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Objective: To evaluate the trends in physical fitness in children and adolescents., Method: The present study focusses on a longitudinal analysis of the single two-legged jump (S2LJ) from children and adolescents, who participated in the DONALD study from 2004 till 2022. P max /body mass (power, surrogate for muscular performance), V max (bounce speed, surrogate for coordination), F max /body mass (force, surrogate for muscular strength) and V max F max / BM (Nerve-Muscle Index, surrogate for jump efficiency) were examined by linear mixed models and propensity-score(PS)-matching analysis., Results: Data from 1,485 measurements from males and 1,445 from females were included. Mean age was 10.9 years for males and 11.4 years for females. The range of the number of repeated S2LJ was 1 to 8, the median was 3. In PS-matching analysis, there was a dose-effect relationship between the test date and the S2LJ parameters in such a way that P max /body mass and F max /body mass decreased with more recent test dates (effect size at a difference in the test date of 1.7 decades: 0.25 - 0.3) whereby V max and V max F max / BM showed no consistent trend., Conclusion: Motor performance in children, assessed by the S2LJ, has decreased over the last two decades, mainly due to lower muscular strength, while motor efficiency and coordination seemed to be unchanged., Competing Interests: The authors have no conflict of interest.

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., (© 2024. The Author(s).)

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., (© 2023. The Author(s).)

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., Competing Interests: The authors have no conflict of interest.

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., Competing Interests: SB, ZU, MH, TK, KM, BI, JB, MTM, TB, BS, SF, CS, MTo, AG, MTue, MS, CR, PB, MFB, CK, KPS, SG, ST, JN, RS, MWeb, GW and OvV declare no conflicts of interest. RG has received personal fees from Biogen and Hoffmann-La Roche and served on advisory boards from Biogen, Hoffmann-La Roche, ITF Pharma, Zambon and research support from Biogen, outside of the submitted work. CDW has received personal fees from Biogen and Hoffmann–La Roche outside of the submitted work. AO has received speaker fees from Biogen outside of the submitted work. OSK received academic research support from the Hannover Medical School (MHH) and the German Neuromuscular Society “Deutsche Gesellschaft fuer Muskelkranke” (DGM e.V.), 2019–2021 (grant no. Sc 23/1); and received honoraria as a speaker and/or funding for travel expenses from the German Neuromuscular Society “Deutsche Gesellschaft fuer Muskelkranke (DGM e.V.), Biogen GmbH, Biermann Verlag GmbH, and MK + S—Medizin, Kommunikation & Service GmbH, outside the submitted work. SP has received speaker fees, non-financial support and research support from Biogen, Roche, AL-S Pharma, Amylyx, Cytokinetics, Ferrer, ITF-Pharma, Zambon, and Sanofi and served on advisory boards of Amylyx, Biogen, Roche, Zambon and ITF Pharma outside of the submitted work. MCW has served on advisory boards for Avexis, Biogen, Grünenthal, Novartis, Pfizer, PharNext, PTC Therapeutics, Roche, Santhera, Sarepta, Ultragenyx, Wave Sciences, received funding for Travel or Speaker Honoraria from Biogen, Novartis, PTC Therapeutics, Santhera, and worked as an ad-hoc consultant for Affinia, Audentes Therapeutics, Avexis, Biogen, BridgeBio, Edgewise, Fulcrum, Grünenthal, ML Bio, Novartis, Pfizer, PharNEXT, PTC Therapeutics, Roche. MWei has received advisory board and consultant honoraria from Biogen and Hoffmann-La Roche, and speaker honoraria and travel support for conference attendance from Biogen, outside of the submitted work. MW is a member of the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD). MF has received a speaker honorarium and non-financial support from Biogen outside the submitted work. HSL is receiving advisory fees from Biogen but has no financial or non-financial conflict of interest to declare related to the content of this manuscript. IC has received research grants and speaker fees from Biogen and Hoffmann-La Roche, outside of the submitted work. PL has received honoraria for advisory boards and consultancies from Stadapharm, Abbvie, Alexion, Bial, ITF Pharma, Desitin, Novartis, Woolsey Pharma outside the scope of this work. MD has received personal fees as speaker/consultant from Biogen and Roche, outside of the submitted work. Aha received research grants from Novartis Gene Therapies, and advisory board honoraria and speaker fees from Biogen, Roche, and Novartis. AR has received advisory board honoraria from Biogen outside of the submitted work. DZ received compensation from Biogen for participation on advisory boards, from Novartis for consultancy work, and travel compensation from Angelini Pharma outside of the submitted work. JCK has received personal fees from Biogen and Roche for advisory boards and development of educational material outside of this study. AHe has received personal fees and non-financial support from Biogen and Desitin for advisory board meetings outside the reported work. CK has received advisory board honoraria from Biogen, Roche and Ipsen Pharma, speaker honoraria from Biogen and unrestricted travel grants from Ipsen outside of the submitted work. SN has received financial support for consultancy and lecturing from Allergan, Hormosan, Lilly, Lundbeck, Novartis, Teva and Medscape, research support from Novartis, all outside of the submitted work. AM has received advisory board honoraria from Hormosan and Sanofi, outside of the submitted work. CN has received personal fees from Biogen and Hoffmann–La Roche outside of the submitted work. HCL received honoraria for speaking and advisory board engagements or academic research support Biogen. MG has received an advisory board honorarium from Hoffmann-La Roche and a speaker fee from Novartis outside of the submitted work. AP received compensation for advisory boards, training activities and research grants from Novartis and Biogen. JK received compensation for clinical research and/or consultancy activities from Biogen, Novartis, Roche and ScholarRock. GB has received research grants from PTC, advisory board honoraria and speaker fees from Biogen, Hoffmann-La Roche, Novartis, Pfizer, PTC and personal fees from Roche outside of the submitted work. PM has received honorary as an advisory board member from Biogen unrelated to this work. GMzH received compensation for serving on scientific advisory boards (Alexion, Roche, LFB) and speaker honoraria (Alexion). WL received advisory board honoraria and speaker fees from Biogen and Roche outside of the submitted work MFB has received honoraria from Biogen, Roche and Novartis as an advisory board member and for lectures from Novartis. US has received honoraria for counseling at advisory boards and invited talks for Biogen, Novartis and Roche. WMF has received compensation for scientific advisory boards for Biogen, Novartis, PTC, Sarepta, Sanofi-Aventis, Roche and Cytokinetics and received travel expenses and speaker fees from Biogen, Novartis, PTC, Roche, Sarepta and Sanofi-Aventis. HLo received support for research projects and clinical trials from Amplo Biotechnology, AMO Pharma, argenx, Biogen, Desitin, Fulcrum Therapeutics, Harmony Biosciences, KYE Pharmaceuticals, Milo Biotechnology, Novartis, Pfizer, PTC Therapeutics, Hoffman-La Roche Limited, Sanofi-Genzyme, Santhera, Sarepta, Satellos, Spark Therapeutics and Ultragenyx. HL is the Editor-in-chief for the Journal of Neuromuscular Diseases (IOS Press). CK has received compensation for lectures and advisory boards as well as research funds from Biogen, Roche and Novartis. ACL is a member of Advisory Boards of Roche Pharma AG, Biogen, Alector and Amylyx. He received compensation for talks from Biologix, the German Society of Neurology, Biogen, Springer Medicine, Amylyx and the company Streamed Up! GmbH. He is involved in trials which are sponsored by Amylyx, Ferrer International, Novartis Research and Development, Mitsubishi Tanabe, Apellis Pharmaceuticals, Alexion, Orion Pharma, the European Union, BMBF, Biogen and Orphazyme, Ionis Pharmaceuticals, QurAlis and Alector. TH has received research grants, advisory board honoraria and speaker fees from Biogen, Hoffmann-La Roche, Novartis and personal fees from Roche and Novartis outside of the submitted work., (© 2024 The Author(s).)

