Breastfeeding and autism spectrum disorder: case-control study / Transtorno do espectro do autismo e aleitamento materno: estudo de caso controle

Abstract Objectives: to evaluate the association between breastfeeding and Autism Spectrum Disorder (ASD) in children and adolescents. Methods: this is a case-control study carried out in the north of the state of Minas Gerais, Brazil, which included 248 children and adolescents diagnosed with ASD (case group) and 886 children and adolescents without a diagnosis of ASD (control group).Interviews were conducted with the mothers of children and adolescents and a semi-structured questionnaire was used to collect data. For data analysis, a multiple logistic regression model was adopted. The magnitude of associations was estimated by the odds ratio (OR). Three multiple models were fitted: Model 1: presence or absence of breastfeeding; Model 2: duration of breastfeeding; Model 3: duration of exclusive breastfeeding. Results: ASD was associated with the absence of breastfeeding in the three adjusted models: Model 1: OR=2.1, CI95%=1.1-4.1; Model 2: OR=2.3, CI95%=1.2-4.5; Model 3: OR=2.3, CI95%=1.2-4.5. Conclusions: individuals with ASD were more likely to have not received breastfeeding, however, due to the nature of case control studies, it cannot be stated that breastfeeding prevents ASD. Conducting a cohort study may clarify this relationship.

Resumo Objetivos: avaliar a associação entre aleitamento materno e Transtorno do Espectro do Autismo (TEA) em crianças e adolescentes. Métodos: trata-se de um estudo caso-controle realizado no norte de Minas Gerais, Brasil, que incluiu 248 crianças e adolescentes com diagnóstico de TEA (grupo caso) e 886 crianças e adolescentes sem diagnóstico de TEA (grupo controle). Foram realizadas entrevistas com as mães das crianças e adolescentes e utilizado um questionário semiestruturado para coleta dos dados. Para análise dos dados foi adotado modelo de regressão logística múltipla. A magnitude das associações foi estimada pela Odds Ratio (OR). Três modelos múltiplos foram ajustados: Modelo 1: presença ou ausência de aleitamento materno; Modelo 2: duração do aleitamento materno; Modelo 3: duração do aleitamento materno exclusivo. Resultados: o TEA foi associado à ausência de aleitamento materno nos três modelos ajustados: Modelo 1: OR=2,1, IC95%=1,1-4,1; Modelo 2: OR=2,3, IC95%=1,2-4,5; Modelo 3: OR=2,3, IC95%=1,2-4,5. Conclusões: os indivíduos com TEA tiveram maiores chances de não terem recebido aleitamento materno, no entanto, devido à natureza dos estudos de caso-controle, não se pode afirmar que o aleitamento materno previna o TEA. A realização de um estudo de coorte poderá esclarecer essa relação.

Cyclic Peptides as Aggregation Inhibitors for Sickle Cell Disease.

Sickle cell disease is a missense genetic disorder characterized by the aggregation of deoxy-HbS into helical fibers that distort erythrocytes into a sickle-like shape. Herein, we investigate, through molecular dynamics, the effect of nine 5-mer cyclic peptides (CPs), tailor-designed to block key lateral contacts of the fibers. Our results show that the CPs bind orthogonally to the main HbS pocket involved in the latter contacts, with some revealing exceedingly long residence times. These CPs display moderate to high specificity, exhibiting molecular recognition events even at a HbS/CP (1:1) ratio. A much lower HbS-CP binding free energy, longer residence times, and higher specificity are also found relative to a previously reported CP with modest in vitro antisickling activity. These results indicate that some of these CPs have the potential to reduce the concentration of aggregation-competent deoxy-HbS, precluding or delaying the formation of lateral contact at the homogeneous nucleation stage.

Probing the Interactions of Thiazole Abietane Inhibitors with the Human Serine Hydrolases ABHD16A and ABHD12.

12-Thiazole abietanes are highly selective reversible inhibitors of hABHD16A that could potentially alleviate neuroinflammation. In this study, we used synthetic chemistry, competitive activity-based protein profiling, and computational methodologies to try to establish relevant structural determinants of activity and selectivity of this class of compounds for inhibiting ABHD16A over ABHD12. Five compounds significantly inhibited hABHD16A but also very efficiently discriminated between inhibition of hABHD16A and hABHD12, with compound 35 being the most effective, at 100 µM (55.1 ± 8.7%; p < 0.0001). However, an outstanding switch in the selectivity toward ABHD12 was observed in the presence of a ring A ester, if the C2' position of the thiazole ring possessed a 1-hydroxyethyl group, as in compound 28. Although our data were inconclusive as to whether the observed enzyme inhibition is allosteric or not, we anticipate that the structure-activity relationships presented herein will inspire future drug discovery efforts in this field.

