2023 UPDATE: Luso-Brazilian evidence-based guideline for the management of antidiabetic therapy in type 2 diabetes.

BACKGROUND: The management of antidiabetic therapy in people with type 2 diabetes (T2D) has evolved beyond glycemic control. In this context, Brazil and Portugal defined a joint panel of four leading diabetes societies to update the guideline published in 2020. METHODS: The panelists searched MEDLINE (via PubMed) for the best evidence from clinical studies on treating T2D and its cardiorenal complications. The panel searched for evidence on antidiabetic therapy in people with T2D without cardiorenal disease and in patients with T2D and atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or diabetic kidney disease (DKD). The degree of recommendation and the level of evidence were determined using predefined criteria. RESULTS AND CONCLUSIONS: All people with T2D need to have their cardiovascular (CV) risk status stratified and HbA1c, BMI, and eGFR assessed before defining therapy. An HbA1c target of less than 7% is adequate for most adults, and a more flexible target (up to 8%) should be considered in frail older people. Non-pharmacological approaches are recommended during all phases of treatment. In treatment naïve T2D individuals without cardiorenal complications, metformin is the agent of choice when HbA1c is 7.5% or below. When HbA1c is above 7.5% to 9%, starting with dual therapy is recommended, and triple therapy may be considered. When HbA1c is above 9%, starting with dual therapyt is recommended, and triple therapy should be considered. Antidiabetic drugs with proven CV benefit (AD1) are recommended to reduce CV events if the patient is at high or very high CV risk, and antidiabetic agents with proven efficacy in weight reduction should be considered when obesity is present. If HbA1c remains above target, intensification is recommended with triple, quadruple therapy, or even insulin-based therapy. In people with T2D and established ASCVD, AD1 agents (SGLT2 inhibitors or GLP-1 RA with proven CV benefit) are initially recommended to reduce CV outcomes, and metformin or a second AD1 may be necessary to improve glycemic control if HbA1c is above the target. In T2D with HF, SGLT2 inhibitors are recommended to reduce HF hospitalizations and mortality and to improve HbA1c. In patients with DKD, SGLT2 inhibitors in combination with metformin are recommended when eGFR is above 30 mL/min/1.73 m2. SGLT2 inhibitors can be continued until end-stage kidney disease.

In deep bioinformatic characterization of a novel fumarate hydratase variant FH c.199T > G; (p.Tyr67Asp) in hereditary leiomyomatosis and renal cell carcinoma.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare, autosomal dominant tumor predisposition syndrome characterized by variable development of multiple skin and uterus leiomyomas and aggressive forms of renal cell carcinoma (RCC). Mutations in fumarate hydratase (FH), one of the proteins in homologous recombination repair, precede the development of HLRCC with high penetrance. Considering the risk of early metastasis of RCC, FH has been included in mutation screening panels. The identification of a pathogenic FH variant guides the screening for tumors in the carriers. However, variants of uncertain significance (VUS) are frequent findings, limiting the clinical value of the mutation screening. Here, we describe the associated phenotype and an in-depth, multi-step Bioinformatic evaluation of the germline FH c.199T > G (p.Tyr67 > Asp) variant segregated in an HLRCC family. Evidence for FH c.199T > G; (p.Tyr67Asp) pathogenicity includes the variant segregation with the disease in three affected family members, its absence in populational databases, and the deep evolutionary conservation of the Tyr67 residue. At the protein level, this residue substitution causes the loss of molecular bonds and ionic interactions, affecting molecular dynamics and protein stability. Considering ACMG/AMP criteria, we propose the reclassification of the FH c.199T > G; (p.Tyr67Asp) variant to "likely pathogenic". In addition, the in-depth, in silico approach used here allowed us to understand how and why FH c.199T > G; (p.Tyr67Asp) could cause HLRCC. This could help in clinical management decisions concerning the monitoring of unaffected family members having this variant.

Phenotypic variation in milk fatty acid composition and its association with stearoyl-CoA desaturase 1 (SCD1) gene polymorphisms in Gir cows.

Individual variation in milk fatty acid (FA) composition has been partially attributed to stearoyl-CoA desaturase 1 (SCD1) gene polymorphisms in taurine breeds, but much less is known for Zebu breeds. This study investigated the phenotypic variation in milk FA composition, and the influence of SCD1 variants on this trait and on milk fat desaturase indices (DI) in Gir cows. The functional impact of SCD1 variants was predicted using bioinformatics tools. Milk and blood samples were collected from 312 cows distributed in 10 herds from five states of Brazil. SCD1 variants were identified through target sequencing, and milk FA composition was determined by gas chromatography. Phenotypic variation in milk FA composition fell within the range reported for taurine breeds, with SCD18 index showing the lowest variation among the DI. Fourteen SCD1 variants were identified, six of which not previously described. Regarding the A293V polymorphism, all cows were homozygous for the C allele (coding for alanine), whereas all genotypes were detected for the second SNP affecting the 293 codon (G > A), with compelling evidence for functional effects. Significant associations (based on raw p-values) were found between this SNP and C12:0, cis-9, trans-11 CLA and short-chain FA, and between another SNP (rs523411937) and C15:0 and odd-chain linear FA. A new SNP on Chr26:21277069 was associated with trans-11 C18:1, cis-9, trans-11 CLA, C18:3 n-3 and n-3 FA. These findings indicate that SCD1 polymorphisms also contributes to the phenotypic variation in milk FA composition of Gir cows, with potential use in their breeding programmes.

