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OBJECTIVE: Huntington's disease (HD) is a neurodegenerative disease caused by a triplet repeat expansion within the gene huntingtin (HTT). Antagonistic pleiotropy is a theory of aging that posits that some genes, facilitating individual fitness early in life through adaptive evolutionary changes, also augment detrimental aging-related processes. Antagonistic pleiotropy theory may explain a positive evolutionary pressure toward functionally advantageous brain development that is vulnerable to rapid degeneration. The current study investigated antagonistic pleiotropy in HD using a years-to-onset paradigm in a unique sample of children and young adults at risk for HD. METHODS: Cognitive, behavioral, motor, and brain structural measures from premanifest gene-expanded (n = 79) and gene nonexpanded (n = 112) participants (6-21 years) in the Kids-HD study were examined. All measures in the gene-expanded group were modeled using a mixed-effects regression approach to assess years-to-onset-based changes while controlling for normal growth. Simultaneously, structure-function associations were also examined. RESULTS: Decades from motor onset, gene-expanded participants showed significantly better cognitive, behavioral, and motor scores versus gene nonexpanded controls, along with larger cerebral volumes and cortical features. After this initial peak, a prolonged deterioration was observed in both functional and structural measures. Far from onset, brain measures were positively correlated with functional measures, supporting the view that functional advantages were mediated by structural differences. INTERPRETATION: Mutant HTT may drive the development of a larger than normal brain that subserves superior early-life function. These findings support the antagonistic pleiotropy theory of HTT in HD, where this gene drives early advantage followed by accelerated aging processes. ANN NEUROL 2024.
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Introduction: Medical curricula implicitly teach that race has a biological basis. Clinical rotations reinforce this misconception as race-based algorithms are used to guide clinical decision-making. This module aims to expose the fallacy of race in clinical algorithms, using the estimated glomerular filtration rate (eGFR) equation as an example. Methods: We created a 60-minute module in consultation with nephrologists. The format was an interactive, case-based presentation with a didactic section. A third-year medical student facilitated the workshops to medical students. Evaluation included pre/post surveys using 5-point Likert scales to assess awareness regarding use of race as a biological construct. Higher scores indicated increased awareness. Results: Fifty-five students participated in the module. Pre/post results indicated that students significantly improved in self-perceived knowledge of the history of racism in medicine (2.6 vs. 3.2, p < .001), awareness of race in clinical algorithms (2.7 vs. 3.7, p < .001), impact of race-based eGFR on quality of life/treatment outcomes (4.5 vs. 4.8, p = .01), differences between race and ancestry (3.7 vs. 4.3, p < .001), and implications of not removing race from the eGFR equation (2.7 vs. 4.2, p < .001). Students rated the workshops highly for quality and clarity. Discussion: Our module expands on others' work to expose the fallacy of race-based algorithms and define its impact on health equity. Limitations include a lack of objective assessment of knowledge acquisition. We recommend integrating this module into preclinical and clinical curricula to discuss the use of race in medical literature and clinical practice.
