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The Fisher distribution is central to palaeomagnetism but presents several problems when used to characterize geomagnetic field directions as observed in sequences of volcanic rocks. First, it introduces a shallowing effect when used to define the mean of any group of directional unit vectors. This is problematic because it can suggest the presence of persistent non-axial dipole components when none are present. More importantly, it fails to capture the observed 'long tail' in distributions of both directions and associated virtual geomagnetic poles in terms of angular distance from a central direction. To achieve a good fit to data, it therefore requires the introduction of a second distribution (and therefore the estimation of additional parameters) or the arbitrary removal of data. Here we present a new distribution to describe palaeomagnetic directions and demonstrate that it overcomes both of these problems, generating robust indicators of both the central direction (or pole position) and the spread of palaeomagnetic data as defined by unit vectors. Starting from the assumption that poles (or directions) have an expected colatitude, rather than a mean location, we derive the spherical exponential distribution. We demonstrate that this new distribution provides a good fit to palaeomagnetic data sets from seven large igneous provinces between 15 and 65 Ma and also those produced by numerical dynamo models. We also use it to derive a new shape parameter which may be used as a diagnostic tool for testing goodness of fit of models to data and use this to argue for a shift in geomagnetic behaviour between 5 and 15 Ma. Furthermore, we point out that this new statistic can be used to determine the most appropriate distribution to be used when constructing confidence limits for poles. [ABSTRACT FROM AUTHOR]

Background/Aims: Intravenous bisphosphonate therapy is the mainstay of medical treatment in osteogenesis imperfecta (OI) and has been shown to increase bone mass, decrease bone pain, improve mobility, and reduce the incidence of fractures. Sclerotic metaphyseal lines parallel to the growth plate are seen on long bone radiographs following cyclical intravenous therapy. These areas create stress risers within the bone that may act as foci for subsequent fractures as exemplified in this clinical case. Methods: An 8-year-old girl with OI sustained a distal radial fracture following 3 years of treatment with 6-monthly intravenous zoledronate. Her diagnosis, response to treatment, and subsequent fracture at a sclerotic metaphyseal line is described. Results: Peripheral quantitative computer tomography was used to characterise the presence of multiple stress risers at the distal forearm. Trabecular bone mineral density fluctuated from 34 to 126% compared to neighbouring 2-mm regions. Conclusion: There remain many unanswered questions about optimal bisphosphonate treatment regimens in children with OI. The formation of stress risers following intravenous bisphosphonate treatment raises the hypothesis that a more frequent and low-dose bisphosphonate regimen would provide more uniform dosing of bone in the growing child and reduce the likelihood of fractures compared to current treatment practices. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Dykes form key pathways for the transport and emplacement of magma within the crust. We have identified syn - and post-emplacement processes recorded across a ~2 m thick basaltic dyke on the Isle of Skye, Scotland. We measured the rock magnetic properties, anisotropy of magnetic susceptibility (AMS) and anisotropy of anhysteretic magnetisation (AARM) across two dyke-thickness profiles spaced 13 m apart along the dyke strike (sites G5 and G6). At 20–25 cm intervals, our samples are very closely spaced compared to standard sampling protocols. Our results show that the dyke's magnetic fabrics originate from two mineral groups: titanomagnetite, which is abundant in the central dyke region at site G5, and iron sulphides (pyrite and pyrrhotite) that dominates the margin regions at both sites. The titanomagnetite occurs in unaltered dyke rock; its magnetic fabrics are primary, having formed during magma solidification, and record lateral magma flow. The pyrrhotite occurs in jointed and hydrothermally altered dyke rock; its petrological and magnetic fabrics are secondary, having originated from a sulphide-rich fluid which infiltrated cooling joints oriented perpendicular to the dyke margins and locally modified the primary magnetic fabrics. At site G6, pyrrhotite also occurs in the dyke centre, suggesting that locally the post-emplacement sulphide-rich fluid permeated into this region; this site is located close to a branch in the dyke and has increased joint frequency, which could explain the enhanced alteration. The presence of syn - (primary) and post-emplacement (secondary) fabrics was only identified due to our high frequency sampling regime and use of both AMS and AARM techniques. We highlight that future magnetic anisotropy studies of dykes may benefit from high sample frequency combined with sampling along-strike and across-thickness. Using both AMS and AARM techniques to detect more variations in magnetic fabrics can reveal more complete syn - and post-emplacement dyke histories. • AMS and AARM can decipher multiple emplacement and solidification stages in dykes. • Margin regions are more susceptible to post emplacement hydrothermal fluids. • Neglected dyke core regions can be used for magma flow directions. • Magnetic and crystal fabrics are variable across dyke thicknesses and strikes. • Different regions of intrusions preserve different parts emplacement history. [ABSTRACT FROM AUTHOR]