Working memory and arithmetic impairments in children with FMR1 premutation and gray zone alleles.

Expansive mutations in familial mental retardation 1 (FMR1) gene have been associated with different phenotypes. Full mutations are associated with intellectual disability and autism spectrum disorder; premutations are associated with math learning difficulties and working memory impairments. In gray zone, neuropsychological development has not yet been described. Objectives: This study aimed to describe the frequency of FMR1 premutation and gray zone alleles in a school population sample representing a broad spectrum of variation in math achievement and detail school achievement and cognitive performance in the children identified with FMR1 premutation or gray zone alleles. Methods: We described a two-phase study. In the first phase, 2,195 school-age children were screened for math achievement. In the second phase, 378 children with normal intelligence were neuropsychologically assessed and genotyped for FMR1. Of these, 121 children (61 girls) performed below percentile 25 in mathematics (MD group) and 257 children (146 girls) performed above percentile 25 (control group). Results: Four pupils presented expanded alleles, one premutation and three gray zone alleles. The girl with the premutation and one boy with a gray zone allele presented impairments in working memory and arithmetic performance below percentile 6, compatible with the diagnosis of developmental dyscalculia. These children's difficulties were not associated with inaccuracy of nonsymbolic number representations or literacy impairments. Dyscalculia in these children seems to be associated mainly with working memory impairments. Conclusions: FMR1 expansions in the gray zone may contribute to dyscalculia in otherwise healthy and normally intelligent children.

Mutações expansivas no gene FMR1 têm sido associadas a diferentes fenótipos. Mutações completas estão associadas a deficiência intelectual e transtorno do espectro do autismo; pré-mutações, com dificuldades de aprendizagem de matemática e comprometimentos de memória de trabalho. Na zona cinzenta o desenvolvimento neuropsicológico ainda não foi descrito. Objetivos: Descrever a frequência de alelos pré-mutados e zona cinzenta em uma amostra escolar que representa amplo espectro de variação do desempenho em Matemática e detalhar o desempenho escolar e cognitivo em crianças identificadas com alelos pré-mutados ou zona cinzenta. Métodos: Aqui, descrevemos um estudo de duas fases. Na primeira fase, 2.195 crianças em idade escolar foram selecionadas para desempenho em Matemática. Na segunda fase, 378 crianças com inteligência normal foram avaliadas neuropsicologicamente e, em seguida, por genotipagem FMR1. Resultados: Tiveram desempenho abaixo do percentil 25 em Matemática (grupo DM) 121 crianças (61 meninas), e tiveram desempenho acima do percentil 25 (grupo controle) 257 crianças (146 meninas). Quatro alunos apresentaram alelos expandidos, sendo uma pré-mutação e três alelos da zona cinza. A menina com a pré-mutação e um menino com o alelo da zona cinza apresentaram prejuízos na memória de trabalho e desempenho aritmético abaixo do percentil 6, compatíveis com o diagnóstico de discalculia do desenvolvimento. As dificuldades dessas crianças não foram associadas à imprecisão de representações não simbólicas de números ou deficiências de alfabetização. A discalculia nessas crianças parece estar associada principalmente a deficiências da memória de trabalho. Conclusões: Em conclusão, expansões na zona cinzenta do FMR1 podem contribuir para a discalculia em crianças saudáveis com inteligência normal.

Do boys with MAOA_LPR*2R allele present cognitive and learning impairments?

Monoamine oxidase A (MAOA) polymorphisms have been associated with antisocial disorders. Less attention has been paid to the cognitive functioning of individuals with different MAOA alleles. No study has described the cognitive phenotype associated with the less frequent, low enzyme activity allele, MAOA_LPR*2R. Objective: We describe the cognitive correlates of boys having MAOA_LPR*2R allele, ascertained in a sample of school children with normal intelligence, not referred for behavioral disorders. Methods: Participants were eight boys, attending from the second to fifth grades in state-run schools. They were identified among 712 children with typical general cognitive ability, genotyped for MAOA_LPR polymorphism. Participants were assessed with general intelligence, mathematics and spelling achievement, and verbal and visuospatial working memory tests. Neuropsychological performance was compared to published standards, using 1 SD below the mean as a cutoff value for low performance. Results: Intelligence of boys with MAOA_LPR*2R allele varied from above average (N=2) to low average in the other children. Five out of eight boys with the MAOA_LPR*2R allele had low mathematics achievement, and three presented additional difficulties with spelling. Four out of eight children had low short-term and working memory performance. Discussion: This is the first study describing cognitive correlates and school performance in boys having the MAOA_LPR*2R allele. Having this allele, and therefore, probably low MAO-A activity, does not necessarily imply low intelligence or low school performance. However, learning difficulties, particularly in math, and low working memory performance were observed in boys having this allele. This suggests a role of MAOA in learning difficulties.

