Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C.

BACKGROUND: Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C. METHODS: In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo. RESULTS: A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred. CONCLUSIONS: Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.).

Motor improvement in children with PMM2-CDG syndrome following a six-month rehabilitation treatment utilising whole-body vibration; a retrospective study.

OBJECTIVE: The aim of this study was to assess the effect of a six-month interval rehabilitation treatment on motor function of children with PMM2-CDG syndrome (#212065 Congenital disorder of glycosylation, Type Ia; CDG1A, OMIM catalogue number). METHODS: The concept 'Auf die Beine' (Center for Prevention and Rehabilitation of the University of Cologne, Germany) combines two short inpatient stays (1 to 2 weeks) with a six-month whole-body vibration (WBV) home-training program. 13 patients with PMM2-CDG syndrome participated in this concept from 2006 until 2015. Assessments at start, six months and 12 months (follow-up): Gross Motor Function Measure (GMFM-66), One-Minute Walk Test (1MWT) and instrumented gait analyses. RESULTS: The GMFM-66 (9 of 13 children) improved by 5.3 (mean) points (SD 3.2) at 12 months (p=0.0039). The 1MWT (6 of 13 children) improved by 19.17 meter (SD 16.51) after 12 months (p=0.0313). Gait analysis (9 of 13 children) measured by pathlength/distance ratio improved by -0.8 (SD 1.9) at 12 months (p=0.0195). CONCLUSION: Patients with PMM2-CDG syndrome benefit from the interval rehabilitation program 'Auf die Beine' including WBV.

Referral rate and false-positive rates in a hearing screening program among high-risk newborns.

AIM: More studies exploring referral rates and false-positive rates are needed to make hearing screening programs in newborns better and cost-effective. Our aim was to study the referral and false-positivity rates among high-risk newborns in our hearing screening program and to analyze the factors potentially associated with false-positive hearing screening test results. METHODS: A retrospective cohort study was done among the newborns hospitalized at a university hospital from January 2009 to December 2014 that underwent hearing screening with a two-staged AABR screening protocol. Referral rates and false-positivity rates were calculated and possible risk factors for false-positivity were analyzed. RESULTS: 4512 newborns were screened for hearing loss in the neonatology department. The referral rate for the two-staged AABR-only screening was 3.8% with false-positivity being 2.9%. Our study showed that the higher the birthweight or gestational age of the newborn, the lower the odds of the hearing screening results being false-positive, and the higher the chronological age of the infant at the time of screening, the higher the odds of the results being false-positive. Our study did not show a clear association between the mode of delivery or gender and false-positivity. CONCLUSION: Among high-risk infants, prematurity and low-birthweight increased the rate of false-positivity in the hearing screening, and the chronological age at the time of the test seems to be significantly associated with false-positivity.

Effect of Long-Term Repeated Interval Rehabilitation on the Gross Motor Function Measure in Children with Cerebral Palsy.

BACKGROUND: The efficacy of interventions for cerebral palsy (CP) has been frequently investigated with inconclusive results and motor function measured by the Gross Motor Function Measure (GMFM-66) is common. OBJECTIVE: In this observational analysis, we quantify the GMFM-66 change scores of the second and third year of a multimodal rehabilitation program (interval rehabilitation including home-based, vibration-assisted training) in children with CP. METHODS: The study was a retrospective analysis of children with CP (2-13 years) participating for a second (n = 262) and third year (n = 86) in the rehabilitation program with GMFM-66 scores at start (M0), after 4 months (M4) of intensive training, and after 8 months of follow-up (M12). A method was previously developed to differentiate between possible treatment effects and expected development under standard of care for GMFM-66 scores using Cohen's d effect size (ES; size of difference). RESULTS: After the treatment phase of 4 months (M4) in the second year, 125 of 262 children were responder (ES ≥ 0.2) and 137 children nonresponder (ES < 0.2); mean ES for nonresponder was -0.212 (trivial) and for responder 0.836 (large). After M4 in the third year, 43 children of 86 were responder (ES = 0.881 [large]) and 43 nonresponder (ES = -0.124 [trivial]). DISCUSSION AND CONCLUSION: Repeated rehabilitation shows a large additional treatment effect to standard of care in 50% of children which is likely due to the intervention, because in the follow-up period (standard of care), no additional treatment effect was observed and the children followed their expected development.

