Bruna de Siqueira Barros

Universidade do Estado do Rio de Janeiro

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Thiago Luiz Nogueira da Silva

Universidade Federal do Rio de Janeiro

Kátia Vergetti Bloch

Universidade Federal do Rio de Janeiro

Maria Cristina Maria Caetano Kuschnir

Universidade do Estado do Rio de Janeiro

Mario Mastrangelo

Policlinico Umberto I

Roser Colomé

Hospital Sant Joan de Déu Barcelona

Daniela Karall

Universität Innsbruck

Aída Ormazábal

Sant Joan de Déu Research Foundation

Roberta Romano

University of Naples Federico II

Marta Pérez‐Ordóñez

Hospital Sant Joan de Déu Barcelona

Itziar Alonso-Colmenero

Hospital Sant Joan de Déu Barcelona

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Hospital Sant Joan de Déu Barcelona

Centre for Biomedical Network Research on Rare Diseases

Universitat de Barcelona

Institut de Recerca Sant Joan de Déu

Instituto de Salud Carlos III

Sant Joan de Déu Research Foundation

Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

Hospital Infantil Universitario Niño Jesús

Inserm

Universidade do Estado do Rio de Janeiro

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L-serine treatment in patients with GRIN-related encephalopathy: a phase 2A, non-randomized study

Brain (2024)

Natalia Juliá‐Palacios Mireia Olivella Mariya Sigatullina Bondarenko Salvador Ibáñez‐Micó Beatriz Muñoz Cabello

Abstract GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2–18 years with GRIN loss-of-function pathogenic variants received L-serine for 52 weeks. Primary end points included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life Inventory, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3 months and 1 day before starting treatment and 1, 3, 6 and 12 months after beginning the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8 years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy. Based on the Vineland Adaptive Behavior Composite standard scores, nine children were classified as mildly impaired (cut-off score > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in the Daily Living Skills domain (P = 0035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity. L-serine normalized the EEG pattern in five children and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve adaptive behaviour, motor function and quality of life, with a better response to the treatment in mild phenotypes.

10.1093/brain/awae041

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ERICA: age at menarche and its association with nutritional status

Jornal de Pediatria (Versão em Português) (2019)

Bruna de Siqueira Barros Maria Cristina Maria Caetano Kuschnir Kátia Vergetti Bloch Thiago Luiz Nogueira da Silva

To estimate the mean age at menarche and its association with nutritional status in Brazilian adolescents. The study sample included female adolescents aged 12–17 who participated in a multicenter, school‐based, country‐wide, cross‐sectional study entitled The Study of Cardiovascular Risk in Adolescents (Estudo de Riscos Cardiovasculares em Adolescentes [ERICA]). Mean and median ages at menarche in Brazil were estimated. The association of age at menarche with sociodemographic data and nutritional status were described as means and their respective 95% confidence intervals. Survival analysis was used to assess the age at menarche according to nutritional status categories and the log‐rank test was used to compare the medians. Bivariate and multivariate analyses were performed using Cox regression to verify the association between menarche and other variables. A total of 73,624 students were evaluated, comprising 40,803 girls, of whom 37,390 reported menarche at a mean age of 11.71 years and a median of 12.41 years. Median age at menarche was lower in overweight and obese girls (p < 0.001). The multivariate analysis showed that excess weight (HR = 1.28; 95% CI 1.21–1.36; p < 0.001) and studying in a private school (HR = 1.06; 95% CI 1.02–1.10; p = 0.003) were associated with menarche. This is a pioneering study in Brazil with national and regional representativeness to estimate the mean and the median age of occurrence of menarche. Adolescents with excess weight had an earlier menarche than their peers, even after adjustment for confounding factors. Estimar a média de idade de ocorrência da menarca e sua associação com o estado nutricional em adolescentes brasileiras. Foram avaliados dados de meninas com 12 a 17 anos a partir de um estudo seccional de base escolar, com representatividade nacional e macrorregional, o ERICA (Estudo de Riscos Cardiovasculares em Adolescentes). Foram estimadas média e mediana de idade de ocorrência da menarca no Brasil, pelo método recordatório. A associação da idade da menarca com dados sociodemográficos e estado nutricional foi descrita como médias e seus respectivos IC95%. Análise de sobrevida foi utilizada para explorar a idade da menarca segundo categorias de estado nutricional e teste logrank foi utilizado para comparação das medianas. Análises bivariada e multivariada foram realizadas por meio da regressão de Cox para verificar a associação entre menarca e demais variáveis. Foram avaliados 73.624 estudantes, 40.803 meninas, das quais 37.390 referiram ter apresentado menarca, sendo a média da idade de ocorrência de 11,71 anos e a mediana de 12,41 anos. As medianas da idade de ocorrência da menarca foram menores naquelas com sobrepeso e obesidade (p < 0,001). A análise multivariada evidenciou que excesso de peso (HR = 1,28, IC95% 1,21‐1,36, p < 0,001) e estudar em escola privada (HR = 1,06, IC95% 1,02‐1,10, p = 0,003) estão associados à menarca. Este foi o primeiro estudo brasileiro com representatividade nacional a estimar a média de idade de ocorrência da menarca. As adolescentes com excesso de peso apresentaram menarca em idade inferior às demais, mesmo após ajuste. Full English text available from: www.revespcardiol.org/en