Polimorfismos da monoaminoxidase A (MAOA) são associados a transtornos antissociais. Menos atenção tem sido dada ao funcionamento cognitivo de indivíduos com diferentes alelos de MAOA. Nenhum estudo descreveu o fenótipo cognitivo associado ao alelo menos frequente, de baixa atividade enzimática, MAOA_LPR*2R. Objetivo: Descrevemos os correlatos cognitivos de meninos com o alelo MAOA_LPR*2R, identificados em uma amostra de escolares com inteligência normal, não encaminhados por transtornos de comportamento. Métodos: Oito meninos com o alelo MAOA_LPR*2R foram identificados entre 712 crianças genotipadas, com inteligência típica, que cursavam do 2º ao 5º ano em escolas públicas. Foram avaliados: inteligência, desempenho em matemática e ortografia, memória de trabalho verbal e visuoespacial. O desempenho foi comparado a normas publicadas, utilizando-se 1 desvio padrão (DP) abaixo da média como ponto de corte para desempenho rebaixado. Resultados: A inteligência dos meninos com alelo MAOA_LPR*2R variou de acima da média (N=2) a médio-inferior nas demais crianças. Cinco dos oito meninos com alelo MAOA_LPR*2R apresentaram desempenho rebaixado em matemática e três apresentaram dificuldades adicionais em ortografia. Quatro dos oito meninos apresentaram baixo desempenho de memória de curto prazo e de trabalho. Discussão: Este é o primeiro estudo a descrever os correlatos cognitivos e o desempenho escolar em meninos com alelo MAOA_LPR*2R. Ter esse alelo não significa necessariamente baixa inteligência ou baixo desempenho escolar. No entanto, dificuldades de aprendizagem, principalmente em matemática, e desempenho rebaixado da memória de trabalho foram observados em mais da metade dos meninos com esse alelo. Isso sugere um papel do MAOA nas dificuldades de aprendizagem.

MAOA-LPR polymorphism and math anxiety: A marker of genetic susceptibility to social influences in girls?

Math anxiety (MA) seems to result from an interaction of genetic vulnerability with negative experiences learning mathematics. Although mathematics achievement does not substantially differ between the sexes, MA levels are usually higher in girls. Molecular genetic markers of MA vulnerability have been seldom explored. This article examines the contribution of the monoamine oxidase A gene (MAOA) to MA and to sex differences in MA. Five hundred and sixty-eight third to fifth graders were genotyped for the MAOA-LPR polymorphism (a repetitive element in MAOA promoter that has been associated with MAOA enzymatic activity), and assessed on general cognitive ability, mathematics achievement, and the cognitive and affective dimensions of MA. MAOA-LPR genotypes were classified as high (MAOA-H) or low (MAOA-L) according to their predicted enzymatic activity. Mixed models controlling for effects of school, sex, general cognitive ability, and mathematics achievement were evaluated. The best fitting model included school, math achievement, sex, MAOA-LPR, and the MAOA-LPR by sex interaction. This indicated that under the MAOA-H dominant model, anxiety toward mathematics interacted with the MAOA genotype: girls with an MAOA-L genotype exhibited higher levels of MA, with a small but significant effect. The association between MAOA-L genotype and MA in girls may represent an example of developmental plasticity.

Do boys with MAOA_LPR*2R allele present cognitive and learning impairments? / Meninos com o alelo maoa_lpr*2r apresentam prejuízos cognitivos e de aprendizagem?

ABSTRACT. Monoamine oxidase A (MAOA) polymorphisms have been associated with antisocial disorders. Less attention has been paid to the cognitive functioning of individuals with different MAOA alleles. No study has described the cognitive phenotype associated with the less frequent, low enzyme activity allele, MAOA_LPR*2R. Objective: We describe the cognitive correlates of boys having MAOA_LPR*2R allele, ascertained in a sample of school children with normal intelligence, not referred for behavioral disorders. Methods: Participants were eight boys, attending from the second to fifth grades in state-run schools. They were identified among 712 children with typical general cognitive ability, genotyped for MAOA_LPR polymorphism. Participants were assessed with general intelligence, mathematics and spelling achievement, and verbal and visuospatial working memory tests. Neuropsychological performance was compared to published standards, using 1 SD below the mean as a cutoff value for low performance. Results: Intelligence of boys with MAOA_LPR*2R allele varied from above average (N=2) to low average in the other children. Five out of eight boys with the MAOA_LPR*2R allele had low mathematics achievement, and three presented additional difficulties with spelling. Four out of eight children had low short-term and working memory performance. Discussion: This is the first study describing cognitive correlates and school performance in boys having the MAOA_LPR*2R allele. Having this allele, and therefore, probably low MAO-A activity, does not necessarily imply low intelligence or low school performance. However, learning difficulties, particularly in math, and low working memory performance were observed in boys having this allele. This suggests a role of MAOA in learning difficulties.