The South Atlantic Anomaly (SAA) is an area of geomagnetic weakness that represents the most significant anomaly in the present‐day field. Notwithstanding anomalies such as these, a long‐lived hypothesis is that, if averaged over sufficient time (104–106 years), the Earth's magnetic field approximates a geocentric axial dipole (GAD). The question of how significant the non‐GAD features are in the time‐averaged field is an important and unresolved one. The SAA has not always been visible in the historic and paleo‐field models; yet an unstable field was reported in the South Atlantic region on a multimillion‐year timescale. This study presents the first paleointensity study from Saint Helena, a volcanic island in the South Atlantic consisting primarily of lavas emplaced between 10 and 8 Ma. While paleointensity success rates were low, we were able to recover results from five independent lavas that together suggest a low field intensity of 10.5 ± 3.0 μT corresponding to a virtual axial dipole moment (VADM) of 2.4 ± 0.7 × 1022 A m2. These low paleointensity estimates suggest a field in the South Atlantic that was not only unstable in directions, but also substantially weaker than expected. We consider this to constitute further evidence that the SAA is not a single occurrence but rather, the latest in a series of recurring weaknesses in the field in this region, probably caused by Reversed Flux Patches on the Core Mantle Boundary. Plain Language Summary: The Earth's magnetic field is created by liquid iron convecting within the outer core. This field is highly variable. In the South Atlantic region, there is a large patch where the field is less strong than expected, causing us and our technology to be less protected against solar radiation. In that region lies Saint Helena, a volcanic island from which we collected samples that we used for paleomagnetic analysis. We performed experiments to derive the intensity of the field at that location when the rocks formed, which was 10–8 million years ago. Our results show that the magnetic field of Saint Helena was very weak during that interval suggesting that the modern irregular weak patch has been a recurring irregularity on a multimillion‐year timescale. This suggests that the weakness is most likely linked to heterogeneities in the lowermost mantle, which interfere with convective flow in the outer core. Key Points: The first paleointensity results from Saint Helena suggest a low field in the South Atlantic between 10 and 8 MaLow paleointensity estimates provide further support of recurring anomalous behavior caused by reverse flux patches under AfricaResults from successful Ar/Ar experiments show that the Saint Helena volcanoes were active between 10 and 8 Ma [ABSTRACT FROM AUTHOR]

TheMesozoic Dipole Low (MDL) is a period, covering at least ~80 My, of low dipole moment that ended at the start of the Cretaceous Normal Superchron. Recent studies of Devonian age Siberian localities identified similarly low field values a few tens of million years prior to the Permo-Carboniferous Reverse Superchron (PCRS). To constrain the length and timing of this potential dipole low, this study presents paleointensity estimates from Strathmore (~411 to 416Ma) and Kinghorn (~332 Ma) lava flows, United Kingdom. Both localities have been studied for paleomagnetic poles (Q values of 6 to 7), and the sites were assessed for their suitability for paleointensity from paleodirections, rock magnetic analysis, and microscopy. Thermal and microwave experiments were used to determine site mean paleointensity estimates of ~3 to 51 µT (6 to 98 ZAm²) and 4 to 11 µT (9 to 27 ZAm²) fromthe Strathmore and Kinghorn localities, respectively. These, and all the sites from 200 to 500 Ma from the (updated) Paleointensity database (PINT15), were assessed using the Qualitative Paleointensity criteria (QPI). The procurement of reliable (QPI = 5) weak paleointensity estimates from this and other studies indicates a period of low dipole moment (median field strength of 17 ZAm²) from 332 to 416 Ma. This "Mid-Paleozoic Dipole Low (MPDL)" bears a number of similarities to the MDL, including the substantial increase in field strength near the onset of the PCRS. The MPDL also adds support to the inverse relationship between reversal frequency and field strength and a possible ~200-My cycle in paleomagnetic behavior relating to mantle convection. [ABSTRACT FROM AUTHOR]