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.)., (Copyright © 2024 Massachusetts Medical Society.)

Background/objective: Neurofilament light chain (NfL) has been proposed as a biomarker reflecting disease severity and therapy response in children with spinal muscular atrophy type 1 and 2 (SMA1 and 2). The objective of this study was to examine how serum NfL changes after gene replacement therapy (GRT) with onasemnogene abeparvovec-xioi., Methods: We measured NfL in serum probes from 19 patients (10 SMA 1 and 6 SMA 2; 15 previously treated with nusinersen or risdiplam; 12 male) before and at variable time points after GRT. These values were related to motor scores (CHOP-Intend, HFMSE and RULM)., Results: Median age at GRT was 19 months (range 2-46 months). Median NfL of all patients before GRT was 39 pg/ml (range 0-663 pg/ml; normal values <25 pg/ml), increased significantly to 297 pg/ml (range 61-1,696 pg/ml; p<0,002) 1 month after GRT, and decreased to 49 pg/ml (range 24-151 pg/ml) after 6 months. Subjects pre-treated with nusinersen or risdiplam had lower baseline NfL levels than naïve patients (p<0,005), but absolute increases of NfL were similar in both groups. While motor scores were improved in 14 out of 18 SMA patients (78%) 6 months after GRT NfL values differed not significantly from those measured at baseline (p = 0,959)., Conclusion: Serum NfL showed a paradoxical transient increase after GRT in both, pre-treated and naïve patients, which may reflect an immunological reaction in the CNS related to transfection of neuronal cells by AAV9. The clinical meaning of this increase should be assessed in future studies. Our findings encourage regular monitoring of NfL in OA treated patients., Competing Interests: MF-B has received honoraria from Biogen, Roche and Novartis as an advisory board member and for lectures from Novartis. AH has received honoraria from Biogen, Roche and Novartis as an advisory board member and for lectures. CDW has received honoraria from Biogen as an advisory board member and for lectures and as an advisory member and consultant from Roche. She also received travel expenses from Biogen. CW has received honoraria from Biogen, Roche and Novartis as an advisory board member and for lectures. ZU has received honoraria and grants from Biogen as a consultant. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Flotats-Bastardas, Bitzan, Grell, Martakis, Winter, Zemlin, Wurster, Uzelac, Weiß and Hahn.)

