N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study.

BACKGROUND: Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded phase IIb clinical trial. Here, we describe the development of a study protocol (Sponsor Code "IB1001-301") for the chronic treatment of symptoms in adult and pediatric patients with NPC. METHODS: This multinational double-blind randomized placebo-controlled crossover phase III study will enroll patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites. Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments. DISCUSSION: Pre-clinical as well as observational and phase IIb clinical trials have previously demonstrated that IB1001 rapidly improved symptoms, functioning, and quality of life for pediatric and adult NPC patients and is safe and well tolerated. In this placebo-controlled cross-over trial, the risk/benefit profile of IB1001 for NPC will be evaluated. It will also give information about the applicability of IB1001 as a therapeutic paradigm for other rare and common neurological disorders. TRIAL REGISTRATIONS: The trial (IB1001-301) has been registered at www. CLINICALTRIALS: gov (NCT05163288) and www.clinicaltrialsregister.eu (EudraCT: 2021-005356-10). Registered on 20 December 2021.

Interaction of body fat percentage and height with appendicular functional muscle-bone unit.

The interaction of body fat percentage and height with appendicular BMC for LBM was analyzed. Only body fat had significant negative correlation with the appendicular BMC for LBM. PURPOSE/INTRODUCTION: For the clinical evaluation of the functional muscle-bone unit, it was proposed to evaluate the adaptation of the bone to the acting forces. A frequently used parameter for this is the total body less head bone mineral content (TBLH-BMC) determined by dual-energy X-ray absorptiometry (DXA) in relation to the total body lean body mass (LBM). Body fat percentage seemed to correlate negatively and height positively with TBLH-BMC for LBM. It was supposed that appendicular BMC for LBM is a more accurate surrogate for the functional muscle-bone unit since appendicular LBM does not incorporate the mass of internal organs. The aim of this study was to analyze the interaction of body fat percentage and height with appendicular BMC for LBM. METHODS: As part of the National Health and Nutrition Examination Survey (NHANES) study, between the years 1999 and 2004, whole-body DXA scans on randomly selected Americans from 8 years of age were carried out. From all eligible DXA scans, three major US ethnic groups were evaluated (non-Hispanic Whites, non-Hispanic Blacks, and Mexican Americans) for further statistical analysis. RESULTS: For the statistical analysis, the DXA scans of 8190 non-Hispanic White children and adults (3903 female), of 4931 non-Hispanic Black children and adults (2250 female), and 5421 of Mexican American children and adults (2424 female) were eligible. Only body fat had a significant negative correlation with the appendicular BMC for LBM. CONCLUSIONS: Only body fat had significant negative correlation with appendicular BMC for LBM, and thus, should be addressed when evaluating functional muscle-bone unit.

Individualized evaluation of lumbar bone mineral density in children with cerebral palsy.

Lumbar spine bone mineral density (LS-BMD) assessed by dual-energy X-ray absorptiometry (DXA) is used in children with cerebral palsy (CP) to evaluate bone health. LS-BMD results in children with CP are influenced significantly by their height, BMI, and mobility level. An adjustment for these parameters might improve the clinical significance of the method. PURPOSE/INTRODUCTION: DXA evaluation is considered useful in children with CP to assess bone health. For this purpose, LS-BMD is often used. The aim of the study was to estimate the effect of height, BMI, and reduced mobility level of children with CP on LS-BMD and to develop a method to adjust individual results of LS-BMD for these factors. METHODS: We conducted a monocentric retrospective analysis of data collected in children and adolescents with CP, who participated in a rehabilitation program and had no history of recurrent fractures. The DXA scan was part of the routine examination for participants older than 4 years of age. The relationship between height and BMI for age Z-scores and age-adjusted LS-BMD Z-scores was analyzed. RESULTS: LS-DXA scans of 500 children and adolescents with CP (Gross Motor Function Classification System levels I-V) were included in the statistical analysis (217 female). The mean age was 9.4 years (± 3.7 years). Children with moderate to severe CP had significantly (p < 0.001) lower LS-BMD Z-scores than children with mild CP. We provided nomograms to adjust individual LS-BMD results to their height, BMI, and mobility level. CONCLUSIONS: LS-BMD results in children with CP were influenced significantly by their height, BMI, and mobility level. An adjustment of the LS-BMD results to height, BMI, and mobility level might improve the clinical significance of an individual result.

Individualized evaluation of lumbar bone mineral density and bone mineral apparent density in children and adolescents.