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.Trial registration: ClinicalTrials.gov NCT02915705. [ABSTRACT FROM AUTHOR]

X-linked hypophosphataemia (XLH) is the most common heritable form of rickets. Prevalence data varies across the literature between 1 in 20,000 and 1 in 200,000 per population. Australian and New Zealand Paediatric Surveillance Units collected cross-sectional data from paediatricians on existing cases to estimate prevalence and characteristics of paediatric XLH in Australia and New Zealand. Seventy-five cases in Australia and 18 cases in New Zealand were identified. Estimated minimum prevalence based on these cases was 1.33 (1.04–1.66) per 100,000 and 1.60 per 100,000 (95%CI 0.97–2.58) in Australia and New Zealand respectively, with actual prevalence likely higher due to incomplete ascertainment. Despite a family history in most cases, delayed diagnosis was common, with 49 % diagnosed after 2 years of age. Delayed diagnosis was more common in sporadic versus familial cases. Most common clinical characteristics included leg bowing (89 %), bone and joint pain (68 %), abnormal gait (57 %) and short stature (49 %). There was a significant burden of orthopaedic disease and surgeries and a high rate of complications of nephrocalcinosis and hyperparathyroidism (32 % and 20 % respectively). Additionally, while guidelines stress the importance of multidisciplinary care, many did not have access to recommended health professionals, with only 3 % seeing a psychologist and 68 % seeing a dentist. This is despite the high psychological burden of XLH and a significant proportion (41 %) of this cohort having dental issues (tooth abscess, dental capping, tooth extraction). There were two cases from NZ without data available. Of the 91 cases with data collected, 46 % were on burosumab therapy. Consistent with clinical trials, those on burosumab had a higher serum phosphate levels (p < 0.001) at most recent follow-up. Three cases reported cancellation of orthopaedic surgery due to improvement in lower limb deformity after commencement of burosumab. These data describe the multisystem burden of disease for children with XLH with care impacted by delayed diagnosis and a lack of access to many health professionals, especially psychological support. [Display omitted] • Estimated prevalence of paediatric XLH is 1.6 and 1.9 per 100,000 population in New Zealand and Australia. • Late diagnosis is common, and there are high rates of complications (hyperparathyroidism and nephrocalcinosis) • Many children with XLH do not have access to dental or psychological care [ABSTRACT FROM AUTHOR]

Improvements in the spatial and temporal coverage of paleomagnetic data are essential to better evaluate paleofield behaviour over the past 10 Myr, especially due to data scarcity at low latitudes in the South American region. Here, we provide new Pleistocene-Holocene (0–2 Ma age interval) paleodirectional data from three volcanic systems (Doña Juana Volcanic Complex, Galeras Volcanic Complex and Morasurco Volcano) in southwestern Colombia between latitudes 1.2 and 1.4°N. A total of 38 paleodirectional sites were studied using progressive alternating field and thermal demagnetization treatments. After excluding transitional data, we obtain thirty site-mean directions for analysis of paleosecular variation (PSV) and the time-averaged field (TAF) in the study area. The mean direction (Dec = 351.2°, Inc = −3.4°, α 95 = 6.2°, k = 20.0) and the paleomagnetic pole (Plat = 80.7°N, Plon = 173.1°E, A 95 = 5.2°, K = 29.1) of these sites are not statistically compatible with the expected geocentric axial dipole (GAD) field direction and geographic north pole, respectively. Virtual geomagnetic pole dispersion (S B) for our filtered dataset (S B (2 Ma) = 15.2 12.0 17.6°) and the Brunhes chron (S B (Bru) = 16.0 11.6 19.1°) are consistent at the 95% confidence level with South American studies at equatorial latitudes and recent PSV models for the 0–10 Ma and Brunhes intervals. Likewise, the corresponding inclination anomaly (Δ I) for two age groups Δ I 2 Ma = − 5.9 −12.1 0.3° and Δ I Bru = − 5.3 −13.7 3.1° suggests large deviations relative to the GAD model, in accordance with predictions from zonal TAF models. The high VGP dispersion could be linked to strong longitudinal variability of the magnetic equator position over South America. This feature reflects the presence of significant non-dipole field components in this region that have been detected in geomagnetic field models for the most recent centuries and millennia, probably associated with the presence of the South Atlantic Magnetic Anomaly in the South American region. [Display omitted] [ABSTRACT FROM AUTHOR]