Reference Centiles for the Evaluation of Nutritional Status in Children using Body Fat Percentage, Fat Mass and Lean Body Mass Index.

BACKGROUND: Body fat percentage (BF%), fat mass index (FMI), and lean body mass index (LBMI) are often used to evaluate the nutritional status of children. Until now, no pediatric FMI reference centiles are applicable for GE Healthcare Lunar DXA systems. The aim of the study was to generate age-specific BF%, FMI, and LBMI references centiles for GE Healthcare Lunar DXA systems. METHODOLOGY: Published values from the National Health and Nutrition Examination Survey 1999-2004 (age 8-20 years) were used to generate the reference centiles for the non-Hispanic black, non-Hispanic white, and Mexican American NHANES population. The LMS and LMSP methods were used to generate the reference centiles. RESULTS: Data of 2433 non-Hispanic black children (972 females), 2026 non-Hispanic white children (873 females), and 2547 Mexican American children (1010 females) were eligible. CONCLUSIONS: We presented age-specific reference centiles for BF%, FMI, and LBMI for children and adolescents which were ethnicity specific (non-Hispanic black, non-Hispanic white, and Mexican American) and directly applicable to Prodigy and iDXA GE Healthcare Lunar systems with software version 14.0. We proposed the use of BF%, FMI, and LBMI together to evaluate nutritional status in children.

The Appendicular Lean Mass Index Is a Suitable Surrogate for Muscle Mass in Children with Cerebral Palsy.

BACKGROUND: Densitometrically measured lean body mass (LBM) is often used to quantify skeletal muscle mass in children with cerebral palsy (CP). Since LBM depends on the individual's height, the evaluation of $\frac{{{\rm{LBM}}}}{{heigh{t^2}}}\ $ (lean BMI) is often recommended. However, LBM includes not only skeletal muscle mass but also the mass of skin, internal organs, tendons, and other components. This limitation applies to a far lesser extent to the appendicular lean mass index (LMIapp). OBJECTIVES: The aim of the study was to evaluate skeletal muscle mass in children with CP using total lean BMI (LMItot) and LMIapp. METHODS: The present study was a monocentric retrospective analysis of prospectively collected data among children and adolescents with CP participating in a rehabilitation program. In total, 329 children with CP [148 females; Gross Motor Function Classification Scale (GMFCS) I, 32 children; GMFCS II, 73 children; GMFCS III, 133 children; GMFCS IV, 78 children; and GMFCS V, 13 children] were eligible for analysis. The mean age was 12.3 ± 2.75 y. Pediatric reference centiles for age-adjusted LMIapp were generated using data from NHANES 1999-2004. Low skeletal muscle mass was defined as a z score for DXA determined LMItot and LMIapp less than or equal to -2.0. RESULTS: The z scores for LMIapp were significantly lower than LMItot in children with CP, GMFCS levels II-V (P < 0.001), with the exception of GMFCS level I (P = 0.121), where no significant difference was found. The prevalence of low LMItot (16.1%; 95% CI: 16.1, 20.1%) was significantly lower (P < 0.001) than the prevalence of LMIapp (42.2%; 95% CI: 36.9, 47.9%) in the study population. CONCLUSIONS: The prevalence of low skeletal muscle mass in children with CP might be underestimated by LMItot. LMIapp is more suitable for the evaluation of skeletal muscle mass in children with CP.

Anthropometric measurements to identify undernutrition in children with cerebral palsy.