Unraveling the Aquaporin-3 Inhibitory Effect of Rottlerin by Experimental and Computational Approaches.

The natural polyphenolic compound Rottlerin (RoT) showed anticancer properties in a variety of human cancers through the inhibition of several target molecules implicated in tumorigenesis, revealing its potential as an anticancer agent. Aquaporins (AQPs) are found overexpressed in different types of cancers and have recently emerged as promising pharmacological targets. Increasing evidence suggests that the water/glycerol channel aquaporin-3 (AQP3) plays a key role in cancer and metastasis. Here, we report the ability of RoT to inhibit human AQP3 activity with an IC50 in the micromolar range (22.8 ± 5.82 µM for water and 6.7 ± 2.97 µM for glycerol permeability inhibition). Moreover, we have used molecular docking and molecular dynamics simulations to understand the structural determinants of RoT that explain its ability to inhibit AQP3. Our results show that RoT blocks AQP3-glycerol permeation by establishing strong and stable interactions at the extracellular region of AQP3 pores interacting with residues essential for glycerol permeation. Altogether, our multidisciplinary approach unveiled RoT as an anticancer drug against tumors where AQP3 is highly expressed providing new information to aquaporin research that may boost future drug design.

RELIABILITY OF THE ISOMETRIC DYNAMOMETER IN CONTROL, PARAPLEGIC, AND AMPUTEE INDIVIDUALS.

Objective: To determine the Intraclass Correlation Coefficient (ICC), Standard Error of Measurement (SEM), Minimum Detectable Change (MDC), and the Minimum Clinically Important Difference (MCID) of the isometric measurements of muscle strength of trunk extension and of flexion and knee extension at maximum contraction in healthy, paraplegic, and amputee individuals, by using an isometric dynamometer with a belt for stabilization. Methods: An observational cross-sectional study was carried out to assess the reliability of a portable isometric dynamometer in the trunk extension and flexion and knee extension movements of each group. Results: In all measurements, ICC ranged from 0.66 to 0.99, SEM from 0.11 to 3.73 kgf, and MDC from 0.30 to 10.3 kgf. The MCID of the movements ranged from 3.1 to 4.9 kgf in the amputee group and from 2.2 to 3.66 kgf in the paraplegic group. Conclusion: The manual dynamometer demonstrated good intra-examiner reliability, presenting moderate and excellent ICC results. Thus, this device is a reliable resource to measure muscle strength in amputees and paraplegics. Level of Evidence II, Cross-Sectional Study.

Objetivo: Determinar o coeficiente de correlação intraclasse (CCI), o erro padrão da medida (EPM), a mínima mudança detectável (MMD) e a mínima mudança clinicamente importante (MMCI) das medidas isométricas de força muscular da extensão de tronco e da flexão e extensão de joelho em contração máxima de indivíduos saudáveis, paraplégicos e amputados, usando um dinamômetro isométrico com cinto para estabilização. Métodos: Foi realizado um estudo observacional transversal para avaliar a confiabilidade de um dinamômetro portátil isométrico nos movimentos de extensão de tronco e de flexão e extensão de joelho de cada grupo. Resultados: Em todas as medidas o CCI apresentou uma variação de 0,66 a 0,99, o EPM de 0,11 a 3,73 kgf e a MMD de 0,30 a 10,3 kgf. A MMCI dos movimentos variou de 3,1 a 4,9 kgf no grupo de amputados e de 2,2 a 3,66 kgf no grupo de paraplégicos. Conclusão: O dinamômetro manual demonstrou boa confiabilidade intraexaminador, com variação de CCI de moderada à excelente, apresentando-se como um recurso confiável para mensurar força muscular de amputados e paraplégicos. Nível de Evidência II, Estudo Observacional Transversal.

Rescue of Rare CFTR Trafficking Mutants Highlights a Structural Location-Dependent Pattern for Correction.