Central giant cell granulomas (CGCG) are rare osteolytic, benign but often locally aggressive tumours of bone. Surgical curettage may not be possible in extensive lesions and resection carries high morbidity, especially in growing children, and previous medical therapies have had variable efficacy and high recurrence rates. Interruption of receptor activator of nuclear factor-kappa B ligand (RANKL) signalling holds promise as an effective therapeutic strategy for these tumours. To evaluate the efficacy and safety of our protocol for denosumab treatment of CGCG in children. Retrospective review of 4 patients treated with denosumab using a standardised protocol for CGCG in a tertiary paediatric centre. Denosumab 70 mg/m2 was given 4-weekly, followed by 2 doses of zoledronate 0.025 mg/kg, aimed at preventing rebound hypercalcaemia. Treatment of CGCG resulted in metabolic remission in all patients, but recurrence, detected by positron emission tomography (PET), occurred at 6 months in three patients and 12 months in one patient. Three patients developed symptomatic hypercalcaemia 4–5 months and one patient asymptomatic hypercalcaemia 7 months after cessation of denosumab, with 3 requiring additional bisphosphonate treatment. Denosumab produced a radiological and metabolic response in our patients, but metabolic recurrence occurred in all patients. PET imaging was effective for monitoring treatment response and early detection of recurrence. Incidence of rebound hypercalcaemia in this paediatric cohort was high. We present proposed changes to our protocol with the aim of producing sustained remission and preventing rebound hypercalcaemia. • Denosumab induces remission of CGCG in children. • Useful when surgery contraindicated or to delay surgery until skeletal maturity • PET imaging useful to monitor treatment response • Recurrence is common. • High risk of rebound hypercalcemia, requires prophylaxis and monitoring [ABSTRACT FROM AUTHOR]

Osteogenesis imperfecta (OI) or brittle bone disease is a genetic disorder that results in bone fragility. Bisphosphonates such as zoledronic acid (ZA) are used clinically to increase bone mass and reduce fracture risk. Human growth hormone (hGH) has been used to promote long bone growth and forestall short stature in children with OI. The potential for hGH to improve bone quality, particularly in combination with ZA has not been robustly studied. A preclinical study was performed using n = 80 mice split evenly by genotype (WT, Col1a2 +/G610C ). Groups of n = 10 were treated with +/−ZA and +/−hGH in a factorial design for each genotype. Outcome measures included bone length, isolated muscle mass, bone parameters assessed by microCT analysis, dynamic histomorphometry, and biomechanical testing. Treatment with hGH alone led to an increase in femur length in WT but not OI mice, however bone length was increased in both genotypes with the combination of hGH/ZA. MicroCT showed that hGH/ZA treatment increased cortical BV in both WT (+15%) and OI mice (+14.3%); hGH/ZA were also found to be synergistic in promoting cortical thickness in OI bone. ZA was found to have a considerably greater positive impact on trabecular bone than hGH. ZA was found to suppress bone turnover, and this was rescued by hGH treatment in terms of cortical periosteal perimeter, but not by dynamic bone remodeling. Statistically significant improvements in long bone by microCT did not translate into improvements in mechanical strength in a 4-point bending test, nor did vertebral strength improve in L4 compression testing in WT/OI bone. These data support hGH/ZA combination as a treatment for short stature, however the improvements granted by hGH alone and in combination with ZA on bone quality are modest. Increased periosteal perimeter does show promise in improving bone strength in OI, however a longer treatment time may be required to see effects on bone strength through mechanical testing. • The impact of hGH and ZA were assessed in a mouse model of osteogenesis imperfecta. • hGH/ZA cotreatment increased femur length in OI mice. • hGH and ZA showed synergy to increase cortical but not trabecular bone volume. • The overall impact of hGH on bone metrics was less than that seen for ZA. [ABSTRACT FROM AUTHOR]