AIM: To evaluate the diagnostic performance of anthropometric indicators to identify undernutrition in children with cerebral palsy (CP). METHOD: The present study was a monocentric retrospective analysis of prospectively collected data among children and adolescents with CP participating in a rehabilitation program. Undernutrition was defined as a z-score for dual-energy X-ray absorptiometry (DXA) determined body fat percentage less or equal to -2.0. The cut-off values for body mass index (BMI) of the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC), and the cut-off values for BMI and height for age of the Robert Koch Institut (RKI) were evaluated. RESULTS: In total, 329 children with CP (181 males, 148 females, Gross Motor Function Classification System levels I-V) were eligible for analysis. The mean age was 12 years 4 months (SD 2y 9mo). The BMI cut-off values showed the following sensitivities and specificities: WHO, sensitivity of 0.474 (95% confidence interval [CI] 0.244-0.711), specificity of 0.897 (95% CI: 0.857-0.928); CDC, sensitivity of 0.632 (95% CI: 0.384-0.837), specificity of 0.819 (95% CI: 0.772-0.861); RKI, sensitivity of 0.789 (95% CI: 0.544-0.939), specificity of 0.732 (95% CI: 0.679-0.781); and for height for age, sensitivity of 0.263 (95% CI: 0.091-0.512), specificity of 0.668 (95% CI: 0.612-0.720). INTERPRETATION: BMI had a high specificity but very low sensitivity in identifying undernutrition in children with CP. Z-scores for height for age had even lower specificity and sensitivity and seemed not to be appropriate for predicting undernutrition in children with CP. WHAT THIS PAPER ADDS: Body mass index (BMI) z-scores had a high specificity but very low sensitivity in identifying undernutrition in children with cerebral palsy (CP). Height z-scores were not appropriate for predicting undernutrition in children with CP. Undernutrition assessed by BMI was overestimated in children with CP versus when assessed by dual-energy X-ray absorptiometry (DXA).

MEDICIONES ANTROPOMÉTRICAS PARA IDENTIFICAR DESNUTRICIÓN EN NIÑOS CON PARÁLISIS CEREBRAL: OBJETIVO: Evaluar el rendimiento diagnóstico de los indicadores antropométricos para identificar la desnutrición en niños con parálisis cerebral (PC). MÉTODO: El presente estudio realizado en un solo centro de atención, fue un análisis retrospectivo de datos recopilados prospectivamente entre niños y adolescentes con PC que participan en un programa de rehabilitación. La desnutrición se definió como una puntuación z para la absorciometría de rayos X de energía dual (DXA), y porcentaje de grasa corporal determinado menor o igual a -2,0. Fueron evaluados los valores de corte para el índice de masa corporal (IMC) de la Organización Mundial de la Salud (OMS) y los Centros para el Control y la Prevención de Enfermedades (CDC), y los valores de corte para el IMC y la altura para la edad del Robert Koch Institut (RKI). RESULTADOS: En total, 329 niños con PC (181 varones, 148 mujeres, con niveles I - V del Sistema de clasificación de la función motora gruesa) fueron elegibles para el análisis. La edad media fue de 12 años 4 meses (DS 2a 9m). Los valores de corte del IMC mostraron las siguientes sensibilidades y especificidades: OMS, sensibilidad de 0,474 (intervalo de confianza del 95% [IC] 0,244-0,711), especificidad de 0,897 (IC del 95%: 0,857-0,928); CDC, sensibilidad de 0,632 (IC del 95%: 0,384 a 0,837), especificidad de 0,819 (IC del 95%: 0,772 a 0,861); RKI, sensibilidad de 0,789 (IC 95% 0,544-0,939), especificidad de 0,732 (IC 95% 0,679-0,781); y para la altura para la edad, la sensibilidad de 0,263 (IC del 95%: 0,091 a 0,512), la especificidad de 0,668 (IC del 95%: 0,612 a 0,720). INTERPRETACIÓN: El IMC tenía una alta especificidad, pero una sensibilidad muy baja para identificar la desnutrición en niños con PC. Las puntuaciones Z para la altura para la edad tenían una especificidad y sensibilidad aún más bajas y no parecían ser adecuadas para predecir la desnutrición en niños con PC.