Cystic Fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Currently, more than 2100 variants have been identified in the gene, with a large number being very rare. The approval of modulators that act on mutant CFTR protein, correcting its molecular defect and thus alleviating the burden of the disease, revolutionized the field of CF. However, these drugs do not apply to all patients with CF, especially those with rare mutations-for which there is a lack of knowledge on the molecular mechanisms of the disease and the response to modulators. In this work, we evaluated the impact of several rare putative class II mutations on the expression, processing, and response of CFTR to modulators. Novel cell models consisting of bronchial epithelial cell lines expressing CFTR with 14 rare variants were created. The variants studied are localized at Transmembrane Domain 1 (TMD1) or very close to the signature motif of Nucleotide Binding Domain 1 (NBD1). Our data show that all mutations analyzed significantly decrease CFTR processing and while TMD1 mutations respond to modulators, those localized in NBD1 do not. Molecular modeling calculations confirm that the mutations in NBD1 induce greater destabilization of CFTR structure than those in TMD1. Furthermore, the structural proximity of TMD1 mutants to the reported binding site of CFTR modulators such as VX-809 and VX-661, make them more efficient in stabilizing the CFTR mutants analyzed. Overall, our data suggest a pattern for mutation location and impact in response to modulators that correlates with the global effect of the mutations on CFTR structure.

Decoding the secrets: how conformational and structural regulators inhibit the human 20S proteasome.

Acquired resistance to drugs that modulate specific protein functions, such as the human proteasome, presents a significant challenge in targeted therapies. This underscores the importance of devising new methodologies to predict drug binding and potential resistance due to specific protein mutations. In this work, we conducted an extensive computational analysis to ascertain the effects of selected mutations (Ala49Thr, Ala50Val, and Cys52Phe) within the active site of the human proteasome. Specifically, we sought to understand how these mutations might disrupt protein function either by altering protein stability or by impeding interactions with a clinical administered drug. Leveraging molecular dynamics simulations and molecular docking calculations, we assessed the effect of these mutations on protein stability and ligand affinity. Notably, our results indicate that the Cys52Phe mutation critically impacts protein-ligand binding, providing valuable insights into potential proteasome inhibitor resistance.

Reliability of the isometric dynamometer in control, paraplegic, and amputee individuals / Confiabilidade do dinamômetro isométrico em indivíduos controle, paraplégicos e amputados

ABSTRACT Objective: To determine the Intraclass Correlation Coefficient (ICC), Standard Error of Measurement (SEM), Minimum Detectable Change (MDC), and the Minimum Clinically Important Difference (MCID) of the isometric measurements of muscle strength of trunk extension and of flexion and knee extension at maximum contraction in healthy, paraplegic, and amputee individuals, by using an isometric dynamometer with a belt for stabilization. Methods: An observational cross-sectional study was carried out to assess the reliability of a portable isometric dynamometer in the trunk extension and flexion and knee extension movements of each group. Results: In all measurements, ICC ranged from 0.66 to 0.99, SEM from 0.11 to 3.73 kgf, and MDC from 0.30 to 10.3 kgf. The MCID of the movements ranged from 3.1 to 4.9 kgf in the amputee group and from 2.2 to 3.66 kgf in the paraplegic group. Conclusion: The manual dynamometer demonstrated good intra-examiner reliability, presenting moderate and excellent ICC results. Thus, this device is a reliable resource to measure muscle strength in amputees and paraplegics. Level of Evidence II, Cross-Sectional Study.

RESUMO Objetivo: Determinar o coeficiente de correlação intraclasse (CCI), o erro padrão da medida (EPM), a mínima mudança detectável (MMD) e a mínima mudança clinicamente importante (MMCI) das medidas isométricas de força muscular da extensão de tronco e da flexão e extensão de joelho em contração máxima de indivíduos saudáveis, paraplégicos e amputados, usando um dinamômetro isométrico com cinto para estabilização. Métodos: Foi realizado um estudo observacional transversal para avaliar a confiabilidade de um dinamômetro portátil isométrico nos movimentos de extensão de tronco e de flexão e extensão de joelho de cada grupo Resultados: Em todas as medidas o CCI apresentou uma variação de 0,66 a 0,99, o EPM de 0,11 a 3,73 kgf e a MMD de 0,30 a 10,3 kgf. A MMCI dos movimentos variou de 3,1 a 4,9 kgf no grupo de amputados e de 2,2 a 3,66 kgf no grupo de paraplégicos. Conclusão: O dinamômetro manual demonstrou boa confiabilidade intraexaminador, com variação de CCI de moderada à excelente, apresentando-se como um recurso confiável para mensurar força muscular de amputados e paraplégicos. Nível de Evidência II, Estudo Observacional Transversal.

