in the supine position, with retroverted pelvis and semiflexed knees. Acrylic markers were positioned on surgical tape in eight predetermined anatomical points. We analyzed 4 variables in lateral view and 11 in anterior view (angular and linear) (ImageJ®), divided into two stages: 1. same frames - three blinded evaluators analyzed frames previously selected by the main researcher (inter-rater analysis 1), reviewing these same frames after 15 days (intra-rater analysis 1); 2. different frames - each evaluator selected the frames from the original video and repeated the protocol (inter-rater analysis 2), with a review after 15 days (intra-rater analysis 2). In stage 2, we tested the reliability of the entire process, from image selection to the analysis of variables. Data agreement and reproducibility were obtained by the intraclass correlation coefficient (ICC). Results: Agreement was high, particularly in angular variables (ICC 0.82 to 0.99). Linear variables ranged between very good and excellent in analysis 1 (same frames: ICC 0.64 to 0.99) and analysis 2 (different frames: ICC 0.44 to 0.89). Conclusions: The present study suggests that the proposed protocol for the thoracoabdominal motion analysis of preterm neonates has high reliability.

RESUMO Objetivo: Mensurar a confiabilidade intra e interexaminador de um protocolo de avaliação biofotogramétrica da mobilidade toracoabdominal de prematuros. Métodos: Estudo de caráter transversal e analítico. Incluíram-se filmagens de 40 prematuros em duas vistas (lateral e superior), realizadas em supino, pelve retrovertida e joelhos em semiflexão. Marcadores de acrílico foram posicionados sobre Micropores em oito pontos anatômicos predeterminados. Foram analisadas 4 variáveis na vista lateral e 11 na vista superior (angulares e lineares) (ImageJ®), divididas em duas etapas: (1-Frames iguais) análises de fotogramas previamente selecionados pela pesquisadora principal por três avaliadores cegos (análise interexaminador 1), com reanálise desses mesmos fotogramas após 15 dias (análise intraexaminador 1); (2-Frames diferentes) cada avaliador selecionou os fotogramas por meio do vídeo original e repetiu o protocolo (análise interexaminador 2), com reanálise após 15 dias (análise intraexaminador 2). Em (2), foi testada a confiabilidade de todo o processo de análise, desde a separação das imagens até a análise das variáveis. A concordância e reprodutibilidade dos dados foram obtidas pelo coeficiente de correlação intraclasse (CCI). Resultados: Houve concordância forte, com ênfase nas variáveis angulares (CCI [0,82 a 0,99]). As variáveis lineares apresentaram variação entre muito boa e excelente na análise 1 (frames iguais: CCI 0,64 a 0,99) e na análise 2 (frames diferentes: CCI entre 0,44 e 0,89). Conclusões: O presente estudo sugere forte confiabilidade do protocolo proposto para análise da movimentação toracoabdominal de neonatos prematuros.

Construction and validation of the neonatal nutritional risk screening tool / Construção e validação da ferramenta de avaliação de risco nutricional neonatal

ABSTRACT Objective: To develop and validate both the content and reliability of the Neonatal Nutritional Risk Screening Tool (FARNNeo). Methods: Methodological study, convergent care. The instrument was built prior to the literature review and was analyzed by eight judges, during three cycles of the Delphi technique. The judges assessed their relevance and clarity with responses on the Likert scale with three levels, in addition to suggestions. The validation of the instrument was calculated using the agreement rate and content validity index (CVI). After content validation, the instrument was applied by four assisting nutritionists to verify reliability, using Cronbach`s alpha coefficient and the agreement between the evaluators by the Kappa coefficient. Results: All items of the instrument`s content reached the minimum agreement rate (90%) and/or CVI (0.9), except for item three, which in the first cycle obtained CVI 0.77 and 40% of agreement and, in the second cycle, CVI 0.75 and 38% agreement. At the end of the third cycle, all items had CVI values above 0.9. In the instrument application, alpha of 0.96 and Kappa of 0.74 were obtained, which reflect adequate values of internal consistency and agreement between the evaluators. Conclusions: FARNNeo proved to be reliable, clear, relevant, and reproducible for tracking early nutritional risk, systematizing the care of Brazilian newborns admitted to an intensive care unit.