MEDIDAS ANTROPOMÉTRICAS PARA IDENTIFICAR SUBNUTRIÇÃO EM CRIANÇAS COM PARALISIA CEREBRAL: OBJETIVO: Avaliar o desempenho diagnóstico de indicadores antropométricos para avaliar subnutrição em crianças com paralisia cerebral (PC). MÉTODO: O presente estudo foi uma análise monocêntrica retrospectiva de dados coletados prospectivamente entre crianças e adolescentes com PC que participavam de um programa de reabilitação. A subnutrição foi definida como um escore z para porcentagem de gordura corporal determinada por absorciometria de dupla energia de raio-X (DXA) menor ou igual a -2.0. Os valores de corte para o índice de massa corporal IMC) da Organização Mundial de Saúde (OMS) e dos Centros para Controle e Prevenção de Doenças (CCPD), e os valores de corte para IMC e altura por idade do Robert Koch Institut (RKI) foram avaliados. RESULTADOS: No total, 329 crianças com PC (181 do sexo masculino, 148 do sexo feminino, níveis do Sistema de Classificação da Função Motora Grossa I-V) foram elegíveis para análise. A média de idade foi 12 anos e 4 meses (DP 2a 9m). Os valores de corte do IMC mostraram as seguintes sensibilidades e especificidades: OMS, sensibilidade de 0,474 (intervalo de confiança [IC] a 95% 0,244-0,711), especificidade de 0,897 (IC 95% 0,857-0,928); CCPD, sensibilidade de 0,632 (IC 95% 0,384-0,837), especifididade de 0,819 (IC 95% 0,772-0,861); RKI, sensibilidade de 0,789 (IC 95% 0,544-0,939), especificidade de 0,732 (IC 95% 0,679-0,781); e de altura por idade, sensibilidade de 0,263 (IC 95% 0,091-0,512), especificidade de 0,668 (IC 95% 0,612-0,720). INTERPRETAÇÃO: O IMC teve alta especificidade mas sensibilidade muito baixa para identificar subnutrição em crianças com PC. Os escores z para altura por idade tiveram especificidade ainda menor e não pareceram apropriados para predizer subnutrição em crianças com PC.

Development of disorder-specific normative data for growth in children with cerebral palsy.

The purpose of this study was to create growth-percentiles for Caucasian children with cerebral palsy (CP). The studied parameters were height and age. In a retrospective analysis, we converted measurements collected in our center to create disorder-specific percentiles of normative data. Patients were stratified due to sex (male and female) and to mobility levels using the gross motor function classification system (GMFCS) (A = walking; GMFCS I-III, B = non walking; GMFCS IV-V) into four groups. In total, 2363 measurements in patients 0-18 years were collected. The mean age for group "Am" was 6.8 years (n = 862), group "Bm" 7.6 years (n = 563), group "Af" 7.7 years (n = 600), and group "Bf" 8.2 years (n = 366). The created percentiles for all groups were below the reference percentiles for healthy Caucasian children (KiGGS). The median curve for children with GMFCS levels I-III is slightly above the 3rd percentile, whereas the 50th percentile for GMFCS levels IV-V is mostly below the 3rd KiGGS centile.Conclusion: In conclusion, children with cerebral palsy are smaller than healthy children. The difference between 50th percentile of CP patients compared to healthy children supports the need for the use of disorder-specific growth charts. Those charts can help clinicians differentiate growth disorders in patients with CP. What is Known: • Children with cerebral palsy are shorter than healthy children and height is influenced by level of ambulation. • Currently, only reference percentiles of American children with mixed ethical backgrounds are available to evaluate growth. What is New: • This paper presents disorder-specific reference percentiles for longitudinal growth of Caucasian children with cerebral palsy depending on motor function. • These percentiles allow to asses longitudinal growth in children with cerebral palsy to detect other additional diseases impairing growth.

Differences in cost consciousness between physicians and nurses in German neonatal intensive care units.

AIM: This study assessed the cost consciousness of nurses and physicians in German neonatal intensive care units (NICUs) and identified factors affecting cost consciousness. METHODS: This study on cost consciousness was part of the German Safety4NICU study, a cross-sectional survey conducted from 2015 to 2016. All 224 German NICUs were invited to take part in the survey, and written consent was obtained from the leading physicians and nurses. The various professions were addressed via specific questionnaires. The cost survey tool identified the participants' responsibility and their desired focus on cost consciousness. RESULTS: Of the 1406 nurses and 496 physicians from 84 NICUs, 64.4% of the nurses and 62.5% of the physicians agreed that they shared responsibility for controlling costs. The computed score to define the overall cost consciousness level was 4.47. We identified a significantly positive association between cost consciousness, longer total clinical work experience and a decreased number of NICU intensive care beds. Increased cost consciousness was found in both men and physicians. Other hospital characteristics did not have an effect. CONCLUSION: Neonatology is a medical speciality where the tension between economics and the benefit of patients is extremely high. We found a moderate level of cost consciousness among NICU physicians and nurses.