Association between autism spectrum disorder and peripartum events: a case-control study / Associação entre o transtorno do espectro do autismo e eventos periparto: estudo de caso-controle

Abstract Objective: To assess the association between peripartum events and autism spectrum disorder (ASD) development in children and adolescents. Methods: The current research is a case-control study in northern Minas Gerais state, Brazil. The inclusion criteria in the case group included individuals whose medical records reported an autistic disorder diagnosis, individuals had this diagnosis further confirmed by Northern Minas Autistic Support Association and specialized clinics, and their mothers had to answer positively to the question: "Was your child diagnosed with autism spectrum disorder?" in the data collection instrument. Thus, the case group included 253 mothers of children/adolescents of 2-15 years old diagnosed with autism. The inclusion criteria in the control group included 852 individuals belonging to the same age group and enrolled in the same schools as the case group. A semi-structured questionnaire was applied for mothers of children/adolescents, and the multiple logistic regression model was adopted for data analysis. Gross and adjusted Odds Ratios (ORa) were used to estimate the magnitude of the associations. Results: Autistic disorder was associated with the presence of meconium in amniotic fluid (AF) (ORa 1.67; 95% confidence interval [95%CI] 1.06-2.65) and cesarean delivery type (ORa 1.65; 95%CI 1.17-2.32). Emergency cesarean section increased autistic disorder development likelihood (ORa 2.38; 95%CI 1.61-3.51). Children and adolescents with ASD were more likely to have been exposed to two or more unfavorable peripartum events and obstetric complications than control groups (ORa 1.59; 95%CI 1.01-2.51). Conclusions: Meconium stained amniotic fluid, delivery by cesarean, and two or more unfavorable peripartum events are variables that should be considered in studies about ASD etiology.

RESUMO Objetivo: Avaliar a associação entre os eventos periparto e o desenvolvimento do transtorno do espectro autista (TEA) em crianças/adolescentes. Métodos: Trata-se de um estudo de caso-controle desenvolvido no norte de Minas Gerais, Brasil. Os critérios de inclusão do grupo caso foram indivíduos com diagnóstico de TEA por laudo médico, confirmado pela Associação Norte Mineira de Apoio ao Autista ou por clínicas especializadas, e as mães que responderam positivamente a: "Seu filho foi diagnosticado com TEA?". Assim, o grupo caso incluiu 253 mães de crianças/adolescentes com 2-15 anos diagnosticadas com autismo. O critério de inclusão no grupo controle abrangeu 852 indivíduos pertencentes à mesma faixa etária e matriculados nas mesmas escolas que o grupo caso. Um questionário semiestruturado foi aplicado às mães e o modelo de regressão logística múltipla foi adotado para a análise de dados. Para estimar a magnitude das associações, utilizou-se Odds Ratio (OR) bruta e ajustada. Resultados: O TEA foi associado à presença de mecônio no líquido amniótico (ORa 1,67; intervalo de confiança [IC95%] 1,06-2,65) e ao parto cesáreo (ORa 1,65; IC95% 1,17-2,32). A cesárea de emergência aumentou a chance de desenvolvimento do autismo (ORa 2,38; IC95% 1,61-3,51). Crianças/adolescentes com autismo apresentaram maior chance de exposição a dois ou mais eventos desfavoráveis de parto (ORa 1,59; IC95% 1,01-2,51). Conclusões: A presença de mecônio no líquido amniótico, cesárea de emergência e mais de um evento de parto desfavorável são fatores que devem ser considerados nos estudos sobre a etiologia do transtorno autístico.

In Silico Characterization of African Swine Fever Virus Nucleoprotein p10 Interaction with DNA.

