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In a randomized, open-label phase 3 study of 61 children aged 1-12 years old with X-linked hypophosphatemia (XLH) previously treated with conventional therapy, changing to burosumab every 2 weeks (Q2W) for 64 weeks improved the phosphate metabolism, radiographic rickets, and growth compared with conventional therapy. In this open-label extension period (weeks 64-88), 21 children continued burosumab Q2W at the previous dose or crossed over from conventional therapy to burosumab starting at 0.8 mg/kg Q2W with continued clinical radiographic assessments through week 88. Efficacy endpoints and safety observations were summarized descriptively for both groups (burosumab continuation, n = 6; crossover, n = 15). At week 88 compared with baseline, improvements in the following outcomes were observed in the burosumab continuation and crossover groups, respectively: mean (SD) RGI-C rickets total score (primary outcome), +2.11 (0.27) and +1.89 (0.35); mean (SD) RGI-C lower limb deformity score, +1.61 (0.91) and +0.73 (0.82); and mean (SD) height Z-score + 0.41 (0.50) and +0.08 (0.34). Phosphate metabolism normalized rapidly in the crossover group and persisted in the continuation group. Mean (SD) serum alkaline phosphatase decreased from 169% (43%) of the upper limit of normal (ULN) at baseline to 126% (51%) at week 88 in the continuation group and from 157% (33%) of the ULN at baseline to 111% (23%) at week 88 in the crossover group. During the extension period, treatment-emergent adverse events (AEs) were reported in all 6 children in the burosumab continuation group and 14/15 children in the crossover group. The AE profiles in the randomized and extension periods were similar, with no new safety signals identified. Improvements from baseline in radiographic rickets continued in the extension period among children with XLH who remained on burosumab. Children who crossed over from conventional therapy to burosumab demonstrated a rapid improvement in phosphate metabolism and i, This study was sponsored and funded by Ultragenyx Pharmaceutical Inc. in partnership with Kyowa Kirin International plc. Medical writing support was provided by Ben Scott, PhD (Scott Medical Communications, LLC) and was funded by Ultragenyx Pharmaceutical Inc. Additional editorial support was provided by Jamie Ziobro, an employee and share holder of Ultragenyx Pharmaceutical Inc. At Indiana University, the research was done at the Indiana Clinical and Translational Sciences Institute, funded in part by UL1TR002529 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical, and Translational Sciences Award. In Montreal and St. Louis, the work was also supported by the Shriners of North America. Dr. Ward is supported by a Tier 1 (Senior) Research Chair in Pediatric Bone Disorders from the University of Ottawa and Children's Hospital of Eastern Ontario Research Institute.

Plain Language Summary: Nearly synchronous global changes in geomagnetic polarity give both a detailed irregular pacing to geological time and provide a glimpse into heat transfer processes across the core—mantle boundary which drives the Earth's geodynamo. Although the Late Carboniferous is characterized by some well‐studied reversals, details of the tempo of polarity changes in the Early Carboniferous are unknown. This work addresses this by providing a detailed record of polarity changes over a ∼2 million year interval at around 334.5–332.5 million years ago‐from the Trowbarrow Quarry section in NW England. We demonstrate that these limestones likely preserve magnetization from close to their time of formation and record at least 31 polarity reversals. These observations support the idea that the Earth's dynamo was in a hyperactive reversing state similar to those sustained for tens of Myr in the Late Jurassic, parts of the Cambrian and the Late Ediacaran. It further corroborates a ∼200 Myr cyclicity in paleomagnetic field behavior since the Precambrian, potentially linked to variable core heat flow forced by mantle convection.

PURPOSE: In an open label, randomized, controlled, phase 3 trial in 61 children 1 to 12 years old with X-linked hypophosphatemia (XLH), burosumab improved rickets versus continuing conventional therapy with active vitamin D and phosphate. Here, we conducted an analysis to determine whether skeletal responses differed when switching to burosumab versus continuing higher or lower doses of conventional therapy. METHODS: Conventional therapy dose groups were defined as: higher dose phosphate >40 mg/kg [HPi], lower dose phosphate ≤40 mg/kg [LPi], higher dose alfacalcidol >60 ng/kg or calcitriol >30 ng/kg [HD], and lower dose alfacalcidol ≤60 ng/kg or calcitriol ≤30 ng/kg [LD]. RESULTS: At Week 64, the Radiographic Global Impression of Change (RGI-C) for rickets was higher (better) in children randomized to burosumab versus conventional therapy for all pre-baseline dose groups: HPi (+1.72 versus +0.67), LPi (+2.14 versus +1.08), HD (+1.90 versus +0.94), LD (+2.11 versus +1.06). At Week 64, the RGI-C for rickets was also higher in children randomized to burosumab (+2.06) versus conventional therapy for all on-study dose groups: HPi (+1.03), LPi (+1.05), HD (+1.45), LD (+0.72). Serum alkaline phosphatase also decreased in the burosumab treated patients more than in the conventional therapy group, regardless of on-study phosphate and active vitamin D doses. MAIN CONCLUSIONS: Prior phosphate or active vitamin D doses did not influence treatment response after switching to burosumab among children with XLH and active radiographic rickets. Switching from conventional therapy to burosumab improved rickets and serum alkaline phosphatase more than continuing either higher or lower doses of phosphate or active vitamin D.