Prevalence and risk factors for hearing loss in high-risk neonates in Germany.

AIM: Hearing loss in infants is often diagnosed late, despite universal screening programmes. Risk factors of hearing impairment in high-risk neonates, identified from population-based studies, can inform policy around targeted screening. Our aim was to determine the prevalence and the risk factors of hearing loss in a high-risk neonatal population. METHODS: This was a retrospective cohort study of neonates hospitalised at the University Hospital Cologne, Germany from January 2009 to December 2014 and were part of the newborn hearing screening programme. Multivariable regression analyses using the lasso approach was performed. RESULTS: Data were available for 4512 (43% female) neonates with a mean gestational age at birth of 35.5 weeks. The prevalence of hearing loss was 1.6%, and 42 (0.9%) neonates had permanent hearing loss. Craniofacial anomalies, hyperbilirubinaemia requiring exchange transfusion, oxygen supplementation after 36 weeks of gestation and hydrops fetalis showed associations with permanent hearing loss. CONCLUSION: Our findings of risk factors for hearing loss were consistent with other studies. However, some commonly demonstrated risk factors such as perinatal infections, meningitis, sepsis and ototoxic drugs did not show significant associations in our cohort. Targeted screening based on risk factors may help early identification of hearing loss in neonates.

Motor Function Improvement in Children with Ataxia Receiving Interval Rehabilitation, Including Vibration-Assisted Hometraining: A Retrospective Study.

BACKGROUND: Physiotherapy, including vibration-assisted therapy, has been proven to be effective for patients with ataxic cerebral palsy. Herewith, we studied the effect of a functional, goal-oriented interval rehabilitation program, including vibration-assisted home-training on the motor function of children with congenital ataxias. PATIENTS: 45 children (mean age 7.7 years, SD 4.70) with ataxia, having received a 6-month home-based side-alternating vibration-assisted therapy combined with intensive, goal-oriented, functional rehabilitation intervals, were included in the study, classified according to the progressive or non-progressive ataxia character. METHOD: Retrospective analysis of the prospectively collected data of the registry of the Cologne rehabilitation program "Auf die Beine". Motor abilities have been assessed prior to the intervention (M0), after 6 months of home-training (M6) as well as in a follow-up 6 months later (M12). We performed a gait analysis, a 1-minute walking test (1-MWT), and the Gross Motor Function Measure (GMFM-66). RESULTS: The GMFM-66 improvement (M6-M0 vs. M12-M6) was statistically significant with median improvement of 2.4 points (non-progressive) and 2.9 points (progressive) respectively, and clinically relevant. The 1-MWT improvement was statistically significant and clinically relevant for non-progressive ataxia. CONCLUSION: The intensive training, including vibration-assisted therapy significantly improved the motor function of children with ataxia. Six months later the skills were preserved in children with progressive ataxia and could be further developed in non-progressive forms.

Childhood Vaccination Against Seasonal Influenza to Reduce the Overall Burden of Disease: Ethical Perspectives.

INTRODUCTION: Childhood immunisation against seasonal influenza promises to reduce the burden of disease through herd immunity. The option of intranasal vaccination seemed to offer a more acceptable vaccination for children, as they are perceived to be less invasive. Yet, intranasal vaccines have been recently proven not to be as effective as presumed. In Germany, contradictory recommendations of the Standing Committee on Vaccination (STIKO) first, to use and then, in October 2016, not use these vaccines have been issued for the 2016-2017 season, whereas recommendations not to use them were already issued in the USA (CDC, ACIP). This controversy spurs the discussion of immunisation programmes for children again. Despite studies discussing the effectiveness of a comprehensive immunisation programme targeting children also in the German and wider European context, an accompanying ethical discussion is missing. METHODOLOGY: We discuss several policy options from different key ethical perspectives that are widely used in public health: if seasonal influenza vaccination should be intensively offered to or even made mandatory for children to decrease the societal burden of the disease. RESULTS: Various ethical perspectives reflect the question how to balance individual autonomy, personal benefit and population benefit differently. DISCUSSION: A convincing justification for suggestions on immunisation policies has to balance norms anchored in different ethical theories. There are good reasons to offer immunisation programmes against seasonal influenza to children, using a voluntary, possibly incentive-based approach.