RESUMO Objetivo: Desenvolver e validar o conteúdo e a confiabilidade da Ferramenta de Avaliação do Risco Nutricional Neonatal (FARNNeo). Métodos: Estudo metodológico, convergente assistencial. O instrumento foi construído previamente à revisão da literatura e analisado por oito juízes, durante três ciclos da técnica Delphi. Os juízes avaliaram sua pertinência e clareza com respostas na escala Likert com três níveis, além de sugestões. A validação do instrumento foi calculada pela taxa de concordância e índice de validade de conteúdo (IVC). Após a validação do conteúdo, o instrumento foi aplicado por quatro nutricionistas assistenciais para verificar a fidedignidade, utilizando o coeficiente de alfa de Cronbach e a concordância entre os avaliadores pelo coeficiente Kappa. Resultados: Todos os itens do conteúdo do instrumento alcançaram o valor mínimo da taxa de concordância (90%) e/ou IVC (0,9), com exceção do item três, que no primeiro ciclo obteve IVC 0,77 e 40% de concordância e, no segundo ciclo, IVC 0,75 e 38% de concordância. No fim do terceiro ciclo, todos os itens obtiveram valores de IVC acima de 0,9. Na aplicação da ferramenta, obteve-se alfa de 0,96 e Kappa de 0,74, que refletem valores adequados de consistência interna e concordância entre os avaliadores. Conclusões: A FARNNeo mostrou-se confiável, clara, pertinente e reprodutível para rastreamento do risco nutricional precoce, sistematizando o atendimento de recém-nascidos brasileiros internados em centro de terapia intensiva.

Red reflex technique training simulator in newborns / Simulador para o treinamento da técnica do reflexo vermelho em recém-nascidos

Abstract: Introduction: The Red Reflex Test (RRT) consists of visualizing the reflection that light causes in the retina when it passes through the pupil. It is a screening test for pathologies that can lead to blindness, which still have great social and economic impact on families and the government. Teaching through simulators allows students and health professionals to acquire and improve their clinical skills. Objective: The aim of the study is to develop a low-cost dummy, 3D printed and based on the Arduino platform, for the training of the red reflex technique (RRT) in newborns and evaluate its educational effectiveness. Method: A RRT dummy was presented to 7 expert judges: 6 pediatricians and 1 ophthalmologist to evaluate its applicability in medical learning. For this purpose, they used a 14-item Likert scale of 5 points. Subsequently, 40 individuals participated in a course: 33 medical students, 5 pediatric residents, a nurse and a general physician. The participants were randomly assigned to two groups: control (CG) and experimental (EG) group. Each group consisted of 20 participants. The EG went through 4 stages: 1) theoretical background; 2) handling of the simulator; 3) simulated clinical practice and; 4) evaluation in real-life patients. Whereas the CG went through the following teaching methodological processes: 1) theoretical background; 2) direct training in real-life patients and; 4) practical evaluation in a real-life patient. After each respective group intervention, both groups were assessed on their learning in 40 newborns at Santa Casa de Misericórdia do Pará Foundation in Belém, state of Pará, Brazil. Results: At the judges' evaluation regarding the simulator positive items (design, similarity, interest, relevance, content, memorization, didactics, previous reminiscence, comprehension and application), 49.2% answered 'strongly agree' and 44.4%, 'agree'. Regarding the negative questions (difficulty in understanding, information overload, abstraction, difficulty in handling and clarity of operation), 40.0% answered 'strongly disagree', and 57.1%, 'disagree'. The judges were 94.9% favorable to the use of the simulator in medical education. However, comparing the two groups of students, regarding the time of exam, the results showed no statistically significant difference (p-value = 0.29). Conclusions: The dummy showed its applicability for the learning of RRT, with the advantage of being able to perform the exam without having to disturb a real-life patient.

Resumo: Introdução: O Teste do Reflexo Vermelho (TRV) consiste em visualizar o reflexo que a luz causa na retina ao passar pela pupila. Dessa forma, o TRV tria patologias que levam à cegueira e pode reduzir o impacto social e econômico das famílias e do governo. O ensino por meio de simuladores permite que estudantes e profissionais de saúde adquiram e melhorem as habilidades clínicas. Objetivos: Este estudo teve como objetivos desenvolver um manequim de baixo custo, impresso em 3D e baseado na plataforma Arduino, para o treinamento do TRV em recém-nascidos e avaliar a eficácia educacional desse exame. Métodos: Um manequim do TRV foi apresentado a sete juízes especialistas - seis pediatras e um oftalmologista - que avaliaram a aplicabilidade do teste na aprendizagem médica. Para isso, utilizaram a escala Likert de 14 itens de 5 pontos. Posteriormente, 40 participantes participaram de um curso: 33 estudantes de Medicina, cinco residentes em pediatria, uma enfermeira e um médico generalista. Dividiram-se aleatoriamente os participantes em dois grupos: controle (GC) e experimental (GE). Cada grupo foi composto por 20 participantes. Submeteu-se o GC ao ensino convencional em pacientes reais. O GE passou por quatro etapas: 1. fundamentação teórica, 2. manipulação do simulador, 3. prática clínica simulada e 4. avaliação nos pacientes reais. No GC, adotaram-se os seguintes passos: 1. fundamentação teórica, 2. treinamento direto em pacientes reais e 3. avaliação em pacientes reais. Após a intervenção de cada grupo, os dois grupos foram avaliados quanto à aprendizagem em 40 recém-nascidos da Fundação Santa Casa de Misericórdia do Pará, em Belém, no Pará. Resultados: Na avaliação dos juízes em relação aos itens positivos para o simulador (design, similaridade, interesse, relevância, conteúdo, memorização, didática, reminiscência anterior, compreensão e aplicação), 49,2% afirmaram que concordavam fortemente e 44,4% mencionaram apenas que concordavam. Nas questões negativas (dificuldade de entendimento, sobrecarga de informação, abstração, dificuldade de manuseio e clareza de operação), 40,0% discordaram fortemente e 57,1% discordaram. Os juízes concordaram em 94,9% a favor do uso do simulador na educação médica. Porém, comparando os dois grupos de estudantes, em relação ao tempo de exame, os resultados não mostraram diferença estatisticamente significante (p = 0,29). Conclusão: O manequim mostrou aplicabilidade na aprendizagem do TRV, com a vantagem de realizar o exame sem que o paciente real fosse incomodado.