African swine fever virus (ASFV) is the etiological agent of a highly contagious, hemorrhagic infectious swine disease, with a tremendous sanitary and economic impact on a global scale. Currently, there are no globally available vaccines or treatments. The p10 protein, a structural nucleoprotein encoded by ASFV, has been previously described as capable of binding double-stranded DNA (dsDNA), which may have implications for viral replication. However, the molecular mechanism that governs this interaction is still unknown, mostly due to the lack of a structural model for this protein. In this work, we have generated an ab initio model of the p10 protein and performed extensive structural characterization, using molecular dynamics simulations to identify the motifs and residues regulating DNA recognition. The helix-turn-helix motif identified at the C-terminal region of the protein was shown to be crucial to the dsDNA-binding efficiency. As with other DNA-binding proteins, two distinct serine and lysine-rich regions found in the two helices were identified as key players in the binding to DNA, whose importance was later validated using experimental binding assays. Altogether, these findings may contribute to a better understanding of the p10 function in ASFV replication.

Association between autism spectrum disorder and peripartum events: a case-control study.

OBJECTIVE: To assess the association between peripartum events and autism spectrum disorder (ASD) development in children and adolescents. METHODS: The current research is a case-control study in northern Minas Gerais state, Brazil. The inclusion criteria in the case group included individuals whose medical records reported an autistic disorder diagnosis, individuals had this diagnosis further confirmed by Northern Minas Autistic Support Association and specialized clinics, and their mothers had to answer positively to the question: "Was your child diagnosed with autism spectrum disorder?" in the data collection instrument. Thus, the case group included 253 mothers of children/adolescents of 2-15 years old diagnosed with autism. The inclusion criteria in the control group included 852 individuals belonging to the same age group and enrolled in the same schools as the case group. A semi-structured questionnaire was applied for mothers of children/adolescents, and the multiple logistic regression model was adopted for data analysis. Gross and adjusted Odds Ratios (ORa) were used to estimate the magnitude of the associations. RESULTS: Autistic disorder was associated with the presence of meconium in amniotic fluid (AF) (ORa 1.67; 95% confidence interval [95%CI] 1.06-2.65) and cesarean delivery type (ORa 1.65; 95%CI 1.17-2.32). Emergency cesarean section increased autistic disorder development likelihood (ORa 2.38; 95%CI 1.61-3.51). Children and adolescents with ASD were more likely to have been exposed to two or more unfavorable peripartum events and obstetric complications than control groups (ORa 1.59; 95%CI 1.01-2.51). CONCLUSIONS: Meconium stained amniotic fluid, delivery by cesarean, and two or more unfavorable peripartum events are variables that should be considered in studies about ASD etiology.

Optimization of an in Silico Protocol Using Probe Permeabilities to Identify Membrane Pan-Assay Interference Compounds.

Membrane pan-assay interference compounds (PAINS) are a class of molecules that interact nonspecifically with lipid bilayers and alter their physicochemical properties. An early identification of these compounds avoids chasing false leads and the needless waste of time and resources in drug discovery campaigns. In this work, we optimized an in silico protocol on the basis of umbrella sampling (US)/molecular dynamics (MD) simulations to discriminate between compounds with different membrane PAINS behavior. We showed that the method is quite sensitive to membrane thickness fluctuations, which was mitigated by changing the US reference position to the phosphate atoms of the closest interacting monolayer. The computational efficiency was improved further by decreasing the number of umbrellas and adjusting their strength and position in our US scheme. The inhomogeneous solubility-diffusion model (ISDM) used to calculate the membrane permeability coefficients confirmed that resveratrol and curcumin have distinct membrane PAINS characteristics and indicated a misclassification of nothofagin in a previous work. Overall, we have presented here a promising in silico protocol that can be adopted as a future reference method to identify membrane PAINS.

Alchemical Design of Pharmacological Chaperones with Higher Affinity for Phenylalanine Hydroxylase.

Phenylketonuria (PKU) is a rare metabolic disease caused by variations in a human gene, PAH, encoding phenylalanine hydroxylase (PAH), and the enzyme converting the essential amino acid phenylalanine into tyrosine. Many PKU-causing variations compromise the conformational stability of the encoded enzyme, decreasing or abolishing its catalytic activity, and leading to an elevated concentration of phenylalanine in the blood, which is neurotoxic. Several therapeutic approaches have been developed to treat the more severe manifestations of the disorder, but they are either not entirely effective or difficult to adhere to throughout life. In a search for novel pharmacological chaperones to treat PKU, a lead compound was discovered (compound IV) that exhibited promising in vitro and in vivo chaperoning activity on PAH. The structure of the PAH-IV complex has been reported. Here, using alchemical free energy calculations (AFEC) on the structure of the PAH-IV complex, we design a new generation of compound IV-analogues with a higher affinity for the enzyme. Seventeen novel analogues were synthesized, and thermal shift and isothermal titration calorimetry (ITC) assays were performed to experimentally evaluate their stabilizing effect and their affinity for the enzyme. Most of the new derivatives bind to PAH tighter than lead compound IV and induce a greater thermostabilization of the enzyme upon binding. Importantly, the correspondence between the calculated alchemical binding free energies and the experimentally determined ΔΔGb values is excellent, which supports the use of AFEC to design pharmacological chaperones to treat PKU using the X-ray structure of their complexes with the target PAH enzyme.