Context: In an open-label, randomized, controlled, phase 3 trial in 61 children aged 1 to 12 years with X-linked hypophosphatemia (XLH), burosumab improved rickets vs continuing conventional therapy with active vitamin D and phosphate., Objective: We conducted an analysis to determine whether skeletal responses differed when switching to burosumab vs continuing higher or lower doses of conventional therapy., Methods: Conventional therapy dose groups were defined as higher-dose phosphate [greater than 40 mg/kg] (HPi), lower-dose phosphate [40 mg/kg or less] (LPi), higher-dose alfacalcidol [greater than 60 ng/kg] or calcitriol [greater than 30 ng/kg] (HD), and lower-dose alfacalcidol [60 ng/kg or less] or calcitriol [30 ng/kg or less] (LD)., Results: At week 64, the Radiographic Global Impression of Change (RGI-C) for rickets was higher (better) in children randomly assigned to burosumab vs conventional therapy for all prebaseline dose groups: HPi (+1.72 vs +0.67), LPi (+2.14 vs +1.08), HD (+1.90 vs +0.94), LD (+2.11 vs +1.06). At week 64, the RGI-C for rickets was also higher in children randomly assigned to burosumab (+2.06) vs conventional therapy for all on-study dose groups: HPi (+1.03), LPi (+1.05), HD (+1.45), LD (+0.72). Serum alkaline phosphatase (ALP) also decreased in the burosumab-treated patients more than in the conventional therapy group, regardless of on-study phosphate and active vitamin D doses., Conclusion: 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 ALP more than continuing either higher or lower doses of phosphate or active vitamin D., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Aneurysmal bone cysts (ABC) are rare osteolytic, benign but often locally aggressive tumours of the long bones or vertebrae. For spinal ABC, surgical management, embolisation or sclerotherapy alone often carry high morbidity and/or high recurrence rates. Interruption of receptor activator of nuclear factor-kappa B ligand (RANKL) signalling holds promise as an effective therapeutic strategy for these tumours. We aimed to review the approach to surgical management and evaluate the efficacy and safety of denosumab for ABC of the spine in children. Retrospective review of 7 patients treated with denosumab using a standardised protocol for ABC of the spine in a tertiary paediatric centre. Surgical intervention was only conducted if there was spinal instability or significant neurological impairment. Denosumab 70 mg/m 2 was given 4-weekly for at least 6 months, followed by 2 doses of zoledronate 0.025 mg/kg, aiming to prevent rebound hypercalcaemia. All patients achieved stability of the spine and resolution of neurological impairment, if present. Six patients achieved metabolic remission and have ceased denosumab without recurrence to date; the other showed clinical and radiological improvement without complete metabolic remission. Three patients developed symptomatic hypercalcaemia 5-7 months after cessation of denosumab, requiring additional bisphosphonate treatment. We present our algorithm for the surgical and medical management of paediatric spinal ABC. Denosumab produced a radiological and metabolic response in all patients, with complete remission in most. Follow-up time was not long enough to evaluate the endurance of response after cessation in some patients. Incidence of rebound hypercalcaemia in this paediatric cohort was high, prompting a change to our protocol., (© 2023. Crown.)