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Algoritmos , Curriculum , Tasa de Filtración Glomerular , Estudiantes de Medicina , Humanos , Estudiantes de Medicina/estadística & datos numéricos , Estudiantes de Medicina/psicología , Tasa de Filtración Glomerular/fisiología , Encuestas y Cuestionarios , Grupos Raciales/estadística & datos numéricos , Educación de Pregrado en Medicina/métodos , Masculino , Racismo , FemeninoRESUMEN
OBJECTIVES: To assess sex-specific differences in the association between pre-transfusion haemoglobin values and early neurodevelopmental function. DESIGN: Observational follow-up of infants with birth weights <1000 g and gestational ages 22-28 weeks who were enrolled in the NICHD Neonatal Research Network Transfusion of Prematures (TOP) Trial at 19 U.S. sites, 2012-2017. MAIN OUTCOME MEASURES: Pretransfusion haemoglobin values were obtained longitudinally through 36 weeks' postmenstrual age. The infant's mean pretransfusion haemoglobin was used as a marker of degree of anaemia (n=1655 measures). Measures of brain function were obtained at 22-26 months' corrected age using the Bayley Scales of Infant & Toddler Development, third edition (BSID-III) (n=1290 BSID-III scores). Sex-specific estimates for the linear relation between pretransfusion haemoglobin and BSID-III scores were obtained from repeated-measures regression analysis, adjusted for gestational age, birth weight, study site, clinical characteristics, and demographic covariates. RESULTS: The relation of pretransfusion haemoglobin with 24-month BSID-III scores showed significant, independent interactions with both (1) sex (p=0.046) and (2) retinopathy of prematurity (ROP; p=0.004). In 614 males, BSID-III scores were higher by 1.07 points per g/dL (95% CI 1.58 to 4.33; p=0.008), not differing significantly among the three subscales (cognitive, language and motor; p=0.94). In 247 infants with ROP, BSID-III scores were higher by 2.95 points per g/dL (95% CI 0.28 to 1.87; p<0.0001), uniformly across subscales (p=0.73). These associations were non-significant in 676 females (p=0.96) and 1043 infants without ROP (p=0.81). CONCLUSIONS: This study demonstrates sex-specific associations between mean pretransfusion haemoglobin (a marker of the severity of anaemia throughout the neonatal intensive care unit [NICU] hospitalisation) and early neurodevelopmental function at 22-26 months' corrected age.
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Cognición , Hemoglobinas , Recien Nacido Prematuro , Humanos , Femenino , Masculino , Hemoglobinas/análisis , Hemoglobinas/metabolismo , Recién Nacido , Recien Nacido Prematuro/sangre , Cognición/fisiología , Factores Sexuales , Lactante , Edad Gestacional , Desarrollo Infantil/fisiología , Estudios de Seguimiento , Preescolar , Anemia/sangreRESUMEN
Children with isolated cleft of the lip and/or palate (iCL/P) have been shown to be at risk for impaired reading ability. Structural and functional neuroimaging studies have revealed subtle morphological and functional abnormalities correlated to cognition and reading ability. However, the integrity of white matter tracts and their potential relationship to reading performance in iCL/P is under-studied. The purpose of the present study was to evaluate white matter integrity related to cognition and reading skills among participants with and without iCL/P. Data from two cross-sectional, case/control studies with similar neuropsychological batteries and diffusion tensor imaging (DTI) protocols were combined. The final sample included 210 participants (ages 7 to 27 years). Group and sex differences in fractional anisotropy (FA) values were examined between participants with (n = 105) and without (n = 105) iCL/P. Potential associations between FA values and age, cognition, and reading skills were also evaluated separately by group and sex. Sex effects were prominent in association and projection fibers, and effects of cleft status were found in association fibers and cerebellar regions, with isolated associations to reading skills. Findings provide preliminary understanding of microstructural associations to cognitive and reading performance among children, adolescents, and young adults with iCL/P.
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This study evaluated the effectiveness of academic screening measures in relation to parent-reported diagnoses.Multicenter, retrospective cohort study including structured interviews, questionnaires, and chart reviews.Six North American cleft centers.Children (n = 391) with cleft lip and/or palate, ages 8 to 10 years of age (192 male) and their guardians were recruited during regular clinic visits.Parent and child ratings on the Pediatric Quality of Life Inventory (PedsQL) School Scale, child report on CleftQ School Scale, parent report on the Adaptive Behavior Assessment System-Third Edition Functional Academics (ABAS-FA) Scale and Child Behavior Checklist (CBCL) School Competency Scale, parent interview, and medical chart review.Risk for concerns ranged from 12% to 41%, with higher risk reflected on the CBCL-SC compared to other measures. Males with cleft palate were consistently at the highest risk. Only 9% of the sample had a parent-reported diagnosis of a learning or language disability. Ratings from the ABAS-FA and CBCL-SC had the highest utility in identifying those with language and/or learning concerns.As cleft teams work to develop standardized batteries for screening and monitoring of patients, it is important to evaluate the effectiveness of measures in identifying those at highest risk. When screening for language and learning disorders, questions related to potential academic struggles, such as increased school effort or increased school distress, are most useful. Referrals for follow-up evaluation are recommended for those identified at high risk.