Major Achievements in the Design of Quadruplex-Interactive Small Molecules.

Organic small molecules that can recognize and bind to G-quadruplex and i-Motif nucleic acids have great potential as selective drugs or as tools in drug target discovery programs, or even in the development of nanodevices for medical diagnosis. Hundreds of quadruplex-interactive small molecules have been reported, and the challenges in their design vary with the intended application. Herein, we survey the major achievements on the therapeutic potential of such quadruplex ligands, their mode of binding, effects upon interaction with quadruplexes, and consider the opportunities and challenges for their exploitation in drug discovery.

Photobiomodulation therapy prevents dysgeusia chemotherapy induced in breast cancer women treated with doxorubicin plus cyclophosphamide: a triple-blinded, randomized, placebo-controlled clinical trial.

PURPOSE: To evaluate the effectiveness of photobiomodulation (PBMT) in preventing dysgeusia in breast cancer patients treated with doxorubicin-cyclophosphamide (AC). METHODS: This is a phase II, randomized, triple-blind, placebo-controlled clinical trial involving 112 breast cancer patients treated with AC. The patients were divided equally into two groups: a test group treated with 2 J red laser and 3 J infrared laser on 21 points that were symmetrically distributed on the tongue on day 0 of four cycles of AC, and an equal placebo group treated with simulated PBMT to blind the patient, evaluator, and statistician. The clinicopathological and sociodemographic data, results of taste test, and subjective taste analysis, and the QoL, ECOG performance status, body mass index, and other side effects were recorded. The data were analyzed using ANOVA-RM/Bonferroni, Friedman/Dunn, and chi-square/Fisher's exact tests. RESULTS: PBMT patients showed less objective and subjective taste loss (p<0.05). On the other hand, the placebo group showed a higher ECOG status (p=0.037) and more significant weight loss (p<0.001) after four cycles of AC. The QoL was significantly higher in the PBMT group (p<0.05) at all assessment periods, and PBMT treatment also reduced the incidence of cachexia (p=0.020), anorexia (p<0.001), diarrhea (p=0.040), oral mucositis (p=0.020), and vomiting (p=0.008). CONCLUSION: PBMT reduced the taste loss and improved the overall health status and QoL of patients with breast cancer treated with AC. TRIAL REGISTRATION: Brazilian Clinical Trials Registry ( www.ensaiosclinicos.gov.br ) approval number RBR-9qnm34y, registered on 01/05/2021.

Estudo de propriedades psicométricas do M-chat no Brasil / Study of M-chat psychometric proprieties in Brazil / Estudio de las propiedades psicométricas de M-chat en Brasil

O objetivo deste estudo foi avaliar as propriedades psicométricas do Modified Checklist for Autism in Toddlers (M-Chat) em crianças de 24 a 36 meses de idade com (Grupo 1/n = 88) e sem (Grupo 2/n = 1116) o transtorno do espectro do autismo (TEA). Avaliou-se a consistência interna e estimou-se a sensibilidade, especificidade, valor preditivo positivo (VPP), valor preditivo negativo (VPN). Além disso, construiu-se a curva Receiver Operating Characteristic (ROC). Para avaliar a validade discriminante, comparou-se a proporção de falhas entre as crianças com e sem o TEA, utilizando o teste qui-quadrado ou teste Exato de Fisher. Comparou-se ainda o número de falhas segundo sexo, faixa etária e grupo do participante por meio do teste de Mann-Whitney. O M-Chat apresentou consistência interna elevada (0,78 e 0,86), reprodutibilidade satisfatória (Kappa de 0,6 a 0,79 e CCI = 0,87 e 0,89), alta sensibilidade (0,807 e 0,932), especificidade (0,927 e 0,706) e VPN (0,984 e 0,992), porém as estimativas do VPP (0,467 e 0,250) não foram satisfatórias. Quanto à validade discriminante, observou-se que a proporção de falhas foi significativamente maior no grupo de crianças com TEA. Observou-se também que o número de falhas foi maior entre as crianças do sexo masculino, com faixa etária de 25-36 meses e no grupo com TEA. A versão brasileira do M-Chat tem propriedades psicométricas adequadas no que se refere à confiabilidade, sensibilidade, especificidade, VPN e validade discriminante, o que torna recomendável sua aplicação para rastrear crianças com sinais do TEA.(AU)