In a randomized open-label phase 3 trial in 62 children (1–12 years) with X-linked hypophosphatemia (XLH) (NCT 02915705), switching from conventional therapy (oral phosphate plus active vitamin D) to burosumab, a monoclonal antibody targeting fibroblast growth factor 23, significantly improved serum phosphate concentration, rickets, lower-extremity deformities, growth, mobility, and patient-reported outcomes (PROs) at 64 weeks. Children in Europe, USA, Canada, and Australia who completed 64 weeks’ treatment could continue to receive burosumab in the extension period (burosumab continuation group) or cross over from conventional therapy to burosumab (crossover group) to 124 weeks. A Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire was used in children aged ≥5 years to measure Pain Interference, Physical Function Mobility, and Fatigue; health-related quality of life was measured using the SF-10 Health Survey for Children (n=35). Here, we describe changes in PROs from baseline to weeks 64 and 88, and report whether the 3-point minimal important difference (MID) was reached for PROMIS domains (Thissen et al., 2016; PMID 26118768). The mean change from baseline exceeded the MID for Pain Interference at weeks 64 and 88 and for Fatigue at week 64 in the burosumab continuation group, and for Pain Interference and Fatigue at week 88 in the crossover group. Similar improvements in SF-10 Physical Health were seen baseline to week 64 in the burosumab continuation group, and week 64 to 88 in the cross-over group. SF-10 Psychosocial Health changed little in either group at the two timepoints. Treatment with burosumab improved Pain Interference and Fatigue beyond the MID in children with XLH who switched from conventional therapy to receive 24 weeks of burosumab. Improvements were also maintained in children who received an additional 24 weeks’ burosumab treatment.

Changing to burosumab, a monoclonal antibody targeting fibroblast growth factor 23, significantly improved phosphorus homeostasis, rickets, lower-extremity deformities, mobility, and growth versus continuing oral phosphate and active vitamin D (conventional therapy) in a randomized, open-label, phase 3 trial involving children aged 1-12 years with X-linked hypophosphatemia. Patients were randomized (1:1) to subcutaneous burosumab or to continue conventional therapy. We present patient-reported outcomes (PROs) from this trial for children aged ≥ 5 years at screening (n = 35), using a Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire and SF-10 Health Survey for Children. PROMIS pain interference, physical function mobility, and fatigue scores improved from baseline with burosumab at weeks 40 and 64, but changed little with continued conventional therapy. Pain interference scores differed significantly between groups at week 40 (- 5.02, 95% CI - 9.29 to - 0.75; p = 0.0212) but not at week 64. Between-group differences were not significant at either week for physical function mobility or fatigue. Reductions in PROMIS pain interference and fatigue scores from baseline were clinically meaningful with burosumab at weeks 40 and 64 but not with conventional therapy. SF-10 physical health scores (PHS-10) improved significantly with burosumab at week 40 (least-squares mean [standard error] + 5.98 [1.79]; p = 0.0008) and week 64 (+ 5.93 [1.88]; p = 0.0016) but not with conventional therapy (between-treatment differences were nonsignificant). In conclusion, changing to burosumab improved PRO measures, with statistically significant differences in PROMIS pain interference at week 40 versus continuing with conventional therapy and in PHS-10 at weeks 40 and 64 versus baseline., Funding Agency:Kyowa Kirin International

Bilateral basal ganglia abnormalities on MRI are observed in a wide variety of childhood disorders. MRI pattern recognition can enable rationalization of investigations and also complement clinical and molecular findings, particularly confirming genomic findings and also enabling new gene discovery. A pattern recognition approach in children with bilateral basal ganglia abnormalities on brain MRI was undertaken in this international multicentre cohort study. Three hundred and five MRI scans belonging to 201 children with 34 different disorders were rated using a standard radiological scoring proforma. In addition, literature review on MRI patterns was undertaken in these 34 disorders and 59 additional disorders reported with bilateral basal ganglia MRI abnormalities. Cluster analysis on first MRI findings from the study cohort grouped them into four clusters: Cluster 1-T-weighted hyperintensities in the putamen; Cluster 2-T-weighted hyperintensities or increased MRI susceptibility in the globus pallidus; Cluster 3-T-weighted hyperintensities in the globus pallidus, brainstem and cerebellum with diffusion restriction; Cluster 4-T-weighted hyperintensities in the basal ganglia. The 34 diagnostic categories included in this study showed dominant clustering in one of the above four clusters. Inflammatory disorders grouped together in Cluster 1. Mitochondrial and other neurometabolic disorders were distributed across clusters 1, 2 and 3, according to lesions dominantly affecting the striatum (Cluster 1: glutaric aciduria type 1, propionic acidaemia, 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome and thiamine responsive basal ganglia disease associated with SLC19A3), pallidum (Cluster 2: methylmalonic acidaemia, Kearns Sayre syndrome, pyruvate dehydrogenase complex deficiency and succinic semialdehyde dehydrogenase deficiency) or pallidum, brainstem and cerebellum (Cluster 3: vigabatrin toxicity, Krabbe disease). The Cluster 4 pattern wa

info:eu-repo/semantics/published

Background: X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia. Methods: In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2.0, fasting serum phosphorus lower than 0.97 mmol/L (3.0 mg/dL), confirmed PHEX (phosphate-regulating endopep-tidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1: 1) to receive either subcutaneous burosumab starting at 0.8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705. Findings: Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoin, Funding Agencies:Ultragenyx Pharmaceutical Kyowa Kirin International