[Vaccination ethics-a sketch of moral challenges and ethical criteria]. / Impfethik ­ Eine Skizze moralischer Herausforderungen und ethischer Kriterien.

Vaccination recommendations of public health institutes and personal decisions to get vaccinated cannot be grounded on scientific evidence alone. If and under what conditions vaccinations should take place can only be decided for concrete contexts and accompanied by justification processes applying ethical norms and values.This paper offers a normative framework for vaccination ethics. It reflects the principles and argumentation of individual and social ethics and discusses public health ethical tools available in the literature. The specific challenges of autonomous and health literate behavior from a justice perspective are examined. Also discussed is the position of the German Standing Committee on Vaccination (STIKO).

Diagnostic performance of body mass index to identify excess body fat in children with cerebral palsy.

AIM: To assess the diagnostic performance of body mass index (BMI) cut-off values according to recommendations of the World Health Organization (WHO), the World Obesity Federation (WOF), and the German Society for Adiposity (DAG) to identify excess body fat in children with cerebral palsy (CP). METHOD: The present study was a monocentric retrospective analysis of prospectively collected data among children and adolescents with CP participating in a rehabilitation programme. Excess body fat was defined as a body fat percentage above the 85th centile assessed by dual-energy X-ray absorptiometry. RESULTS: In total, 329 children (181 males, 148 females) with CP were eligible for analysis. The mean age was 12 years 4 months (standard deviation 2y 9mo). The BMI cut-off values for 'overweight' according to the WHO, WOF, and DAG showed the following sensitivities and specificities for the prediction of excess body fat in our population: WHO: sensitivity 0.768 (95% confidence interval [CI] 0.636-0.870), specificity 0.894 (95% CI 0.851-0.928); WOF: sensitivity 0.696 (95% CI 0.559-0.812), specificity 0.934 (95% CI 0.898-0.960); DAG: sensitivity 0.411 (95% CI 0.281-0.550), specificity 0.993 (95% CI 0.974-0.999). INTERPRETATION: Body mass index showed high specificity, but low sensitivity in children with CP. Thus, 'normal-weight obese' children with CP were overlooked, when assessing excess body fat only using BMI. WHAT THIS PAPER ADDS: Excess body fat in children with cerebral palsy (CP) is less common than previously reported. Body mass index (BMI) had high specificity but low sensitivity in detecting excess body fat in children with CP. BMI evaluation criteria of the German Society for Adiposity could be improved in children with CP.

The flexion withdrawal reflex increases in premature infants at 22-26 weeks of gestation due to changes in spinal cord excitability.

AIM: Our aim was to study the development of the cutaneous flexion withdrawal reflex among premature infants admitted to the neonatal intensive care unit of the Children's Hospital, University of Cologne, in 2013. METHODOLOGY: This longitudinal cohort study explored the development of spinal cord excitability of 19 premature infants born at 22-26 weeks of gestation. We performed five investigations per subject and studied changes in the reflex threshold with increasing postnatal age at different behavioural states. The premature infants were stimulated with von Frey filaments on the plantar surface of the foot near the first metatarsophalangeal joint during the first 3 days of life and at postnatal ages of 10-14 days, 21-28 days, 49-59 days and a corrected gestational age of 37-40 weeks. RESULTS: The mean gestational age of the premature infants included in the study was 24 weeks. Premature infants with a gestational age of less than 26 weeks presented a flexion withdrawal reflex with a low threshold (0.5-2.85 milli-Newton) in the first 72 hours of life. CONCLUSION: The flexion withdrawal reflex among premature infants born at less than 26 weeks showed a continuous threshold increase with increasing postnatal age, reflecting changes in spinal cord excitability.

Multivariable reference centiles for maximum grip strength in childhood to young adults.