This study aims to assess the psychometric properties of the instrument Modified Checklist for Autism in Toddlers (M-CHAT) in children from 24 to 36 months old with (Group 1/n = 88) and without (Group 2/n = 1116) Autism Spectrum Disorder (ASD). Internal consistency was evaluated and sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were estimated. Also, the Receiver Operating Characteristic (ROC) curve was generated. To evaluate the discriminant validity, the proportion of flaws among children with and without ASD was assessed by applying the Chi-square test or by the Exact Fisher test. The number of flaws based on sex, age group, and participant's group was also compared with the Mann-Whitney Test. The M-CHAT showed high internal consistency (0.78 and 0.86), satisfactory reproductivity (Kappa 0.60 and 0.79 and ICC = 0.87 and 0.89), high sensibility (0.807 and 0.932), specificity (0.927 and 0.706), and NPV (0.984 and 0.992); however, PPV estimates (0.467 and 0.250) were not satisfactory. Regarding the discriminant validity, the proportion of flaws was significantly higher in the group of children with ASD. Moreover, the number of flaws was larger among boys, in the age group 25-36 months, and in the group with ASD. The Brazilian version of M-CHAT has adequate psychometric properties concerning reliability, sensitivity, specificity, NPV and discriminant validity, which makes its application recommendable to track children with ASD signs.(AU)

Ese estudio tuvo como objetivo evaluar las propiedades psicométricas del Modified Checklist for Autism in Toddlers (M-CHAT) en niños de 24 a los 36 meses de edad con (grupo 1/n=88) y sin (grupo 2/n=1116) el trastorno del espectro autista (TEA). Fueron evaluadas la consistencia interna y estimadas la sensibilidad, especificidad, valor predictivo positivo (VPP), valor predictivo negativo (VPN). Además, se construyó la curva Receiver Operating Characteristic (ROC). Para evaluar la validad discriminante se comparó la proporción de los fracasos entre los niños con y sin TEA, utilizando el examen chi-cuadrado o la prueba exacta de Fisher. Se compararon también el número de fracasos según el sexo, edad y grupo de participantes por medio del teste Mann-Whitney. El M-CHAT presentó consistencia interna elevada (0,78 y 0,86), reproductividad satisfactoria (Kappa de 0,60 a 0,79 e CCI = 0,87 e 0,89), alta sensibilidad (0,807 e 0,932), especificidad (0,927 e 0,706) y VPN (0,984 e 0,992), pero las estimativas del VPP (0,467 e 0,250) no fueron satisfactorias. Acerca de la validad discriminante, se observó que la proporción de fallas fue significativamente mayor en el grupo de niños con TEA. El número de fracasos fue mayor entre los niños varones, de 25 a 36 meses de edad y no en el grupo con TEA. La versión brasileña del M-CHAT tiene propiedades psicométricas adecuadas en lo que concierne a la confiabilidad, sensibilidad, especificidad, VPN y validad discriminante, lo que hace que su aplicación sea recomendada para rastrear los niños con señales de TEA.(AU)

In Silico End-to-End Protein-Ligand Interaction Characterization Pipeline: The Case of SARS-CoV-2.