RESUMO. Polimorfismos da monoaminoxidase A (MAOA) são associados a transtornos antissociais. Menos atenção tem sido dada ao funcionamento cognitivo de indivíduos com diferentes alelos de MAOA. Nenhum estudo descreveu o fenótipo cognitivo associado ao alelo menos frequente, de baixa atividade enzimática, MAOA_LPR*2R. Objetivo: Descrevemos os correlatos cognitivos de meninos com o alelo MAOA_LPR*2R, identificados em uma amostra de escolares com inteligência normal, não encaminhados por transtornos de comportamento. Métodos: Oito meninos com o alelo MAOA_LPR*2R foram identificados entre 712 crianças genotipadas, com inteligência típica, que cursavam do 2º ao 5º ano em escolas públicas. Foram avaliados: inteligência, desempenho em matemática e ortografia, memória de trabalho verbal e visuoespacial. O desempenho foi comparado a normas publicadas, utilizando-se 1 desvio padrão (DP) abaixo da média como ponto de corte para desempenho rebaixado. Resultados: A inteligência dos meninos com alelo MAOA_LPR*2R variou de acima da média (N=2) a médio-inferior nas demais crianças. Cinco dos oito meninos com alelo MAOA_LPR*2R apresentaram desempenho rebaixado em matemática e três apresentaram dificuldades adicionais em ortografia. Quatro dos oito meninos apresentaram baixo desempenho de memória de curto prazo e de trabalho. Discussão: Este é o primeiro estudo a descrever os correlatos cognitivos e o desempenho escolar em meninos com alelo MAOA_LPR*2R. Ter esse alelo não significa necessariamente baixa inteligência ou baixo desempenho escolar. No entanto, dificuldades de aprendizagem, principalmente em matemática, e desempenho rebaixado da memória de trabalho foram observados em mais da metade dos meninos com esse alelo. Isso sugere um papel do MAOA nas dificuldades de aprendizagem.

NAToRA, a relatedness-pruning method to minimize the loss of dataset size in genetic and omics analyses.

Genetic and omics analyses frequently require independent observations, which is not guaranteed in real datasets. When relatedness cannot be accounted for, solutions involve removing related individuals (or observations) and, consequently, a reduction of available data. We developed a network-based relatedness-pruning method that minimizes dataset reduction while removing unwanted relationships in a dataset. It uses node degree centrality metric to identify highly connected nodes (or individuals) and implements heuristics that approximate the minimal reduction of a dataset to allow its application to complex datasets. When compared with two other popular population genetics methodologies (PLINK and KING), NAToRA shows the best combination of removing all relatives while keeping the largest possible number of individuals in all datasets tested and also, with similar effects on the allele frequency spectrum and Principal Component Analysis than PLINK and KING. NAToRA is freely available, both as a standalone tool that can be easily incorporated as part of a pipeline, and as a graphical web tool that allows visualization of the relatedness networks. NAToRA also accepts a variety of relationship metrics as input, which facilitates its use. We also release a genealogies simulator software used for different tests performed in this study.

Identification and in silico characterization of structural and functional impacts of genetic variants in milk protein genes in the Zebu breeds Guzerat and Gyr.

Whole genome sequencing of bovine breeds has allowed identification of genetic variants in milk protein genes. However, functional repercussion of such variants at a molecular level has seldom been investigated. Here, the results of a multistep Bioinformatic analysis for functional characterization of recently identified genetic variants in Brazilian Gyr and Guzerat breeds is described, including predicted effects on the following: (i) evolutionary conserved nucleotide positions/regions; (ii) protein function, stability, and interactions; (iii) splicing, branching, and miRNA binding sites; (iv) promoters and transcription factor binding sites; and (v) collocation with QTL. Seventy-one genetic variants were identified in the caseins (CSN1S1, CSN2, CSN1S2, and CSN3), LALBA, LGB, and LTF genes. Eleven potentially regulatory variants and two missense mutations were identified. LALBA Ile60Val was predicted to affect protein stability and flexibility, by reducing the number the disulfide bonds established. LTF Thr546Asn is predicted to generate steric clashes, which could mildly affect iron coordination. In addition, LALBA Ile60Val and LTF Thr546Asn affect exonic splicing enhancers and silencers. Consequently, both mutations have the potential of affecting immune response at individual level, not only in the mammary gland. Although laborious, this multistep procedure for classifying variants allowed the identification of potentially functional variants for milk protein genes.

The quandary of diagnosing mathematical difficulties in a generally low performing population.

Brazilian students' mathematical achievement was repeatedly observed to fall below average levels of mathematical attainment in international studies such as PISA. OBJECTIVE: In this article, we argue that this general low level of mathematical attainment may interfere with the diagnosis of developmental dyscalculia when a psychometric criterion is used establishing an arbitrary cut-off (e.g., performance

O desempenho em matemática dos estudantes brasileiros mostra-se consistentemente abaixo da média mundial em estudos internacionais como o PISA. OBJETIVO: No presente artigo, argumenta-se que um baixo desempenho geral na matemática, a exemplo dos estudantes brasileiros, pode interferir no diagnóstico de discalculia do desenvolvimento quando um critério puramente psicométrico é usado para estabelecer um ponto de corte arbitrário (por exemplo, desempenho

Genetic Diversity and Population Genetic Structure of a Guzerá (Bos indicus) Meta-Population.

The Brazilian Guzerá population originated from a few founders introduced from India. These animals adapted well to the harsh environments in Brazil, were selected for beef, milk, or dual-purpose (beef and milk), and were extensively used to produce crossbred animals. Here, the impact of these historical events with regard to the population structure and genetic diversity in a Guzerá meta-population was evaluated. DNA samples of 744 animals (one dairy, nine dual-purpose, and five beef herds) were genotyped for 21 microsatellite loci. Ho, He, PIC, Fis, Fit, and Fst estimates were obtained considering either farms or lineages as subpopulations. Mean Ho (0.73) and PIC (0.75) suggest that genetic diversity was efficiently conserved. Fit, Fis and Fst values (95% CI) pointed to a low fixation index, and large genetic diversity: Fit (Farms = 0.021-0.100; lineages = 0.021-0.100), Fis (Farms = -0.007-0.076; lineages = -0.014-0.070), and Fst (Farms = 0.0237-0.032; lineages = 0.029-0.038). The dual-purpose herds/selection lines are the most uniform subpopulation, while the beef one preserved larger amounts of genetic diversity among herds. In addition, the dairy herd showed to be genetically distant from other herds. Taken together, these results suggest that this Guzerá meta-population has high genetic diversity, a low degree of population subdivision, and a low inbreeding level.