OBJECTIVES: Maximum grip strength (mGS) is a useful predictor of health-related outcomes in children and adults. The aim of the study was to generate sex- and age-adjusted reference centiles for mGS for children, adolescents and young adults, while adjusting for body height and body mass index (BMI). METHODS: A retrospective analysis of longitudinal data from children and young adults participating in the DOrtmund Nutritional and Anthropometric Longitudinally Designed (DONALD) study (single center, open cohort study) from 2004 to 2022 was conducted. To generate sex-, age-, height- and BMI-adjusted reference centiles, a new algorithm combining multiple linear regression and the LMS method was conducted. RESULTS: Overall, 3325 measurements of mGS of 465 females and 511 males were eligible. The mean age at measurement of females was 12.6 ± 3.9 years, mean age of males was 12.4 ± 4.7 years. The median of number of repeated measurements per individual was 3 (range 1-8). The mGS was significantly (p < 0.001) correlated to body height and BMI (r = 0.303-0.432). Additional reference centiles for the change of z-scores of mGS were generated for children and young adults from 8 to 20 years. CONCLUSIONS: We proposed to evaluate mGS in children, adolescents and young adults with the presented reference centiles adjusted to sex, age, height and BMI. The method presented may also be applicable to other biological variables that depend more than just on sex and age. For the first time, also reference centiles to assess the change of mGS in repeated measurements were presented.

Assessment of the reliability, responsiveness, and meaningfulness of the scale for the assessment and rating of ataxia (SARA) for lysosomal storage disorders.

OBJECTIVE: To evaluate the reliability, responsiveness, and validity of the Scale for the Assessment and Rating of Ataxia (SARA) in patients with lysosomal storage disorders (LSDs) who present with neurological symptoms, and quantify the threshold for a clinically meaningful change. METHODS: We analyzed data from three clinical trial cohorts (IB1001-201, IB1001-202, and IB1001-301) of patients with Niemann-Pick disease type C (NPC) and GM2 Gangliosidoses (Tay-Sachs and Sandhoff disease) comprising 122 patients and 703 visits. Reproducibility was described as re-test reliability between repeat baseline visits or baseline and post-treatment washout visits. Responsiveness was determined in relation to the Investigator's, Caregiver's, and Patient's Clinical Global Impression of Improvement (CGI-I). The CGI-I data was also used to quantify a threshold for a clinically meaningful improvement on the SARA scale. Using a qualitative methods approach, patient/caregiver interviews from the IB1001-301 trial were further used to assess a threshold of meaningful change as well as the breadth of neurological signs and symptoms captured and evaluated by the SARA scale. RESULTS: The Inter-Class Correlation (ICC) was 0.95 or greater for all three trials, indicating a high internal consistency/reliability. The mean change in SARA between repeat baseline and post-treatment washout visit assessments in all trials was -0.05, SD 1.98, i.e., minimal, indicating no significant differences, learning effects or other systematic biases. For the CGI-I responses and change in SARA scores, Area Under the Curve (AUC) values were 0.82, 0.71, and 0.77 for the Investigator's, Caregiver's, and Patient's CGI-I respectively, indicating strong agreement. Further qualitative analyses of the patient/caregiver interviews demonstrated a 1-point or greater change on SARA to be a clinically meaningful improvement which is directly relevant to the patient's everyday functioning and quality of life. Changes captured by the SARA were also paralleled by improvement in a broad range of neurological signs and symptoms and beyond cerebellar ataxia. CONCLUSION: Qualitative and quantitative data demonstrate the reliability and responsiveness of the SARA score as a valid measure of neurological signs and symptoms in LSDs with CNS involvement, such as NPC and GM2 Gangliosidoses. A 1-point change represents a clinically meaningful transition reflecting the gain or loss of complex function.

Long-term efficacy and safety of nusinersen in adults with 5q spinal muscular atrophy: a prospective European multinational observational study.