SARS-CoV-2 triggered a worldwide pandemic disease, COVID-19, for which an effective treatment has not yet been settled. Among the most promising targets to fight this disease is SARS-CoV-2 main protease (Mpro), which has been extensively studied in the last few months. There is an urgency for developing effective computational protocols that can help us tackle these key viral proteins. Hence, we have put together a robust and thorough pipeline of in silico protein-ligand characterization methods to address one of the biggest biological problems currently plaguing our world. These methodologies were used to characterize the interaction of SARS-CoV-2 Mpro with an α-ketoamide inhibitor and include details on how to upload, visualize, and manage the three-dimensional structure of the complex and acquire high-quality figures for scientific publications using PyMOL (Protocol 1); perform homology modeling with MODELLER (Protocol 2); perform protein-ligand docking calculations using HADDOCK (Protocol 3); run a virtual screening protocol of a small compound database of SARS-CoV-2 candidate inhibitors with AutoDock 4 and AutoDock Vina (Protocol 4); and, finally, sample the conformational space at the atomic level between SARS-CoV-2 Mpro and the α-ketoamide inhibitor with Molecular Dynamics simulations using GROMACS (Protocol 5). Guidelines for careful data analysis and interpretation are also provided for each Protocol.

New (Iso)quinolinyl-pyridine-2,6-dicarboxamide G-Quadruplex Stabilizers. A Structure-Activity Relationship Study.

G-quadruplex (G4)-interactive small molecules have a wide range of potential applications, not only as drugs, but also as sensors of quadruplex structures. The purpose of this work is the synthesis of analogues of the bis-methylquinolinium-pyridine-2,6-dicarboxamide G4 ligand 360A, to identify relevant structure-activity relationships to apply to the design of other G4-interactive small molecules bearing bis-quinoline or bis-isoquinoline moieties. Thermal denaturation experiments revealed that non-methylated derivatives with a relative 1,4 position between the amide linker and the nitrogen of the quinoline ring are moderate G4 stabilizers, with a preference for the hybrid h-Telo G4, a 21-nt sequence present in human telomeres. Insertion of a positive charge upon methylation of quinoline/isoquinoline nitrogen increases compounds' ability to selectively stabilize G4s compared to duplex DNA, with a preference for parallel structures. Among these, compounds having a relative 1,3-position between the charged methylquinolinium/isoquinolinium nitrogen and the amide linker are the best G4 stabilizers. More interestingly, these ligands showed different capacities to selectively block DNA polymerization in a PCR-stop assay and to induce G4 conformation switches of hybrid h-Telo G4. Molecular dynamic simulations with the parallel G4 formed by a 21-nt sequence present in k-RAS gene promoter, showed that the relative spatial orientation of the two methylated quinoline/isoquinoline rings determines the ligands mode and strength of binding to G4s.

Identification of Pan-Assay INterference compoundS (PAINS) Using an MD-Based Protocol.

Pan-assay interference compounds (PAINS) are promiscuous molecules with multiple behaviors that interfere with assay readouts. Membrane PAINS are a subset of these compounds that influence the function of membrane proteins by nonspecifically perturbing the lipid membranes that surround them. Here, we describe a computational protocol to identify potential membrane PAINS molecules by calculating the effect that a given compound has on the bilayer deformation propensity.

Hábitos parafuncionais e sintomatologia de pacientes submetidos a intervenções buco-maxilo-faciais em uma clínica escola de fisioterapia: um estudo retrospectivo de 15 anos / PARAFUNCTIONAL HABITS AND SYMPTOMATOLOGY OF PATIENTS SUBMITTED TO BUCO-MAXILLO-FACIAL INTERVENTIONS IN A PHYSIOTHERAPY SCHOOL CLINIC: A RETROSPECTIVE STUDY OF 15 YEARS

Objetivo: Comparar clinicamente os pacientes com desordens buco-maxilo-faciais (DBMF) atendidos em uma clínica-escola de fisioterapia da cidade de Fortaleza. Materiais e métodos: Dentre 5.357 prontuários, foram coletados os dados de 315 prontuários referentes aos pacientes acometidos por DBMF, dentre eles, 62 homens e 253 mulheres. Resultados: O estudo adotou perfil predominante de pacientes do gênero feminino, solteiros, entre 21 a 30 anos, estudantes, que fizeram uso de relaxante muscular; mulheres sentiram dor irradiada, já homens, dor do tipo fina. Bruxismo/endentações/desgaste dentário foram prevalentes em ambos os sexos e os sintomas que apresentaram diferença estatística entre homens e mulheres foram cervicalgia (p=0,0051), cefaleia (p<0,0001), formigamento de membros superiores (p=0,0371) e dor corporal (p=0,0234). Conclusão: Bruxismo/endentações/desgaste dentário foram os prevalentes em ambos os sexos. Entre os homens, o sintoma mais prevalente foi a dor ou cansaço ao mastigar, já entre as mulheres foi a cefaleia.