Craniosynostosis is a rare condition of skull development, manifesting during fetal and early infant development, and is usually congenital. Craniosynostosis secondary to metabolic disorders, such as X-linked hypophosphatemia (XLH), is less common and is typically diagnosed later than congenital craniosynostosis. XLH is a rare, progressive, and lifelong hereditary phosphate-wasting disorder characterized by loss of function of the phosphate-regulating endopeptidase homologue, X-linked gene, which is associated with premature fusion of cranial sutures due to abnormal phosphate metabolism (hypophosphatemia) and altered bone mineralization or elevated levels of fibroblast growth factor 23. This targeted literature review of 38 articles seeks to provide an overview of craniosynostosis in individuals with XLH. The objectives of this review are to increase awareness of the prevalence, presentation, and diagnosis of craniosynostosis in XLH; examine the spectrum of craniosynostosis severity in XLH; discuss the management of craniosynostosis in those with XLH; recognize the complications for patients with XLH; and identify what is known about the burden of craniosynostosis for individuals with XLH. The presentation of craniosynostosis in individuals with XLH tends to manifest slightly later than congenital craniosynostosis and can vary in severity and appearance, making diagnosis difficult and resulting in inconsistent clinical outcomes. Consequently, craniosynostosis in patients with XLH is an underreported and potentially underrecognized condition. There have been no studies investigating the effects of craniosynostosis on the quality of life of people with XLH. Despite a growing awareness among researchers and experienced clinicians, there are still improvements to be made in general awareness and timely diagnosis of craniosynostosis in XLH. The XLH community would benefit from further study into the prevalence of craniosynostosis, the effect of XLH medical therapy on the development of craniosynostosis, and the effects of craniosynostosis on quality of life. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., Competing Interests: SW was an employee of Kyowa Kirin International at the time of writing. AW is an employee of Kyowa Kirin International. CFM has received consultant fees, speaker fees, a travel grant, and a research grant from Kyowa Kirin. AB has received consultant fees and a research grant from Kyowa Kirin., (© 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

X-linked hypophosphataemia (XLH), the most common inherited form of rickets, is caused by a PHEX gene mutation that leads to excessive serum levels of fibroblast growth factor 23 (FGF23). This leads to clinical manifestations such as rickets, osteomalacia, pain, lower limb deformity and overall diminished quality of life. The overarching aims in the management of children with XLH are to improve quality of life by reducing overall burden of disease, optimise an individual's participation in daily activities and promote normal physical and psychological development. Burosumab, a monoclonal antibody targeting FGF23, has been shown to improve biochemistry, pain, function and radiological features of rickets in children with XLH and has transformed management of XLH around the world. Burosumab has been recently approved for clinical use in children with XLH in Australia. This manuscript outlines a clinical practice guideline for the use of burosumab in children with XLH to assist local clinicians, encourage consistency of management across Australia and suggest future directions for management and research. This guideline also strongly advocates for all patients with XLH to have multidisciplinary team involvement to ensure optimal care outcomes and highlights the need to consider other aspects of care for XLH in the era of burosumab, including transition to adult care and the effective coordination of care between local health-care providers and specialist services., (© 2022 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Reduced muscle tone, muscle weakness, and physical fatigue can impact considerably on quality of life for children with neurofibromatosis type 1 (NF1). Human muscle biopsies and mouse models of NF1 deficiency in muscle show intramyocellular lipid accumulation, and preclinical data have indicated that L-carnitine supplementation can ameliorate this phenotype. The aim of this study is to examine whether daily L-carnitine supplementation is safe and feasible, and will improve muscle strength and reduce fatigue in children with NF1. A 12-week Phase 2a trial was conducted using 1000 mg daily oral levocarnitine tartrate supplementation. Recruited children were between 8 and 12 years old with a clinical diagnosis of NF1, history of muscle weakness and fatigue, and naïve to L-carnitine. Primary outcomes were safety (self-reporting, biochemical testing) and compliance. Secondary outcomes included plasma acylcarnitine profiles, functional measures (muscle strength, long jump, handwriting speed, 6-minute-walk test [6MWT]), and parent-reported questionnaires (PedsQL™, CBCL/6-18). Six children completed the trial with no self-reported adverse events. Biochemical tests for kidney and liver function were normal, and the average compliance was 95%. Plasma acylcarnitine levels were low, but within a range not clinically linked to carnitine deficiency. For strength measures, there was a mean 53% increase in dorsiflexion strength (95% confidence interval [CI] 8.89-60.75; p = 0.02) and mean 66% increase in plantarflexion strength (95% CI 12.99-134.1; p = 0.03). In terms of muscle performance, there was a mean 10% increase in long jump distance (95% CI 2.97-16.03; p = 0.01) and 6MWT distance (95% CI 5.88-75.45; p = 0.03). Comparison with the 1000 Norms Project data showed a significant improvement in Z-score for all of these measures. Parent reports showed no negative impact on quality of life, and the perceived benefits led to the majority of individuals remaining on L-carnitine after the study. Twelve weeks of L-carnitine supplementation is safe and feasible in children with NF1, and a Phase 3 trial should confirm the efficacy of treatment., (© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