Background: Evidence for the efficacy of nusinersen in adults with 5q-associated spinal muscular atrophy (SMA) has been demonstrated up to a period of 16 months in relatively large cohorts but whereas patients reach a plateau over time is still to be demonstrated. We investigated the efficacy and safety of nusinersen in adults with SMA over 38 months, the longest time period to date in a large cohort of patients from multiple clinical sites. Methods: Our prospective, observational study included adult patients with SMA from Germany, Switzerland, and Austria (July 2017 to May 2022). All participants had genetically-confirmed, 5q-associated SMA and were treated with nusinersen according to the label. The total Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores, and 6-min walk test (6 MWT; metres), were recorded at baseline and 14, 26, and 38 months after treatment initiation, and pre and post values were compared. Adverse events were also recorded. Findings: Overall, 389 patients were screened for eligibility and 237 were included. There were significant increases in all outcome measures compared with baseline, including mean HFMSE scores at 14 months (mean difference 1.72 [95% CI 1.19-2.25]), 26 months (1.20 [95% CI 0.48-1.91]), and 38 months (1.52 [95% CI 0.74-2.30]); mean RULM scores at 14 months (mean difference 0.75 [95% CI 0.43-1.07]), 26 months (mean difference 0.65 [95% CI 0.27-1.03]), and 38 months (mean difference 0.72 [95% CI 0.25-1.18]), and 6 MWT at 14 months (mean difference 30.86 m [95% CI 18.34-43.38]), 26 months (mean difference 29.26 m [95% CI 14.87-43.65]), and 38 months (mean difference 32.20 m [95% CI 10.32-54.09]). No new safety signals were identified. Interpretation: Our prospective, observational, long-term (38 months) data provides further real-world evidence for the continuous efficacy and safety of nusinersen in a large proportion of adult patients with SMA. Funding: Financial support for the registry from Biogen, Novartis and Roche.

Universal Newborn Hearing Screening Program: 10-Year Outcome and Follow-Up from a Screening Center in Germany.

Regular reporting of quality control is important in newborn hearing screening, ensuring early diagnosis and intervention. This study reports on a population-based newborn hearing screening program in North-Rhine, Germany and a hospital-based screening at a University Hospital for 2007-2016. The two-staged 'screening' and 'follow-up' program involving TEOAE and AABR recruited newborns through participating birth facilities. Results were sent to the regional tracking center, and the data were analyzed based on recommended benchmarks. The percentage of newborns from the participating birth facilities in the region increased from 1.4% in 2007 to 57.5% in 2016. The 10-year coverage rate for these newborns was 98.7%, the referral rate after a failed two-step screening was 3.4%, and the lost-to-follow-up rate was 1%. At the hospital, >95% of the screened newborns completed screening within 30 days, the 10-year referral rate was 5%, and 64% were referred within 3 months of age. The median time for screening completion was 6 days after birth, for referral it was 74 days after birth, and for diagnosis it was 55 days after birth. Regional-centralized tracking centers with uniform structure are necessary for proper quality control. Obligatory participation of birthing facilities and quality reports may improve performance, but the recommended quality criteria need considerable financial and infrastructural expenditure.

Jumping Mechanography: Reference Centiles in Childhood and Introduction of the Nerve-Muscle Index to Quantify Motor Efficiency.

Jumping mechanography provides robust motor function indicators among children. The study aim was to develop centiles for the single 2-leg jump (S2LJ) in German children and adolescents and to identify differences in children with obesity. Data were collected in 2004-2021 through the German DOrtmund Nutritional and Anthropometric Longitudinally Designed (DONALD) study. All participants (6-18 years, mean age 11.4) performed annually an S2LJ aiming for maximum height on a Ground Reaction Force Platform. LMS (lambda-mu-sigma), including resampling, was used to develop centiles for velocity (vmax), jump height (hmax), relative force (Fmax/BW), relative power (Pmax/mass), impulse asymmetry and a new parameter to describe jump efficiency, the Nerve-Muscle Index (NMI), defined as vmax/(Fmax/BW). Data from 882 children and adolescents were analyzed (3062 measurements, median 3 per individual). In females, Fmax/BW values were higher in younger age but remained constant in adolescence. vmax, hmax and Pmax/mass increased in childhood, reaching a plateau in adolescence. In males, vmax, hmax and Pmax/mass showed a constant increase and the Fmax/BW remained lower. Children with obesity showed lower Fmax/BW, hmax, vmax and the NMI, hence, lower velocity per relative force unit and less efficient jump. The centiles should be used to monitor motor development in childhood. The NMI is a surrogate for motor efficiency.