The quandary of diagnosing mathematical difficulties in a generally low performing population / O dilema de diagnosticar dificuldades de aprendizagem da matemática em uma população com desempenho geral aquém do esperado

ABSTRACT. Brazilian students' mathematical achievement was repeatedly observed to fall below average levels of mathematical attainment in international studies such as PISA. Objective: In this article, we argue that this general low level of mathematical attainment may interfere with the diagnosis of developmental dyscalculia when a psychometric criterion is used establishing an arbitrary cut-off (e.g., performance<percentile 10) may result in misleading diagnoses. Methods: Therefore, the present study evaluated the performance of 706 Brazilian school children from 3rd to 5th grades on basic arithmetic operations addition, subtraction, and multiplication. Results: In line with PISA results, children presented difficulties in all arithmetic operations investigated. Even after five years of formal schooling, less than half of 5th graders performed perfectly on simple addition, subtraction, or multiplication problems. Conclusions: As such, these data substantiate the argument that the sole use of a psychometric criterion might not be sensible to diagnose dyscalculia in the context of a generally low performing population, such as Brazilian children of our sample. When the majority of children perform poorly on the task at hand, it is hard to distinguish atypical from typical numerical development. As such, other diagnostic approaches, such as Response to Intervention, might be more suitable in such a context.

RESUMO. O desempenho em matemática dos estudantes brasileiros mostra-se consistentemente abaixo da média mundial em estudos internacionais como o PISA. Objetivo: No presente artigo, argumenta-se que um baixo desempenho geral na matemática, a exemplo dos estudantes brasileiros, pode interferir no diagnóstico de discalculia do desenvolvimento quando um critério puramente psicométrico é usado para estabelecer um ponto de corte arbitrário (por exemplo, desempenho<percentil 10), o que pode resultar em falsos diagnósticos. Métodos: Para tanto, investigou-se o desempenho de 706 estudantes brasileiros do 3º ao 5º ano escolar em operações aritméticas básicas de adição, subtração e multiplicação. Resultados: De forma consistente com os resultados do PISA, as crianças apresentaram dificuldades em todas as operações aritméticas investigadas. Mesmo após cinco anos de escolarização formal, menos da metade dos estudantes do 5º ano foi capaz de completar a tarefa envolvendo cálculos simples de adição, subtração ou multiplicação. Conclusões: Dessa forma, os resultados reforçam o argumento de que o uso exclusivo de um critério psicométrico pode não ser apropriado para o diagnóstico de discalculia no contexto de uma população com desempenho geral baixo, como no caso crianças brasileiras da presente amostra. Quando a maioria das crianças tem um desempenho aquém do esperado, torna-se difícil distinguir o desenvolvimento numérico atípico do típico. Portanto, outras abordagens diagnósticas, como Resposta à Intervenção, podem ser mais adequadas em tal contexto.

Mobile web application for use in the Extended Family Health and Primary Care Center: content and usability validation / Aplicativo móvel para utilização do Núcleo Ampliado de Saúde da Família e Atenção Básica: validação de conteúdo e de usabilidade

ABSTRACT Purpose: to validate the content and usability of the "Network NASF" application, intended for the teams of the Extended Family Health and Primary Care Center (NASF-AB). Methods: eighteen specialists, researchers, and professionals from different fields of study participated to validate the content and usability of the application, carried out in four stages: adjustment of the instrument; administration of the Suitability Assessment of Materials (SAM); validation of the content by calculating the content validity index (CVI); and usability evaluation through the System Usability Scale (SUS), in this order. Results: the participants classified the material as valid regarding both its content and usability. The index achieved in the SAM was 83.5%, as four, out of the six topics in the instrument, had values over 0.78. Hence, these four were considered excellent, while the other two were considered good. The recommendations given by the specialized judges were accepted and the usability index (5.5%) was considered relevant. Conclusion: the application developed for NASF-AB professionals was considered valid regarding its content and usability.

RESUMO Objetivo: validar por conteúdo e usabilidade o aplicativo "NASF em Rede" direcionado para as equipes dos Núcleos Ampliados de Saúde da Família e Atenção Básica (NASF-AB). Métodos: estudo metodológico, no qual participaram 18 especialistas, pesquisadores e profissionais, com diferentes áreas de formação, com vistas à validação de conteúdo e de usabilidade do APP. Realizado em quatro etapas: adaptação do instrumento; aplicação do instrumento de Avaliação de Adequação de Materiais (SAM); validação de conteúdo por meio do cálculo do Índice de Validade de Conteúdo (IVC) e avaliação da usabilidade por meio do System Usability Scale (SUS), respectivamente. Resultados: os participantes classificaram o material como válido, tanto no que concerne ao conteúdo quanto à usabilidade. Obteve-se índice de 83,5% para o instrumental SAM, pois 04 dos 06 tópicos constantes no instrumento apresentaram valores de 0,78, os quais foram considerados excelentes e dois deles foram avaliadas como bons, sendo acolhidas as recomendações dos juízes especialistas. O índice de usabilidade (5,5%) também foi considerado relevante. Conclusão: o aplicativo desenvolvido para profissionais do NASF- AB foi considerado válido quanto ao conteúdo e à usabilidade.