A defining characteristic of the recent geomagnetic field is its dominant axial dipole which provides its navigational utility and dictates the shape of the magnetosphere. Going back through time, much less is known about the degree of axial dipole dominance. Here we use a substantial and diverse set of 3D numerical dynamo simulations and recent observation-based field models to derive a power law relationship between the angular dispersion of virtual geomagnetic poles at the equator and the median axial dipole dominance measured at Earth's surface. Applying this relation to published estimates of equatorial angular dispersion implies that geomagnetic axial dipole dominance averaged over 10 7 -10 9 years has remained moderately high and stable through large parts of geological time. This provides an observational constraint to future studies of the geodynamo and palaeomagnetosphere. It also provides some reassurance as to the reliability of palaeogeographical reconstructions provided by palaeomagnetism.

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 2 -weighted hyperintensities in the putamen; Cluster 2-T 2 -weighted hyperintensities or increased MRI susceptibility in the globus pallidus; Cluster 3-T 2 -weighted hyperintensities in the globus pallidus, brainstem and cerebellum with diffusion restriction; Cluster 4-T 1 -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 was exemplified by distinct T 1 -weighted hyperintensities in the basal ganglia and other brain regions in genetically determined hypermanganesemia due to SLC39A14 and SLC30A10 . Within the clusters, distinctive basal ganglia MRI patterns were noted in acquired disorders such as cerebral palsy due to hypoxic ischaemic encephalopathy in full-term babies, kernicterus and vigabatrin toxicity and in rare genetic disorders such as 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome, thiamine responsive basal ganglia disease, pantothenate kinase-associated neurodegeneration, TUBB4A and hypermanganesemia. Integrated findings from the study cohort and literature review were used to propose a diagnostic algorithm to approach bilateral basal ganglia abnormalities on MRI. After integrating clinical summaries and MRI findings from the literature review, we developed a prototypic decision-making electronic tool to be tested using further cohorts and clinical practice., Competing Interests: None of the authors have any competing interests to declare. All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the National institute for health research, (NIHR) Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Earth's magnetic field is presently characterized by a large and growing anomaly in the South Atlantic Ocean. The question of whether this region of Earth's surface is preferentially subject to enhanced geomagnetic variability on geological timescales has major implications for core dynamics, core-mantle interaction, and the possibility of an imminent magnetic polarity reversal. Here we present paleomagnetic data from Saint Helena, a volcanic island ideally suited for testing the hypothesis that geomagnetic field behavior is anomalous in the South Atlantic on timescales of millions of years. Our results, supported by positive baked contact and reversal tests, produce a mean direction approximating that expected from a geocentric axial dipole for the interval 8 to 11 million years ago, but with very large associated directional dispersion. These findings indicate that, on geological timescales, geomagnetic secular variation is persistently enhanced in the vicinity of Saint Helena. This, in turn, supports the South Atlantic as a locus of unusual geomagnetic behavior arising from core-mantle interaction, while also appearing to reduce the likelihood that the present-day regional anomaly is a precursor to a global polarity reversal., Competing Interests: The authors declare no competing interest.