Lumbar spine bone mineral density (LS-BMD) assessed by dual-energy X-ray absorptiometry (DXA) is used in children to evaluate bone health. LS-BMD results in children are influenced significantly by height and BMI. An adjustment for these parameters may improve the clinical use of the method. PURPOSE/INTRODUCTION: DXA evaluation is considered useful in children to assess bone health. For this purpose, lumbar spine bone mineral density (LS-BMD) and bone mineral apparent density (LS-BMAD) are often used. The aim of the study was to estimate the effect of height and BMI on LS-BMD and LS-BMAD in children and adolescents and to develop a method to adjust individual results for these factors. METHODS: As part of the National Health and Nutrition Examination Survey (NHANES) study, between the years 2005 and 2010 lumbar DXA scans on randomly selected Americans from 8 to 20 years of age were carried out. From all eligible DXA scans, three major US ethnic groups were evaluated (Non-Hispanic Whites, Non-Hispanic Blacks, and Mexican Americans) for further statistical analysis. The relationship between height as well as BMI for age Z-scores and age-adjusted LS-BMD and LS-BMAD Z-scores was analyzed. RESULTS: For the statistical analysis, the DXA scans of 1799 non-Hispanic White children (823 females), of 1696 non-Hispanic Black children (817 females), and of 1839 Mexican American children (884 females) were eligible. The statistical analysis showed that taller and heavier children had significantly (p < 0.001) higher age-adjusted LS-BMD Z-scores than shorter and lighter children. But on LS-BMAD, only BMI and not height had a significant influence. CONCLUSIONS: LS-BMD results in children were influenced significantly by their height and BMI, the LS-BMAD results were only influenced by their BMI. For the first time, the proposed method adjusts LS-BMD and LS-BMAD to BMI. An adjustment of the LS-BMD and LS-BMAD results to these factors might improve the clinical significance of an individual result.

Are there effects of age, gender, height, and body fat on the functional muscle-bone unit in children and adults?

The aim was to describe the effect of age, gender, height, different stages of human life, and body fat on the functional muscle-bone unit. All these factors had a significant effect on the functional muscle-bone unit and should be addressed when assessing functional muscle-bone unit in children and adults. INTRODUCTION: For the clinical evaluation of the functional muscle-bone unit, it was proposed to evaluate the adaptation of the bone to the acting forces. A frequently used parameter for this is the total body less head bone mineral content (TBLH-BMC) determined by dual-energy X-ray absorptiometry (DXA) in relation to the lean body mass (LBM by DXA). LBM correlates highly with muscle mass. Therefore, LBM is a surrogate parameter for the muscular forces acting in everyday life. The aim of the study was to describe the effect of age and gender on the TBLH-BMC for LBM and to evaluate the impact of other factors, such as height, different stages of human life, and of body fat. METHODS: As part of the National Health and Nutrition Examination Survey (NHANES) study, between the years 1999-2006 whole-body DXA scans on randomly selected Americans from 8 years of age were carried out. From all eligible DXA scans (1999-2004), three major US ethnic groups were evaluated (non-Hispanic Whites, non-Hispanic Blacks, and Mexican Americans) for further statistical analysis. RESULTS: For the statistical analysis, the DXA scans of 8190 non-Hispanic White children and adults (3903 female), of 4931 non-Hispanic Black children and adults (2250 female) and 5421 of Mexican-American children and adults (2424 female) were eligible. Age, gender, body height, and especially body fat had a significant effect on the functional muscle-bone unit. CONCLUSIONS: When assessing TBLH-BMC for LBM in children and adults, the effects of age, gender, body fat, and body height should be addressed. These effects were analyzed for the first time in such a large cohort.

Experience with jumping mechanography in children with cerebral palsy.

OBJECTIVES: Jumping mechanography provides robust motor function indicators among healthy children. The aim of the study was to assess the reproducibility and validity of jumping mechanography conducted as single two-legged jump (S2LJ) in children with cerebral palsy (CP). METHODS: 215 S2LJ investigations from a sample of 75 children with CP were eligible for evaluation. For the estimation of the reproducibility, only the baseline set of data per patient were used. Gross motor function was evaluated by the Gross Motor Function Measure (GMFM-66). In 135 S2LJ investigations, GMFM-66 was assessed within a week in the same child. This data was used for validity assessment. RESULTS: Coefficients of variation for the main outcome parameters ranged between 6.15-9.71%, except for jump height (CV%=27.3%). The intraclass correlation coefficients for peak velocity (Vmax) and peak power relative to body weight (Pmax/mass) was 0.927 and 0.931. Vmax and Pmax/mass were also the test parameters with the strongest correlation to the GMFM-66 score (⟩0.7). CONCLUSIONS: S2LJ assessed in the present study provided reproducible outcome measures particularly for Vmax and Pmax/mass in children with CP. Further, Vmax and Pmax/mass showed the strongest correlation with the GMFM-66 score and seem to be the most relevant evaluation criteria.

Teaching Ethics to Pediatric Residents: A Literature Analysis and Synthesis.

BACKGROUND: Ethics education rarely exists in pediatric resident curricula, although ethical conflicts are common in the clinical practice. Ethics education can prepare residents to successfully handle these conflicts. AIM: We searched for methods in teaching ethics to clinical and especially pediatric residents, and identified recurring barriers to ethics teaching and solutions to overcome them. DESIGN: Literature from 4 electronic databases with peer-reviewed articles was screened in 3 phases and analyzed. The literature included papers referring to applied methods or recommendations to teaching ethics to clinical residents, and on a second level focusing especially on pediatrics. An analysis and critical appraisal was conducted. RESULTS: 3 231 articles were identified. 96 papers were included. The applied learning theory, the reported teaching approaches, the barriers to teaching ethics and the provided solutions were studied and analyzed. CONCLUSIONS: We recommend case-based ethics education, including lectures, discussion, individual study; regular teaching sessions in groups, under supervision; affiliation to an ethics department, institutional and departmental support; ethics rounds and consultations not as core teaching activity; recurring problems to teaching ethics, primarily deriving from the complexity of residential duties to be addressed in advance; teaching ethics preferably in the first years of residency. We may be cautious generalizing the implementation of results on populations with different cultural backgrounds.