O ensino de enfermagem em saúde mental na percepção de estudantes / Mental health nursing teaching based on students' perception

Objetivo: Compreender a experiência de estudantes de Enfermagem no processo de ensino-aprendizagem em saúde mental. Métodos: Estudo qualitativo, realizado com oito estudantes de enfermagem de uma instituição pública. As narrativas foram coletadas através de grupo focal, gravadas e transcritas na íntegra. A análise pautou-se na técnica de análise categorial temática. Resultados: Emergiram duas categorias analíticas: Formação em saúde mental na Graduação em Enfermagem e Experiências dos estudantes no processo de ensino-aprendizagem. Conclusão: A experiência discente apontou: a necessidade de potencializar a formação em saúde mental com a criação de disciplinas que abordassem esta área de conhecimento; desenvolvimento de estratégias de integração do conteúdo deste campo específico com o de outras disciplinas; uso de metodologias ativas e inovadoras; maiores oportunidades de atuação na Rede de Atenção Psicossocial; e desenvolvimento de práticas de cuidado em enfermagem que favoreçam a superação da estigmatização da pessoa em sofrimento psíquico. (AU)

Objective: Analyzing nursing students' experience in the teaching-learning process in mental health. Methods: Study qualitative conducted with eight nursing students from a public institution. Participants' narratives were recorded in a focus group and fully transcribed. Data analysis was based on the theme/category-based content analysis technique. Results: Two analytical categories emerged, namely: Mental Health Training in Undergraduate Nursing and Students experiences in teaching-learning process. Conclusion: Students' experience pointed towards the need of improving mental health training by creating a discipline focused on addressing this knowledge field; developing strategies focused on integrating the content of this specific field with that of other disciplines; using active and innovative methodologies; enabling greater opportunities for students to act in the Psychosocial Care Network; and developing nursing care practices to help individuals in psychological distress to overcome stigmatization. (AU)

Objetivo: Entender la experiencia de los estudiantes de enfermería en el proceso de enseñanza-aprendizaje en salud mental. Métodos: Un estudio cualitativo, realizado con ocho estudiantes de enfermería de una institución pública. Las narrativas fueron recopiladas a través de grupo focal, grabadas y totalmente transcritas. El análisis se basó en la técnica de análisis por categoría y tema. Resultados: Surgieron dos categorías analíticas: Formación en Salud Mental en enfermería del pregrado y Experiencias de los estudiantes en la participación en el proceso de enseñanza-aprendizaje. Conclusión: La experiencia de los estudiantes señaló la necesidad de potenciar la formación en salud mental con la creación de disciplina que aborde esta área del conocimiento; el desarrollo de estrategias de integración del contenido de este campo específico con el de otras disciplinas; el uso de metodologías activas e innovadoras; mayores oportunidades de acción en la Red de Atención Psicosocial; y el desarrollo de prácticas de cuidado en enfermería que favorezcan la superación de la estigmatización de la persona con sufrimientos psicológicos. (AU)

The Mini-Mental Examination for Children (MMC): Evidence of validity for children with learning difficulties.

The Mini-Mental Examination for Children (MMC) is a widely used tool for assessing global cognitive deficits, however,is still unknown whether MMC is sensitive for investigating cognitive profiles associated with learning difficulties (LD). OBJECTIVE: Here we investigate the feasibility of using the MMC for screening school-aged children with learning difficulties in spelling and math. METHODS: The MMC and other neurophysiological tests were administered to a sample of 168 children, aged 7 to 12 years. The sample was subdivided into a Control group and LD group (Math Difficulties, Spelling Difficulties, Math and Spelling Difficulties). Diagnostic accuracy was assessed with ROC analysis. Convergent and divergent validity was assessed using correlation analysis. RESULTS: Performance on the MMC was associated with nonverbal intelligence, age and school achievement. The LD group had significantly lower performance on the MMC than the Control group. Performance on the MMC discriminated LD children with a global accuracy of around 0.80. Associations between the MMC and the other neuropsychological variables were higher for finger gnosis (r=0.40) and generally higher for early elementary school grades. The MMC proved satisfactory for identifying LD children with good accuracy. Nonverbal intelligence, and perceptual/motor abilities play an important role in MMC performance. CONCLUSION: The MMC could be a useful instrument for screening children with LD.