CONSTRUCTION AND VALIDATION OF THE NEONATAL NUTRITIONAL RISK SCREENING TOOL.

OBJECTIVE: To develop and validate both the content and reliability of the Neonatal Nutritional Risk Screening Tool (FARNNeo). METHODS: Methodological study, convergent care. The instrument was built prior to the literature review and was analyzed by eight judges, during three cycles of the Delphi technique. The judges assessed their relevance and clarity with responses on the Likert scale with three levels, in addition to suggestions. The validation of the instrument was calculated using the agreement rate and content validity index (CVI). After content validation, the instrument was applied by four assisting nutritionists to verify reliability, using Cronbach`s alpha coefficient and the agreement between the evaluators by the Kappa coefficient. RESULTS: All items of the instrument`s content reached the minimum agreement rate (90%) and/or CVI (0.9), except for item three, which in the first cycle obtained CVI 0.77 and 40% of agreement and, in the second cycle, CVI 0.75 and 38% agreement. At the end of the third cycle, all items had CVI values above 0.9. In the instrument application, alpha of 0.96 and Kappa of 0.74 were obtained, which reflect adequate values of internal consistency and agreement between the evaluators. CONCLUSIONS: FARNNeo proved to be reliable, clear, relevant, and reproducible for tracking early nutritional risk, systematizing the care of Brazilian newborns admitted to an intensive care unit.

INTRA- AND INTER-RATER RELIABILITY OF A BIOPHOTOGRAMMETRIC ASSESSMENT PROTOCOL FOR PRETERM INFANTS.

OBJECTIVE: To measure the intra- and inter-rater reliability of a biophotogrammetric assessment protocol for thoracoabdominal motion in preterm infants. METHODS: This is an analytical cross-sectional study. Footage of 40 preterm infants was made in two views (lateral and anterior). The babies were placed in the supine position, with retroverted pelvis and semiflexed knees. Acrylic markers were positioned on surgical tape in eight predetermined anatomical points. We analyzed 4 variables in lateral view and 11 in anterior view (angular and linear) (ImageJ®), divided into two stages: 1. same frames - three blinded evaluators analyzed frames previously selected by the main researcher (inter-rater analysis 1), reviewing these same frames after 15 days (intra-rater analysis 1); 2. different frames - each evaluator selected the frames from the original video and repeated the protocol (inter-rater analysis 2), with a review after 15 days (intra-rater analysis 2). In stage 2, we tested the reliability of the entire process, from image selection to the analysis of variables. Data agreement and reproducibility were obtained by the intraclass correlation coefficient (ICC). RESULTS: Agreement was high, particularly in angular variables (ICC 0.82 to 0.99). Linear variables ranged between very good and excellent in analysis 1 (same frames: ICC 0.64 to 0.99) and analysis 2 (different frames: ICC 0.44 to 0.89). CONCLUSIONS: The present study suggests that the proposed protocol for the thoracoabdominal motion analysis of preterm neonates has high reliability.

Accuracy of Bilistick (a Point-of-Care Device) to Detect Neonatal Hyperbilirubinemia.

