Development of Lower Extremity Strength in Ambulatory Children With Bilateral Spastic Cerebral Palsy in Comparison With Typically Developing Controls Using Absolute and Normalized to Body Weight Force Values

This cross-sectional study aimed to examine the development of lower limb voluntary strength in 160 ambulatory patients with bilateral spastic cerebral palsy (CP) (106 diplegics/54 quadriplegics) and 86 typically developing (TD) controls, aged 7–16 years. Handheld dynamometry was used to measure isometric strength of seven muscle groups (hip adductors and abductors, hip extensors and flexors, knee extensors and flexors, and ankle dorsiflexors); absolute force (AF) values in pounds were collected, which were then normalized to body weight (NF). AF values increased with increasing age (p < 0.001 for all muscle groups), whereas NF values decreased through adolescence (p < 0.001 for all muscle groups except for hip abduction where p = 0.022), indicating that increases in weight through adolescence led to decreases in relative force. Both AF and NF values were significantly greater in TD subjects when compared with children with CP in all muscle and all age groups (p < 0.001). Diplegics and quadriplegics demonstrated consistently lower force values than TD subjects for all muscle groups, except for the hip extensors where TD children had similar values with diplegics (p = 0.726) but higher than quadriplegics (p = 0.001). Diplegic patients also exhibited higher values than quadriplegics in all muscles, except for the knee extensors where their difference was only indicative (p = 0.056). The conversion of CP subjects' force values as a percentage of the TD subjects' mean value revealed a pattern of significant muscle strength imbalance between the CP antagonist muscles, documented from the following deficit differences for the CP muscle couples: (hip extensors 13%) / (hip flexors 32%), (adductors 27%) / (abductors 52%), and (knee extensors 37%) / (knee flexors 53%). This pattern was evident in all age groups. Similarly, significant force deficiencies were identified in GMFCS III/IV patients when compared with TD children and GMFCS I/II patients. In this study, we demonstrated that children and adolescents with bilateral CP exhibited lower strength values in lower limb muscles when compared with their TD counterparts. This difference was more prevalent in quadriplegic patients and those with a more severe impairment. An important pattern of muscle strength imbalance between the antagonist muscles of the CP subjects was revealed. © Copyright © 2021 Darras, Nikaina, Tziomaki, Gkrimas, Papavasiliou and Pasparakis

Whole Exome Sequencing Points towards a Multi-Gene Synergistic Action in the Pathogenesis of Congenital Combined Pituitary Hormone Deficiency

Combined pituitary hormone deficiency (CPHD) is characterized by deficiency of growth hormone and at least one other pituitary hormone. Pathogenic variants in more than 30 genes expressed during the development of the head, hypothalamus, and/or pituitary have been identified so far to cause genetic forms of CPHD. However, the etiology of around 85% of the cases remains unknown. The aim of this study was to unveil the genetic etiology of CPHD due to congenital hypopituitarism employing whole exome sequencing (WES) in two newborn patients, initially tested and found to be negative for PROP1, LHX3, LHX4 and HESX1 pathogenic variants by Sanger sequencing and for copy number variations by MLPA. In this study, the application of WES in these CPHD newborns revealed the presence of three different heterozygous gene variants in each patient. Specifically in patient 1, the variants BMP4; p.Ala42Pro, GNRH1; p.Arg73Ter and SRA1; p.Gln32Glu, and in patient 2, the SOX9; p.Val95Ile, HS6ST1; p.Arg306Gln, and IL17RD; p.Pro566Ser were identified as candidate gene variants. These findings further support the hypothesis that CPHD constitutes an oligogenic rather than a monogenic disease and that there is a genetic overlap between CPHD and congenital hypogonadotropic hypogonadism. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

Moderately and Late Preterm Infants: Short- and Long-Term Outcomes From a Registry-Based Cohort

Background: While most studies on the association of preterm birth and cerebral palsy (CP) have focused on very preterm infants, lately, attention has been paid to moderately preterm [32 to <34 weeks gestational age (GA)] and late preterm infants (34 to <37 weeks GA). Methods: In order to report on the outcomes of a cohort of moderately and late preterm infants, derived from a population-based CP Registry, a comparative analysis of data on 95 moderately preterm infants and 96 late preterm infants out of 1,016 with CP, was performed. Results: Moderately preterm neonates with CP were more likely to have a history of N-ICU admission (p = 0.001) and require respiratory support (p < 0.001) than late preterm neonates. Birth weight was significantly related to early neonatal outcome with children with lower birth weight being more likely to have a history of N-ICU admission [moderately preterm infants (p = 0.006)/late preterm infants (p < 0.001)], to require ventilator support [moderately preterm infants (p = 0.025)/late preterm infants (p = 0.014)] and not to have neonatal seizures [moderately preterm infants (p = 0.044)/late preterm infants (p = 0.263)]. In both subgroups, the majority of children had bilateral spastic CP with moderately preterm infants being more likely to have bilateral spastic CP and less likely to have ataxic CP as compared to late preterm infants (p = 0.006). The prevailing imaging findings were white matter lesions in both subgroups, with statistically significant difference between moderately preterm infants who required ventilator support and mainly presented with this type of lesion vs. those who did not and presented with gray matter lesions, maldevelopments or miscellaneous findings. Gross motor function was also assessed in both subgroups without significant difference. Among late preterm infants, those who needed N-ICU admission and ventilator support as neonates achieved worse fine motor outcomes than those who did not. Conclusions: Low birth weight is associated with early neonatal problems in both moderately and late preterm infants with CP. The majority of children had bilateral spastic CP and white matter lesions in neuroimaging. GMFCS levels were comparable in both subgroups while BFMF was worse in late preterm infants with a history of N-ICU admission and ventilator support. © Copyright © 2021 Smyrni, Koutsaki, Petra, Nikaina, Gontika, Strataki, Davora, Bouza, Damianos, Skouteli, Mastroyianni, Dalivigka, Dinopoulos, Tzaki and Papavasiliou

Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial

Background: Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms. Methods: NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was −10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov (NCT02790996). Findings: Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference −7% [95% CI −15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group). Interpretation: In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants. Funding: EU Seventh Framework Programme for research, technological development and demonstration