Purpose: Anorexia nervosa (AN) is a chronic and life-threatening eating disorder that can have a considerable negative impact on the growing skeleton. We hypothesized that the long-term impact on bone health may persist even after normalization of body weight., Methods: 41 females (mean age 21.2 ± 2.9 years) with a history of adolescent-onset AN attended a follow-up bone health assessment at 5 years (T5, n = 28) or 10 years (T10, n = 13) after their first AN-related hospital admission. Assessment included dual-energy x-ray absorptiometry measurements of the total body, lumbar spine, and proximal femur, peripheral quantitative computed tomography at the radius and tibia, anthropometric measurements, serum biochemistry, fracture history, and a patient questionnaire., Results: A recovery in body weight and BMI was seen for both the T5 and T10 cohorts (BMI at intake 16.6, BMI at T5-T10 21.2-21.3). Dual-energy x-ray absorptiometry body composition indicated a recovery of fat mass and lean tissue mass. Total BMD was unaffected, but reductions were seen at the femoral neck and arms. Peripheral quantitative computed tomography showed reduced trabecular and cortical bone in the radius, and cortical thinning in the tibia. AN patients showed a statistically significant reduction in measures of radiographic bone health at follow up, although not to a degree that necessitated clinical intervention. Serum insulin-like growth factor 1 was also positively correlated with total BMD and BMC measures. While fracture risk was not increased, a subset of participants (8%) showed multiple (>4) fractures., Conclusion: A longitudinal study of adolescent AN showed persisting negative effects on bone health., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

Bisphosphonate therapy is the mainstay of pharmacological intervention in young people with skeletal fragility. The evidence of its use in a variety of conditions remains limited despite over three decades of clinical experience. On behalf of the Australasian Paediatric Endocrine Group, this evidence-based consensus guideline presents recommendations and discusses the graded evidence (using the GRADE system) for these recommendations. Primary bone fragility disorders such as osteogenesis imperfecta are considered separately from osteoporosis secondary to other clinical conditions (such as cerebral palsy, Duchenne muscular dystrophy). The use of bisphosphonates in non-fragility conditions, such as fibrous dysplasia, avascular necrosis, bone cysts and hypercalcaemia, is also discussed. While these guidelines provide an evidence-based approach where possible, further research is required in all clinical applications in order to strengthen the recommendations made., (© 2018 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

State-of-the-art measurements of the direction and intensity of Earth's ancient magnetic field have made important contributions to our understanding of the geology and palaeogeography of Precambrian Earth. The PALEOMAGIA and PINT( QPI ) databases provide thorough public collections of important palaeomagnetic data of this kind. They comprise more than 4,100 observations in total and have been essential in supporting our international collaborative efforts to understand Earth's magnetic history on a timescale far longer than that of the present Phanerozoic Eon. Here, we provide an overview of the technical structure and applications of both databases, paying particular attention to recent improvements and discoveries.

Marfan syndrome (MFS) is a disorder of the extracellular matrix caused by mutations in the gene encoding fibrillin-1 (FBN1). Recent studies have illustrated the variability in disease severity and clinical manifestations of MFS. Useful genotype-phenotype correlations have been slow to emerge. We screened 57 unrelated patients with MFS or a Marfan-like phenotype using a combination of SSCP and/or DHPLC. We detected 49 different FBN1 mutations, 30 (62%) of which were novel. The mutations comprised 38 substitutions (78%), 10 deletions (20%), and one duplication (2%). There were 28 missense (57%), nine frameshift (18%), eight splice site (16%), and four nonsense mutations (8 %). Genotype-phenotype analysis revealed that patients with an identified FBN1 mutation were more likely to have ectopia lentis and cardiovascular complications compared to those without an identifiable mutation (relative risks of 4.6 and 1.9, respectively). Ectopia lentis was also found to be more prevalent in patients whose mutations involved a cysteine substitution (relative risk 1.6) and less prevalent in those with premature termination mutations (relative risk 0.4). In our hands, we achieved 93% mutation detection for DHPLC analysis of patients who fulfilled the Ghent criteria. Further analysis of detailed clinical information and mutation data may help to anticipate the clinical consequences of specific FBN1 mutations., (Copyright 2003 Wiley-Liss, Inc.)