INTRODUCTION: Early diagnosis and appropriate management of neonatal jaundice is crucial in avoiding severe hyperbilirubinemia and brain injury. A low-cost, minimally invasive, point-of-care (PoC) tool for total bilirubin (TB) estimation which can be useful across all ranges of bilirubin values and all settings is the need of the hour. OBJECTIVE: To assess the accuracy of Bilistick system, a PoC device, for measurement of TB in comparison with estimation by spectrophotometry. DESIGN/METHODS: In this cross-sectional clinical study, in infants who required TB estimation, blood samples in 25-µl sample transfer pipettes were collected at the same time from venous blood obtained for laboratory bilirubin estimation. The accuracy of Bilistick in estimating TB within ±2 mg/dl of bilirubin estimation by spectrophotometry was the primary outcome. RESULTS: Among the enrolled infants, 198 infants were eligible for study analysis with the mean gestation of 36 ± 2.3 weeks and the mean birth weight of 2368 ± 623 g. The median age at enrollment was 68.5 h (interquartile range: 48-92). Bilistick was accurate only in 54.5% infants in measuring TB within ±2 mg/dl difference of TB measured by spectrophotometry. There was a moderate degree of correlation between the two methods (r = 0.457; 95% CI: 0.339-0.561, p value < 0.001). Bland-Altman analysis showed a mean difference of 0.5 mg/dl (SD ± 4.4) with limits of agreement between -8.2 and +9.1 mg/dl. CONCLUSION: Bilistick as a PoC device is not accurate to estimate TB within the clinically acceptable difference (±2 mg/dl) of TB estimation by spectrophotometry and needs further improvement to make it more accurate.

Ampliação do uso do teste do pezinho para a detecção da toxoplasmose congênita / Expansion of the use of the heel test to the detection of congenital toxoplasmosis

CONTEXTO: A toxoplasmose congênita (TC) é uma doença infecciosa que resulta da transferência transplacentária do Toxoplasma gondii para o concepto, decorrente de infecção primária da mãe durante a gestação. Os recém-nascidos que apresentam manifestações clínicas podem ter sinais no período neonatal ou nos primeiros meses de vida. Esses casos costumam ter, com mais frequência, sequelas graves, como acometimento visual em graus variados, sequelas neurológicas, anormalidades motoras e surdez. A prevalência de toxoplasmose é alta no Brasil, podendo variar de 64,9 % a 91,6 %, dependendo da região. Uma porcentagem alta (50-80%) das mulheres em idade fértil são IgG positivas. Entre 20-50% das mulheres em idade reprodutiva são suscetíveis (IgG e IgM negativas) e estão em risco de adquirir a infecção na gestação. Estudos realizados no Brasil mostraram que nascem entre 5-23 crianças infectadas a cada 10.000 nascidos vivos. A inclusão da toxoplasmose no teste de pezinho, complementar à triagem materna, no Brasil, foi sugerida por vários especialistas. Segundo Neto e colaboradores, embora a eficácia a longo prazo do tratamento da TC não tenha sido bem estabelecida, a disponibilidade de diagnósticos confiáveis, a logística funcional e criação de redes para triagem, a gravidade das sequelas e a prevalência muito alta da doença, fazem da triagem neonatal para TC uma alternativa a nenhuma triagem. PERGUNTA: O teste de rastreamento da toxoplasmose congênita através da pesquisa de anticorpos IgM anti-Toxoplasma gondii no sangue colhido em papel filtro é seguro, efetivo e eficiente o suficiente para modificar as condutas e os desfechos imediatos e em longo prazo nos pacientes diagnosticados? Evidências científicas: Segundo dados de estudo nacional a triagem neonatal identificou casos de infecção não detectados pela obtenção de apenas uma ou duas amostras de soro de mulheres grávidas para sorologia de T. gondii, principalmente quando a infecção foi adquirida no final da gravidez. O teste sorológico para diagnóstico da TC que apresentou maior desempenho foi o ISAGA (immunosorbent agglutination assay) com a sensibilidade variando de 54-87% e a especificidade de 77,7-100%. Não há estudos randomizados avaliando a terapia antiparasitária em lactentes e as evidências são oriundas de estudos observacionais. Comparado com os controles históricos (não tratados ou tratados por um mês), o tratamento combinado por 12 meses foi associado a melhores resultados neurológicos, cognitivos e auditivos e prevenção de novas lesões oculares. AVALIAÇÃO ECONÔMICA: Sem qualquer triagem na população, o custo por nascimento seria de R$ 11,42, ou cerca de R$ 33.555.477,36 para todos os nascimentos no Brasil no ano de 2018. A ampliação do teste de pezinho para toxoplasmose congênita, incluindo custos da triagem e do tratamento durante o primeiro ano de vida, teria um custo de R$ 8,19 por nascimento e um custo total de R$ 24.064.742,52 para todos os nascimentos. A triagem pré-natal apresentou maior custo entre as estratégias testadas, R$ 57,96 por nascimento, incluindo a triagem realizada nos três trimestres da gravidez, o tratamento da gestante e da criança. Em um ano, o custo total da triagem pré-natal seria de R$ 170.304.331,68. A realização da triagem neonatal implicaria em R$ 13.516.216,8 de custos salvos em comparação com não fazer nenhuma triagem. Considerando o desfecho sequela relacionado à TC evitada, apesar da triagem neonatal apresentar menor custo ela foi menos eficaz que a triagem pré-natal. A relação custoefetividade incremental em 1 ano foi de R$ 50,02 por sequelas da TC evitadas em comparação à triagem neonatal. A não realização de qualquer triagem foi dominada pelas triagens avaliadas. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: No primeiro cenário, considerando o custo por nascido vivo de R$ 8,19 obtido na avaliação econômica, o impacto orçamentário (IO) seria em torno de R$ 23,9 milhões. Considerando uma taxa de transmissão materno-fetal de 18,5% identificada em estudo epidemiológico brasileiro, o IO entre os cinco anos foi de aproximadamente R$ 55 milhões e considerando uma taxa de transmissão inferior de 3,5% o impacto ficaria aproximadamente R$ 54 milhões. O último cenário considerou a prevalência de toxoplasmose congênita de 6/10.000 nascidos vivos obtendo um IO seria em torno de R$ 55,44 à R$ 55,56 milhões. CONSIDERAÇÕES FINAIS: A TC é um importante problema de saúde, prevalente no Brasil (5-23 crianças infectadas a cada 10.000 nascidos vivos) e associada frequentemente a graves sequelas. A detecção de IgM no período neonatal diagnostica a toxoplasmose congênita em mais de 80% dos casos. O tratamento precoce parece reduzir os danos causados pela doença. A pesquisa de IgM anti-T. gondii para triagem neonatal já foi aplicada em diferentes regiões no Brasil e a relação custo/benefício do diagnóstico precoce é favorável na ausência de triagem pré-natal bem executada. RECOMENDAÇÕES PRELIMINAR DA CONITEC: A Conitec, em sua 84ª reunião ordinária, no dia 04 de dezembro de 2019, recomendou que a matéria fosse disponibilizada em consulta pública com recomendação preliminar favorável à ampliação no SUS do teste de pezinho para detecção da toxoplasmose congênita. Foi considerado que a toxoplasmose congênita é um problema de saúde pública e que o diagnóstico e tratamento precoce possuem potencial para redução das sequelas da doença em crianças. CONSULTA PÚBLICA: O Relatório de Recomendação da Conitec foi disponibilizado por meio da Consulta Pública nº 84/2019 entre os dias 02/01/2020 e 21/01/2020. Foram recebidas 244 contribuições, sendo 110 técnico-científicas e 134 contribuições de experiência ou opinião. Após apreciação das contribuições encaminhadas pela Consulta Pública, o plenário da Conitec entendeu que não houve argumentação suficiente para alterar a recomendação preliminar. RECOMENDAÇÃO FINAL: Os membros da Conitec presentes na 85ª reunião ordinária, no dia 05 de fevereiro de 2020, deliberaram, por unanimidade, por recomendar a ampliação do uso do teste do pezinho para a detecção da toxoplasmose congênita. Foi assinado o Registro de Deliberação nº 507/2020. DECISÃO: Ampliar o uso do teste do pezinho para a detecção da toxoplasmose congênita, no âmbito do Sistema Único de Saúde - SUS, conforme a Portaria nº 5, publicada no Diário Oficial da União nº 44, seção 1, página 130, em 5 de março de 2020.

