Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over one hundred genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate (DLO) required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date thirteen mutations in eighteen patients from fourteen families have been described with varying degrees of clinical severity. We identified and characterized thirty-nine previously unreported cases of ALG1-CDG from thirty-two families and add twenty-six new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2, was seen in all twenty-seven patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.

Objectives Caffeine (CAF) and sedative/anesthetic drugs (SADs) are often coadministered to premature infants in the neonatal intensive care unit (NICU). While SAD neurotoxicity in the developing brain is well established, it is not fully clear whether CAF interacts with SADs and whether this interaction is detrimental. Using a mouse model of prematurity, we hypothesized that CAF would increase apoptotic neurotoxicity when coadministered with SADs. Methods Postnatal day 3 mice were treated with vehicle or 80 mg/kg CAF prior to challenge with 6 mg/kg midazolam, 40 mg/kg ketamine, or 40 μg/kg fentanyl. Six hours later, pups were sacrificed for activated caspase 3 (AC3) immunohistochemistry, and number of AC3 positive cells per mm3 throughout neocortex, hippocampus, caudate, thalamus, and colliculi was analyzed. Results CAF caused a statistically significant increase in AC3 positive cells when coadministered with midazolam (p = 0.002), ketamine (p = 0.014), or fentanyl (p <0.001). Our composite dataset suggests that the addition of CAF to these SADs has a supra-additive effect, causing more neurotoxicity than expected. Conclusions CAF may augment the neurotoxic action of SADs indicated for neonatal sedation/anesthesia in the NICU by triggering widespread apoptosis in the developing brains of premature infants.

Background The AAP recommends 7 to 14-days of antimicrobials for the treatment of urinary tract infections (UTIs), one of the most common bacterial infections of childhood. However, most physicians routinely prescribe at least 10 days of therapy. Prior observational studies suggest that courses shorter than 10 days might be effective. Methods The primary objective was to determine if halting antimicrobial therapy in children who improved clinically after 5 days of therapy (short course therapy) results in a similar failure rate as children who continue antimicrobials for an additional 5 days (standard course therapy). This was a multi-center, randomized, double-blind, placebo-controlled non-inferiority clinical trial of children ages 2 to 10 years with UTI. Subjects treated with 1 of 5 antibiotics (trimethoprim-sulfamethoxazole, amoxicillin-clavulanate, cefixime, cefdinir or cephalexin) were eligible. Children were stratified by presence or absence of fever and were enrolled if they had clinical improvement before Day 5 of treatment. The a priori equivalence interval was set at 0.05 for a one-sided analysis. The primary outcome was development of a symptomatic UTI defined as the presence of symptoms, pyuria, and a positive urine culture. The Intent-to-Treat population included children who took at least one dose of study medication. Results A total of 693 children were randomized, 345 to short course and 348 to standard course. Median age was 4 years old (IQR; 2-6), 652 (96.3%) were female and 255 were febrile (37%). Treatment success rate was 322/336 (96%) for short course and 326/328 (99%) for standard course. The 95% upper CI limit for the difference was 0.054. Treatment failure was not related to age group, fever at presentation, antibiotic type, or study site. There were no significant differences between groups the in the rates of adverse events, recurrent infection, clinical symptoms that may have been related to UTI, or emergent antibiotic resistance. Conclusion In children aged 2 months to 10 years with UTI, halting antimicrobial therapy in children who had exhibited clinical improvement after 5 days and continuing for an additional 5 days both resulted in high success rates. However, short course was inferior to treatment for 10 days. Disclosures Kevin J. Downes, MD, Merck, Inc. (Grant/Research Support) Brian T. Fisher, DO, MPH, MSCE, Astellas (Advisor or Review Panel member)Merck (Grant/Research Support)Pfizer (Grant/Research Support)