Mini-exame mental para crianças (MMC) é uma ferramenta amplamente utilizada para avaliar déficits cognitivos globais, no entanto, ainda é desconhecido se a MMC é sensível para investigar perfis cognitivos associados a dificuldades de aprendizagem. OBJETIVO: Aqui nós investigamos a viabilidade de usar MMC para triagem de crianças em idade escolar com dificuldades de aprendizagem em ortografia e matemática. MÉTODOS: MMC e outros testes neuropsicológicos foram administrados em uma amostra de 168 crianças de 7 a 12 anos de idade. A amostra foi subdividida em um Grupo Controle e um grupo LD (dificuldade na matemática, na escrita, ou na escrita e na matemática). A acurácia diagnóstica foi analisada através de uma análise de curva ROC. A validade convergente e divergente foi investigada através de análises de correlações. RESULTADOS: A performance no MMC foi associada com a inteligência não verbal, idade e desempenho escolar. O grupo LD apresentou desempenho significativamente inferior ao Grupo Controle no MMC. A performance no MMC pôde identificar crianças LD com uma acurácia global em torno de 0.80. As associações entre MMC e outras variáveis neuropsicológicas foram maiores para gnosias digitais (r=0.40) e em geral, mais altas nas séries iniciais. O MMC se mostrou satisfatório para identificar crianças LD com uma boa acurácia. A inteligência não verbal, habilidades perceptivas/motoras tem um importante papel na performance no MMC. CONCLUSÃO: O MMC pode ser um instrumento útil para o rastreamento de crianças com LD.

The Mini-Mental Examination for Children (MMC): Evidence of validity for children with learning difficulties / Mini-exame do estado mental para crianças (mmc): evidência de validade para crianças com dificuldades de aprendizagem

ABSTRACT The Mini-Mental Examination for Children (MMC) is a widely used tool for assessing global cognitive deficits, however,is still unknown whether MMC is sensitive for investigating cognitive profiles associated with learning difficulties (LD). Objective: Here we investigate the feasibility of using the MMC for screening school-aged children with learning difficulties in spelling and math. Methods: The MMC and other neurophysiological tests were administered to a sample of 168 children, aged 7 to 12 years. The sample was subdivided into a Control group and LD group (Math Difficulties, Spelling Difficulties, Math and Spelling Difficulties). Diagnostic accuracy was assessed with ROC analysis. Convergent and divergent validity was assessed using correlation analysis. Results: Performance on the MMC was associated with nonverbal intelligence, age and school achievement. The LD group had significantly lower performance on the MMC than the Control group. Performance on the MMC discriminated LD children with a global accuracy of around 0.80. Associations between the MMC and the other neuropsychological variables were higher for finger gnosis (r=0.40) and generally higher for early elementary school grades. The MMC proved satisfactory for identifying LD children with good accuracy. Nonverbal intelligence, and perceptual/motor abilities play an important role in MMC performance. Conclusion: The MMC could be a useful instrument for screening children with LD.

RESUMO Mini-exame mental para crianças (MMC) é uma ferramenta amplamente utilizada para avaliar déficits cognitivos globais, no entanto, ainda é desconhecido se a MMC é sensível para investigar perfis cognitivos associados a dificuldades de aprendizagem. Objetivo: Aqui nós investigamos a viabilidade de usar MMC para triagem de crianças em idade escolar com dificuldades de aprendizagem em ortografia e matemática. Métodos: MMC e outros testes neuropsicológicos foram administrados em uma amostra de 168 crianças de 7 a 12 anos de idade. A amostra foi subdividida em um Grupo Controle e um grupo LD (dificuldade na matemática, na escrita, ou na escrita e na matemática). A acurácia diagnóstica foi analisada através de uma análise de curva ROC. A validade convergente e divergente foi investigada através de análises de correlações. Resultados: A performance no MMC foi associada com a inteligência não verbal, idade e desempenho escolar. O grupo LD apresentou desempenho significativamente inferior ao Grupo Controle no MMC. A performance no MMC pôde identificar crianças LD com uma acurácia global em torno de 0.80. As associações entre MMC e outras variáveis neuropsicológicas foram maiores para gnosias digitais (r=0.40) e em geral, mais altas nas séries iniciais. O MMC se mostrou satisfatório para identificar crianças LD com uma boa acurácia. A inteligência não verbal, habilidades perceptivas/motoras tem um importante papel na performance no MMC. Conclusão: O MMC pode ser um instrumento útil para o rastreamento de crianças com LD.

Heterosis in COMT Val158Met Polymorphism Contributes to Sex-Differences in Children's Math Anxiety.

Math anxiety (MA) is a phobic reaction to math activities, potentially impairing math achievement. Higher frequency of MA in females is explainable by the interaction between genetic and environmental factors. The molecular-genetic basis of MA has not been investigated. The COMT Val158Met polymorphism, which affects dopamine levels in the prefrontal cortex, has been associated with anxiety manifestations. The valine allele is associated with lower, and the methionine allele with higher, dopamine availability. In the present study, the effects of sex and COMT Val158Met genotypes on MA were investigated: 389 school children aged 7-12 years were assessed for intelligence, numerical estimation, arithmetic achievement and MA and genotyped for COMT Val158Met polymorphism. The Math Anxiety Questionnaire (MAQ) was used to assess the cognitive and affective components of MA. All genotype groups of boys and girls were comparable regarding genotype frequency, age, school grade, numerical estimation, and arithmetic abilities. We compared the results of all possible genetic models: codominance (Val/Val vs. Val/Met vs. Met/Met), heterosis (Val/Met vs. Val/Val plus Met/Met), valine dominance (Val/Val plus Val/Met vs. Met/Met), and methionine dominance (Met/Met plus Val/Met vs. Val/Val). Models were compared using AIC and AIC weights. No significant differences between girls and boys and no effects of the COMT Val158Met polymorphism on numerical estimation and arithmetic achievement were observed. Sex by genotype effects were significant for intelligence and MA. Intelligence scores were higher in Met/Met girls than in girls with at least one valine allele (valine dominance model). The best fitting model for MA was heterosis. In Anxiety Toward Mathematics, heterozygous individuals presented MA levels close to the grand average regardless of sex. Homozygous boys were significantly less and homozygous girls significantly more math anxious. Heterosis has been seldom explored, but in recent years has emerged as the best genetic model for some phenotypes associated with the COMT Val158Met polymorphism. This is the first study to investigate the genetic-molecular basis of MA.