A Simulation Study to Assess the Effect of Analytic Error on Neonatal Glucose Measurements Using the Canadian Pediatric Society Position Statement Action Thresholds.

BACKGROUND: The Canadian Pediatric Society (CPS) has endorsed an algorithm for the screening and immediate management of babies at risk of neonatal hypoglycemia that provides time-dependent glucose concentration action thresholds. The objective of this study was to evaluate the impact of glucose analytic error (bias and imprecision) on the misclassification of glucose meter results from a neonatal intensive care unit (NICU) using the CPS guidelines. METHODS: A simulation dataset of true glucose values (N = 100 000) was derived by finite mixture model analysis of NICU glucose data (N = 23 749). Bias and imprecision were added to create measured glucose values. The percentages of measured glucose values that were misclassified at CPS action thresholds were determined by Monte Carlo simulation. RESULTS: Measurement biases ranging from -20 to +20 mg/dL combined with coefficients of variation 0% to 20% were evaluated to predict misclassification rates at 32, 36, and 47 mg/dL. The models demonstrated low risk of false normoglycemia-at 5% CV and +10 mg/dL bias: 0.8% to 5% misclassification at the 32 and 47 mg/dL thresholds due to bias. The models demonstrated risk of false hypoglycemia-at 5% CV and -10 mg/dL bias: 3% to 12.5% misclassification at 32 and 47 mg/dL thresholds due to both bias and imprecision. CONCLUSION: Using CPS action thresholds, the simulation model predicted the proportion of neonates at risk of inappropriate clinical action-both of omission or "failure to treat" and commission or "overtreatment" in response to NICU glucose meter results at specific bias and imprecision values.

