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GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2-18 years with GRIN loss-of-function pathogenic variants received L-serine for 52 weeks. Primary end points included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life Inventory, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3 months and 1 day before starting treatment and 1, 3, 6 and 12 months after beginning the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8 years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy. Based on the Vineland Adaptive Behavior Composite standard scores, nine children were classified as mildly impaired (cut-off score > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in the Daily Living Skills domain (P = 0035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity. L-serine normalized the EEG pattern in five children and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve adaptive behaviour, motor function and quality of life, with a better response to the treatment in mild phenotypes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Importance: Handwriting legibility and speed assessments have a critical role in identifying and evaluating handwriting problems, which are common among children., Objective: The objective was to evaluate the psychometric properties and clinical utility of handwriting assessments for children ages 3 to 16 yr., Data Sources: A systematic review was conducted in CINAHL, PubMed (MEDLINE), Scopus, and education databases, with no time limits. The search strategy included a combination of the following keywords: handwriting, write, children, assessment, and validity. The exclusion criteria were assessment tools that were electronic, that focused on cognitive components of handwriting, or that only evaluated alphabets other than Latin., Study Selection and Data Collection: The systematic review was carried out on the basis of the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. The protocol was registered in the Prospective Register of Systematic Reviews (PROSPERO)., Findings: The 14 included instruments had a total sample of 4,987 children. Internal consistency ranged from moderate (.73; Writing Readiness Inventory Tool in Context) to high (.98; Letter Writing). The interexaminer reliability values of the 11 direct assessment instruments ranged from .77 (Systematic Screening for Handwriting Difficulties) to 1.00 (Handwriting Speed Test)., Conclusions and Relevance: In this systematic review, existing tools were evaluated by clinical utility and the quality of psychometric properties. Direct assessments showed good psychometric properties. Indirect and self-assessment tools demonstrated poor psychometric properties. Further research on screening tools and tools in other languages is needed. What This Article Adds: Specific learning disorders (e.g., dysgraphia) negatively affect academic learning and, when prolonged in time, self-concept. However, handwriting legibility and speed assessments could be used to identify and evaluate these learning disorders if an early referral to occupational therapy is carried out., (Copyright © 2023 by the American Occupational Therapy Association, Inc.)

One of the challenges for producing active chitinase formulations relies on the gap between the laboratory tests and the biological scenarios where the enzyme will perform its function. In this work, we have employed different Langmuir monolayer arrays to evaluate the interfacial behavior of a recently purified recombinant chitinase, Chi18-5. We have demonstrated that two conformations exist for the chitinase at pH values close to its pI, showing very distinct structural properties at the air/aqueous interface. Enzyme activity was assessed by implementing different kinetic approaches and using a chitosan-1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) mixed film as organized substrate model membrane. Combining these strategies, we demonstrated that better catalytic efficiencies can be obtained for Chi18-5 at pH 5. Moreover, the chitinase activity at the air/aqueous interface can be tuned by introducing in situ pH modifications over the surrounding milieu. We also studied the changes in the topography at the mesoscale level using Brewster Angle Microscopy (BAM). We found that Chi18-5 segregated onto the chitosan domains of the membrane, showing differences in homogeneity depending on the pH imposed. Alternatively, pure Chi18-5 was tested for immobilization onto a hydrophilic activated solid support using the Langmuir-Blodgett technique. Atomic Force Microscopy (AFM) analyses showed successfully stabilization and preservation of molecular features attributed to the pH at which the enzyme deposition was performed., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ismael D. Bianco reports financial support was provided by Universidad Nacional de la Rioja. Silvina R. Salinas reports financial support was provided by CONICET., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: We conducted research to investigate the effects of the eruption sequence of posterior teeth, arch dimensions, and incisor inclination on dental crowding., Material and Methods: A cross-sectional analytic study was performed on 100 patients (54 boys and 46 girls; mean ages: 11.69 and 11.16 years, respectively). Seq1 (canine-3-/second premolar-5-) or Seq2 (5/3) eruption sequences were recorded in maxilla, and Seq3 (canine-3-/first premolar-4-) or Seq4 (4/3) eruption sequences in mandible; tooth size, available space, tooth size-arch length discrepancy (TS-ALD), arch lengths, incisor inclination and distance, and skeletal relationship were noted., Results: The most common eruption sequences in the maxilla and mandible were Seq1 (50.6%), and Seq3 (52.1%), respectively. In the maxilla, posterior tooth sizes were larger in crowded cases. In the mandible, anterior and posterior tooth sizes were larger in crowded patients. No relationship between incisor variables and the maxillo-mandibular relationship and dental crowding was found. A negative correlation between inferior TS-ALD and the mandibular plane was found., Conclusions: Seq1 and Seq 2 in the maxilla and Seq 3 and Seq 4 in the mandible were equally prevalent. An eruption sequence of 3-5 in the maxilla and 3-4 in the mandible is more likely to cause crowding.