Genetic variants of VWF gene in type 2 von Willebrand disease.

INTRODUCTION: von Willebrand disease (VWD) is the most common inherited bleeding disorder. Few studies have explored the molecular basis of type 2 VWD. AIM: This study aimed to identify variants associated with type 2 VWD. METHODS: We collected clinical and laboratory data, as well as response to desmopressin and bleeding assessment tool (BAT) score in patients diagnosed with type 2 VWD. We sequenced exons 17, 18, 20 and 28 of the VWF gene. RESULTS: We identified 19 different variants in 40 unrelated patients (47.5%). Most of the variants (84.2%) were found in exon 28. A total of 10/19 variants (52.6%) were identified as "likely causative" in 17/40 patients (42.5%), according to the ISTH-SSC and EAHAD VWF gene mutations databases. Nine variants were initially identified as potentially benign. However, through analyses in silico, four of these variants were reclassified as "likely pathogenic" (Ile1380Val, Asn1435Ser, Ser1486Leu and Tyr1584Cys). Response to desmopressin was associated with three variants: Met740Ile, Arg1597Gln and Tyr1584Cys. Major bleeding was associated with variants related to VWD subtypes 2B and 2M. CONCLUSION: In conclusion, we identified 19 variants, of which 14 are "likely pathogenic" and therefore associated with VWD. We suggest a possible association of pathogenic variants with major bleeding, response to desmopressin and BAT score ≥10, although this requires further confirmation.

Numerical Processing Impairment in 22q11.2 (LCR22-4 to LCR22-5) Microdeletion: A Cognitive-Neuropsychological Case Study.

Although progress has been made, the cognitive, biological and, particularly, the genetic underpinnings of math learning difficulties (MD) remain largely unknown. This difficulty stems from the heterogeneity of MD and from the large contribution of environmental factors to its etiology. Understanding endophenotypes, e.g., the role of the Approximate Number System (ANS), may help understanding the nature of MD. MD associated with ANS impairments has been described in some genetic conditions, e.g., 22q11.2 deletion syndrome (22q11.2DS or Velocardiofacial syndrome, VCFS). Recently, a girl with MD was identified in a school population screening. She has a new syndrome resulting from a microdeletion in 22q11.2 (LCR22-4 to LCR22-5), a region adjacent to but not overlapping with region 22q11.2 (LCR22-2 to LCR22-4), typically deleted in VCFS. Here, we describe her cognitive-neuropsychological and numerical-cognitive profiles. The girl was assessed twice, at 8 and 11 years. Her numerical-cognitive performance at both times was compared to demographically similar girls with normal intelligence in a single-case, quasi-experimental study. Neuropsychological assessment was normal, except for relatively minor impairments in executive functions. She presented severe and persistent difficulties in the simplest single-digit calculations. Difficulties in commutative operations improved from the first to the second assessment. Difficulties in subtraction persisted and were severe. No difficulties were observed in Arabic number writing. Difficulties in single-digit calculation co-occurred with basic numerical processing impairments in symbolic and non-symbolic (single-digit comparison, dot sets size comparison and estimation) tasks. Her difficulties suggest ANS impairment. No difficulties were detected in visuospatial/visuoconstructional and in phonological processing tasks. The main contributions of the present study are: (a) this is the first characterization of the neuropsychological phenotype in 22q11.2DS (LCR22-4 to LCR22.5) with normal intelligence; (b) mild forms of specific genetic conditions contribute to persistent MD in otherwise typical persons; (c) heterogeneity of neurogenetic underpinnings of MD is suggested by poor performance in non-symbolic numerical processing, dissociated from visuospatial/visuoconstructional and phonological impairments; (d) similar to what happens in 22q11.2DS (LCR22-2 to LCR22-4), ANS impairments may also characterize 22q11.2DS (LCR22-4 to LCR22-5).

Evidence for a Role of ACTN3 R577X Polymorphism in Football Player's Career Progression.

The aim was to investigate a possible role of the ACTN3 R577X polymorphism in a Brazilian football player's career progression. 2 questions were formulated: 1. Does ACTN3 polymorphism affect the probability of an individual being a professional football player? 2. Does this polymorphism affect the progression of the athlete throughout his career? The study included 353 players from first division Brazilian football clubs in the following categories: under-14 (U-14), U-15, U-17, U-20, and professional (PRO). The control group (CON) was composed of 100 healthy non-athletes. The chi-squared test was used to assess differences between the allele and genotype frequencies. Comparing football categories, the XX genotype was less frequent among professional players than in the U-20 (p<0.05) or the U-15 category (p<0.05). The RX genotype also presented more frequently in the PRO category than the U-14 category (p<0.05). Moreover, a trend towards a higher frequency of the RX genotype and a lower frequency of the XX genotype was observed in the professional category compared to U-20. These results suggest that the genotype in the ACTN3 polymorphism affects the probability of a football player progressing throughout his career and becoming professional, meaning that playing football selects against the ACTN3 XX genotype.