Transcutaneous bilirubin nomogram for the first 144 hours in Thai neonates.

Objectives: To develop an hour-specific transcutaneous bilirubin (TcB) nomogram for Thai neonates and to compare the ability of this nomogram with that of Bhutani's total serum bilirubin (TSB) nomogram for prediction of significant hyperbilirubinemia requiring phototherapy.Methods: Healthy Thai neonates, gestational age ≥35-week-gestation and birth weight ≥2000 grams were enrolled. Neonates who could not attend the postdischarge follow-up at our center were excluded. TcB measurements were routinely performed at 6 am and 6 pm using JM103 transcutaneous bilirubinometer until the neonates were discharged or received phototherapy. TcB levels were also measured at least once during 24-72 hours after discharge and thereafter depending on the pediatricians' decision. The nomogram was developed from the TcB data during age 12-144 hours of neonates who did not require phototherapy. The TcB values that obtained predischarge or before receiving phototherapy of all neonates were used to determine the predictive ability of this nomogram and Bhutani's TSB nomogram.Results: A total of 1071 neonates were included. Two hundred forty-one neonates (22.5%) required phototherapy. The nomogram was constructed using 4834 hour-specific TcB values. It provided a good prediction with the area under curve (AUC) of 0.89. The 75th percentile tract revealed sensitivity and negative predictive value (NPV) of 87.1 and 95.4% while that of the 40th percentile tract were 97.9 and 98.5% respectively. When Bhutani's nomogram was used, the AUC was 0.84. The sensitivity and NPV of the 75th percentile tract were 56.4 and 88.2%, and for the 40th percentile tract were 97.1 and 98.0% respectively.Conclusion: The newly developed TcB nomogram revealed slightly better predictive ability than Bhutani's TSB nomogram for term and late preterm Thai neonates who were the population with high prevalence of significant hyperbilirubinemia. The 40th percentile curve of both nomograms should be considered as an appropriate cut-off level for prediction.

Accuracy of the Bilicare™ transcutaneous bilirubinometer as the predischarge screening tool for significant hyperbilirubinemia in healthy term and late preterm neonates.

Background: The Bilicare™ is a new device that measures transcutaneous bilirubin (TcB) level at the ear pinna. There are only few studies which have evaluated its accuracy in clinical practice.Objective: This study aims to determine the accuracy of Bilicare™ as a predischarge screening tool in late preterm and term neonates and to define the optimal cutoff point for determining the need to measure total serum bilirubin (TSB).Methods: The 35 weeks' gestation or more and healthy neonates who underwent predischarge TSB measurement were enrolled. Bilicare™ TcB was measured within 30 minutes of blood sampling. Paired TcB and TSB data were analyzed.Results: We collected 214 paired samples. Mean age (SD) at TcB measurement was 57.17 (7.47) hours. Mean TSB (SD) was 9.79 (2.83) mg/dL. TcB showed a significant correlation with TSB (r = 0.84, r2 = 0.7). The mean difference (SD) between TcB and TSB was 0.7 (0.21) mg/dL (95%CI 0.49-0.91). TcB tended to overestimate TSB level at the TSB values of <12 mg/dL but underestimate at the higher TSB level. The accuracy of using TcB values to detect neonates who required phototherapy was 92.5%. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 78.3, 94.2, 62.1, and 97.3%, respectively. If TcB +3 mg/dL was applied as a cutoff point, the sensitivity, specificity, PPV, and NPV were 100, 53.9, 20.7, and 100%, respectively.Conclusions: Bilicare™ TcB and TSB measurements were well correlated. The TcB level +3 mg/dL could detect all neonates who had significant hyperbilirubinemia requiring phototherapy during their birth hospitalization.

Informed Decision Making Regarding Prenatal Aneuploidy Screening.

OBJECTIVE: To explore informed decision making for prenatal aneuploidy screening (PAS) by investigating the relationships among women's understanding of PAS, their health literacy, and their satisfaction with their decisions regarding PAS. DESIGN: A descriptive, cross-sectional, correlational study. SETTING: Southeastern United States. PARTICIPANTS: Ninety-five adult women who were at least 18 weeks pregnant; most were White non-Hispanic (n = 75, 78.9%) and college educated (n = 56, 59.0%). METHODS: Potential participants were invited to complete an online survey that was distributed via e-mail to recipients of an electronic pregnancy and parenting newsletter. The survey included questions about women's understanding of PAS, their health literacy, and their satisfaction with their decisions regarding PAS based on three validated instruments. I used descriptive statistics, bivariate correlational analysis, and multiple linear regression to analyze the data. RESULTS: Higher level of education (ß =.225, p = .038) and higher scores from the Health Literacy Questionnaire's scale Ability to Actively Engage With Health Care Providers (ß =.317, p = .004) were significantly associated with increased understanding of PAS. Higher scores on two scales from the Health Literacy Questionnaire, Feeling Understood andSupportedby Health Care Providers (ß =.329 , p = .004) and Ability to Find Good Health Information (ß = .402, p = .013), were significantly associated with greater satisfaction with decisions regarding prenatal aneuploidy screening. Forty-two percent (n = 40) of participants did not report satisfaction with PAS. CONCLUSION: A woman's health literacy and her ability to actively engage with health care providers are critical for informed decision making about PAS. Findings highlight the need for woman-centered strategies to promote open and intentional communication about PAS.