Menarche

10.1016/j.jpedp.2018.01.010

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ERICA: age at menarche and its association with nutritional status

Jornal de Pediatria (2018)

Bruna de Siqueira Barros Maria Cristina Maria Caetano Kuschnir Kátia Vergetti Bloch Thiago Luiz Nogueira da Silva

To estimate the mean age at menarche and its association with nutritional status in Brazilian adolescents. The study sample included female adolescents aged 12–17 who participated in a multicenter, school-based, country-wide, cross-sectional study entitled The Study of Cardiovascular Risk in Adolescents (Estudo de Riscos Cardiovasculares em Adolescentes [ERICA]). Mean and median ages at menarche in Brazil were estimated. The association of age at menarche with sociodemographic data and nutritional status were described as means and their respective 95% confidence intervals. Survival analysis was used to assess the age at menarche according to nutritional status categories and the log-rank test was used to compare the medians. Bivariate and multivariate analyses were performed using Cox regression to verify the association between menarche and other variables. A total of 73,624 students were evaluated, comprising 40,803 girls, of whom 37,390 reported menarche at a mean age of 11.71 years and a median of 12.41 years. Median age at menarche was lower in overweight and obese girls (p < 0.001). The multivariate analysis showed that excess weight (HR = 1.28; 95% CI 1.21–1.36; p < 0.001) and studying in a private school (HR = 1.06; 95% CI 1.02–1.10; p = 0.003) were associated with menarche. This is a pioneering study in Brazil with national and regional representativeness to estimate the mean and the median age of occurrence of menarche. Adolescents with excess weight had an earlier menarche than their peers, even after adjustment for confounding factors. Estimar a média de idade de ocorrência da menarca e sua associação com o estado nutricional em adolescentes brasileiras. Foram avaliados dados de meninas com 12 a 17 anos a partir de um estudo seccional de base escolar, com representatividade nacional e macrorregional, o ERICA (Estudo de Riscos Cardiovasculares em Adolescentes). Foram estimadas média e mediana de idade de ocorrência da menarca no Brasil, pelo método recordatório. A associação da idade da menarca com dados sociodemográficos e estado nutricional foi descrita como médias e seus respectivos IC95%. Análise de sobrevida foi utilizada para explorar a idade da menarca segundo categorias de estado nutricional e teste logrank foi utilizado para comparação das medianas. Análises bivariada e multivariada foram realizadas por meio da regressão de Cox para verificar a associação entre menarca e demais variáveis. Foram avaliados 73.624 estudantes, 40.803 meninas, das quais 37.390 referiram ter apresentado menarca, sendo a média da idade de ocorrência de 11,71 anos e a mediana de 12,41 anos. As medianas da idade de ocorrência da menarca foram menores naquelas com sobrepeso e obesidade (p < 0,001). A análise multivariada evidenciou que excesso de peso HR = 1,28,IC95% 1,21 -1,36, p < 0,001 e estudar em escola privada HR = 1,06, IC95% 1,02 -1,10, p = 0,003 estão associados à menarca. Este foi o primeiro estudo brasileiro com representatividade nacional a estimar a média de idade de ocorrência da menarca. As adolescentes com excesso de peso apresentaram menarca em idade inferior às demais, mesmo após ajuste.

Menarche

Association (psychology)

10.1016/j.jped.2017.12.004

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Citations (61)

ERICA: cardiovascular risks associated with oral contraceptive use among Brazilian adolescents

Jornal de Pediatria (2021)

Bruna de Siqueira Barros Maria Cristina Caetano Kuschnir Fábio Chigres Kuschnir Érica Azevedo de Oliveira Costa Jordão

To investigate the association between oral contraceptive use and cardiovascular risks, including metabolic syndrome and their components in Brazilian adolescents.This study used data from the Study of Cardiovascular Risks in Adolescents (Estudo de Riscos Cardiovasculares em Adolescentes - ERICA), a nationwide, cross-sectional, school-based study with individuals aged 12-17 years. Sociodemographic variables and OC use were assessed by a self-administered questionnaire. International Diabetes Federation criteria were used to define metabolic syndrome. Descriptive statistics were reported as prevalence and their respective confidence interval of 95% of oral contraceptives according to variables. Logistic regression was performed. Crude and adjusted odds ratios were calculated.This subsample was composed of 22,682 female adolescents, of which 12.65% reported using oral contraceptives and their use was associated with hypertension and hypertriglyceridemia. These associations remained statistically significant after adjusting for age, school region, race, and tobacco use with an increase of 2.68 (1.66 - 4.32) and 3.45 (2.56 - 4.65) times, respectively.The present study was the first to examine the association between the use of oral contraceptives and cardiovascular risk factors among the largest number of female Brazilian adolescents. This method was significantly associated with hypertension, hypertriglyceridemia. Teenagers using oral contraceptives should be monitored for side effects, including blood pressure measurements and advised to avoid smoking.

Cross-sectional study

10.1016/j.jped.2021.03.006

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Citations (20)