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.

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., (© 2023. The Author(s).)

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 (v max ), jump height (h max ), relative force (F max /BW), relative power (P max /mass), impulse asymmetry and a new parameter to describe jump efficiency, the Nerve-Muscle Index (NMI), defined as v max /(F max /BW). Data from 882 children and adolescents were analyzed (3062 measurements, median 3 per individual). In females, F max /BW values were higher in younger age but remained constant in adolescence. v max , h max and P max /mass increased in childhood, reaching a plateau in adolescence. In males, v max , h max and P max /mass showed a constant increase and the F max /BW remained lower. Children with obesity showed lower F max /BW, h max , v max 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.

Background and Objectives: GM2 gangliosidoses (Tay-Sachs and Sandhoff diseases) are rare, autosomal recessive, neurodegenerative diseases with no available symptomatic or disease-modifying treatments. This clinical trial investigated N-acetyl-l-leucine (NALL), an orally administered, modified amino acid in pediatric (≥6 years) and adult patients with GM2 gangliosidoses., Methods: In this phase IIb, multinational, open-label, rater-blinded study (IB1001-202), male and female patients aged ≥6 years with a genetically confirmed diagnosis of GM2 gangliosidoses received orally administered NALL for a 6-week treatment period (4 g/d in patients ≥13 years, weight-tiered doses for patients 6-12 years), followed by a 6-week posttreatment washout period. For the primary Clinical Impression of Change in Severity analysis, patient performance on a predetermined primary anchor test (the 8-Meter Walk Test or the 9-Hole Peg Test) at baseline, after 6 weeks on NALL, and again after a 6-week washout period was videoed and evaluated centrally by blinded raters. Secondary outcomes included assessments of ataxia, clinical global impression, and quality of life., Results: Thirty patients between the age of 6 and 55 years were enrolled. Twenty-nine had an on-treatment assessment and were included in the primary modified intention-to-treat analysis. The study met its CI-CS primary end point (mean difference 0.71, SD = 2.09, 90% CI 0.00, 1.50, p = 0.039), as well as secondary measures of ataxia and global impression. NALL was safe and well tolerated, with no serious adverse reactions., Discussion: Treatment with NALL was associated with statistically significant and clinically relevant changes in functioning and quality of life in patients with GM2 gangliosidosis. NALL was safe and well tolerated, contributing to an overall favorable risk:benefit profile. NALL is a promising, easily administered (oral) therapeutic option for these rare, debilitating diseases with immense unmet medical needs., Trial Registration Information: The trial is registered with ClinicalTrials.gov (NCT03759665; registered on November 30, 2018), EudraCT (2018-004406-25), and DRKS (DRKS00017539). The first patient was enrolled on June 7, 2019., Classification of Evidence: This study provides Class IV evidence that NALL improves outcomes for patients with GM2 gangliosidoses., (© 2022 American Academy of Neurology.)

We explored the existence and application of standard operating procedures (SOPs) for pain management (PM) in German neonatal intensive care units (NICUs), and identified the factors associated with their application in practice. This study was part of the Safety4NICU project, a cross-sectional survey conducted from 2015 to 2016. All 224 German NICUs were invited to participate, providing written consent from the head neonatologist and head nurse. We distributed questionnaires to the head neonatologist, the head nurse, and the NICU staff (physicians and nurses). We asked the head neonatologist whether written SOPs for PM existed, and we asked the staff whether these SOPs were applied in their daily routine. We received evaluable responses from 468 physicians and 1251 nurses from 76 NICUs. Of these 76 NICUs, the head neonatologists from 54 NICUs (71.1%) reported that written SOPs for PM exist. However, only 48.5% of the physicians and 53.7% of the nurses declared that these existing SOPs were also applied. We found various predictors for the existing SOPs as being applied, depending on the profession. For physicians, clinical training was important (OR: 2.482, p  ≤ 0.05), while for nurses their working experience was a decisive predictor (OR: 1.265, p  ≤ 0.05). For both, a high level of perceived cooperative norms between physicians and nurses increased the probability that SOPs for PM were applied, whereas a high bed turnover rate decreased that probability. According to the responses from head neonatologists, written SOPs for PM were common in German NICUs. However, if management strategies on pain existed, this did not mean that these were directly applied in the daily routine. Clinical training of the staff, the promotion of adequate interprofessional cooperation, as well as allowing time to deal with these SOPs might be all essential measures to strengthen the application., Competing Interests: The authors have no conflicts of interest to declare., (© 2022 The Authors. Paediatric and Neonatal Pain published by John Wiley & Sons Ltd.)

Objective: To investigate the safety and efficacy of N-acetyl-L-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann-Pick disease type C (NPC) patients., Methods: In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients ≥ 13 years, weight-tiered doses for patients 6-12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments., Results: 33 subjects aged 7-64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75, p = 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred., Conclusions: NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC. CLINICALTRIALS., Gov Identifier: NCT03759639., (© 2021. The Author(s).)