Health professionals' views of newborn pulse oximetry screening in a midwifery-led maternity setting. "It's a good thing to do, but fund it!"

OBJECTIVE: To understand from health professionals who care for newborns their views on the introduction of pulse oximetry screening for the detection of hypoxaemia in a midwifery-led maternity setting. Although oximetry screening for newborns is internationally accepted, national screening is not yet introduced in New Zealand. In this context, we drew on maternity carers' reflections during a feasibility study of oximetry screening to provide perspectives on barriers and enablers to universal screening. METHODS: Data were generated from nine focus groups during five months of 2018 in two north island regions of New Zealand. Participants' (n = 45) opinions about the use of oximetry screening in newborns were analysed thematically using an inductive approach. FINDINGS: Overall, participants stated pulse oximetry screening was easy to do, non-invasive, and worthwhile. Midwives were reassured by screening that provided evidence of either a healthy baby or a need for urgent review. From participants' reports, we identified three themes: (1) oximetry screening for newborns is reassuring, practical and worthwhile; (2) midwifery services workload expectations and under-resourcing will hinder universal screening, and (3) location of the baby at the time of screening could impede universal access. CONCLUSION AND IMPLICATIONS FOR PRACTICE: Midwives viewed implementing a national pulse oximetry screening programme as sensible but problematic unless resourced and funded appropriately. Policymakers should view the concerns of midwives about human and physical resources as significant and account for the need to resource this screening programme appropriately as a priority before implementation.

Quantification of Underivatized Amino Acids on Dry Blood Spot, Plasma, and Urine by HPLC-ESI-MS/MS.

Enzyme deficiencies in amino acid metabolism may increase the levels of a single or several compounds in physiological fluids becoming diagnostically significant biomarkers for one or a group of metabolic disorders. Therefore, it is important to monitor a wide range of free amino acids simultaneously and to quantify them. This is time consuming if we use the classical methods and, especially now that many laboratories have introduced Newborn Screening Programs for the semiquantitative analysis, the detection and quantification of some amino acids need to be performed in a short time to reduce the rate of false positives.We have modified the stable isotope dilution HPLC-ESI-MS/MS method previously described by Qu (Qu et al., 2002) for a more rapid, robust, sensitive, and specific detection and quantification of underivatized amino acids. The modified method reduces the time of analysis to 10 min with very good reproducibility of retention times and a better separation of the metabolites and their isomers.The omission of the derivatization step, enabled to achieve some important advantages: fast and simple sample preparation, exclusion of artifacts, and interferences. The use of this technique is highly sensitive and specific and allowed to monitor 40 underivatized amino acids including the key isomers and quantification of some of them, in order to cover many diagnostically important intermediates of metabolic pathways.We propose this HPLC-ESI-MS/MS method for underivatized amino acids as a support for the newborn screening as secondary test using the same dried blood spots for a more accurate and specific examination in case of suspected metabolic diseases. In this way we avoid plasma collection from the patient as it normally occurs, reducing anxiety for the parents and further costs for analysis.The same method was validated and applied also to plasma and urine samples with good reproducibility, accuracy, and precision. The fast run time, the feasibility of high sample throughput, and the small amount of sample required make this method very suitable for routine analysis in the clinical setting.

A rapid smartphone-based lactate dehydrogenase test for neonatal diagnostics at the point of care.

There is a growing recognition of the importance of point-of-care tests (POCTs) for detecting critical neonatal illnesses to reduce the mortality rate in newborns, especially in low-income countries, which account for 98 percent of reported neonatal deaths. Lactate dehydrogenase (LDH) is a marker of cellular damage as a result of hypoxia-ischemia in affected organs. Here, we describe and test a POC LDH test direct from whole blood to provide early indication of serious illness in the neonate. The sample-in-result-out POC platform is specifically designed to meet the needs at resource-limited settings. Plasma is separated from whole blood on filter paper with dried-down reagents for colorimetric reaction, combined with software for analysis using a smartphone. The method was clinically tested in newborns in two different settings. In a clinical cohort of newborns of Stockholm (n = 62) and Hanoi (n = 26), the value of R using Pearson's correlation test was 0.91 (p < 0.01) and the R2 = 0.83 between the two methods. The mean LDH (±SD) for the reference method vs. the POC-LDH was 551 (±280) U/L and 552 (±249) U/L respectively, indicating the clinical value of LDH values measured in minutes with the POC was comparable with standardized laboratory analyses.

How skin anatomy influences transcutaneous bilirubin determinations: an in vitro evaluation.

BACKGROUND: Transcutaneous bilirubinometry is an effective screening method for neonatal hyperbilirubinemia. Current transcutaneous bilirubin (TcB) meters are designed for the "standard" situation of TcB determinations on the forehead or sternum of term newborns. We hypothesize that skin anatomy can considerably influence TcB determinations in non-standard situations-e.g., on preterm newborns or alternative body locations. METHODS: A commercially available TcB meter (JM-105) was evaluated in vitro on phantoms that accurately mimic neonatal skin. We varied the mimicked cutaneous hemoglobin content (0-2.5 g/L), bone depth (0.26-5.26 mm), and skin maturity-related light scattering (1.36-2.27 mm-1) within the clinical range and investigated their influence on the TcB determination. To obtain a reference frame for bone depth at the forehead, magnetic resonance head scans of 46 newborns were evaluated. RESULTS: The TcB meter adequately corrected for mimicked hemoglobin content. However, TcB determinations were influenced considerably by clinically realistic variations in mimicked bone depth and light scattering (deviations up to 72 µmol/L). This greatly exceeds the specified accuracy of the device (±25.5 µmol/L). CONCLUSION: As bone depth and light scattering vary with gestational maturity and body location, caretakers should be cautious when interpreting TcB measurements on premature newborns and non-standard body locations.

A Novel Icterometer for Hyperbilirubinemia Screening in Low-Resource Settings.

BACKGROUND: Severe neonatal hyperbilirubinemia (>20 mg/dL) affects ∼1 million infants annually. Improved jaundice screening in low-income countries is needed to prevent bilirubin encephalopathy and mortality. METHODS: The Bili-ruler is an icterometer for the assessment of neonatal jaundice that was designed by using advanced digital color processing. A total of 790 newborns were enrolled in a validation study at Brigham and Women's Hospital (Boston) and Sylhet Osmani Medical College Hospital (Sylhet, Bangladesh). Independent Bili-ruler measurements were made and compared with reference standard transcutaneous bilirubin (TcB) and total serum bilirubin (TSB) concentrations. RESULTS: Bili-ruler scores on the nose were correlated with TcB and TSB levels (r = 0.76 and 0.78, respectively). The Bili-ruler distinguished different clinical thresholds of hyperbilirubinemia, defined by TcB, with high sensitivity and specificity (score ≥3.5: 90.1% [95% confidence interval (CI): 84.8%-95.4%] and 85.9% [95% CI: 83.2%-88.6%], respectively, for TcB ≥13 mg/dL). The Bili-ruler also performed reasonably well compared to TSB (score ≥3.5: sensitivity 84.5% [95% CI: 79.1%-90.3%] and specificity 83.2% [95% CI: 76.1%-90.3%] for TSB ≥11 mg/dL). Areas under the receiver operating characteristic curve for identifying TcB ≥11, ≥13, and ≥15 were 0.92, 0.93, and 0.94, respectively, and 0.90, 0.87, and 0.86 for identifying TSB ≥11, ≥13, and ≥15. Interrater reliability was high; 97% of scores by independent readers fell within 1 score of one another (N = 88). CONCLUSIONS: The Bili-ruler is a low-cost, noninvasive tool with high diagnostic accuracy for neonatal jaundice screening. This device may be used to improve referrals from community or peripheral health centers to higher-level facilities with capacity for bilirubin testing and/or phototherapy.

Association between ankyloglossia and breastfeeding.

PURPOSE: To analyze the association between ankyloglossia and breastfeeding. METHODS: A cross-sectional study was undertaken on 130 newborn infants in exclusive breastfeeding with Apgar score ≥ 8 within the first five days of life. The research was approved by the Ethics Committee on Human Research. The data collection was performed by the researcher and by three trained speech therapists of the team. The protocols applied were the Neonatal Tongue Screening Test from the Lingual Frenulum Protocol for Infants, the UNICEF Breastfeeding Observation Aid, and the collection of maternal complaints related to the difficulty in breastfeeding was also considered. The data were submitted to statistical analysis - chi-square test and Fisher's exact test, with a significance level of 5%. RESULTS: When correlating the data, the statistical analysis revealed an association between ankyloglossia and the items of suckling category of the Breastfeeding Observation Aid. The association between complaint of difficulty in breastfeeding and ankyloglossia was also seen. CONCLUSION: On the first days of life, ankyloglossia is associated with the mother's breastfeeding complaint and with the newborn's sucking difficulty.