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PDF file - 81K, Supplementary data comprising the materials and methods for (i) crystallography (ii) gene expression studies (iii) siRNA studies and Supplementary Figure legends 1-7

XLS file - 703K, Gene expression data for CCT128930: Genes that showed at least a 1.5 Fold Change in at least one treated sample compared to vehicle control and were differentially expressed between the treatment groups (Welch ANOVA FDR5%)

Purpose: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component.Experimental Design: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148.Results: AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK, and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer, and PTEN-deficient MES-SA uterine tumor xenografts was shown. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell-cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 as a result of compensatory feedback loops was observed.Conclusions: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which shows a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human phase I trial. Clin Cancer Res; 18(14); 3912–23. ©2012 AACR.

XLS file - 66K, Genes that showed at least a 1.5 Fold Change in at least one treated sample compared to vehicle control and were differentially expressed between the treatment groups (Welch ANOVA FDR5%) for both CCT128930 and AT13148

PDF file - 553K, Supplementary Figure 1. Phosphorylation of AKT substrates remains suppressed, despite pSer473 AKT induction. Supplementary Figure 2. The pharmacokinetic-pharmacodynamic profile and antitumor activity of AT13148 in PTEN-deficient PC3 human prostate cancer xenografts. Supplementary Figure 3. Pharmacodynamic biomarker study of AT13148(40mg/kg) in MES-SA human tumor xenografts. Supplementary Figure 4. The antitumour activity of AT13148 in mutant KRAS A549 human lung cancer xenografts. Supplementary Figure 5. Mouse body weight data for the MES-SA (Figure 4B) and BT474 (Figure 4C) efficacy studies. Supplementary Figure 6. The effect of AT13148 versus CCT128930 on apoptosis and cell cycle distribution in U87MG human glioblastoma cells. Supplementary Figure 7. Differential effects of 24h treatment of 10M each of the AGC kinase inhibitor AT13148 and the selective AKT inhibitor CCT128930 on cell cycle effects in PTEN-deficient U87MG human glioblastoma cells. Supplementary Table 1. Summary of the inhibitory activity of 10��M AT13148 against in vitro. Supplementary Table 2. Summary of the inhibitory activity of AT13148 against a panel of protein kinases Supplementary Table 3. Summary of the in vitro cytotoxicity of AT13148 against a panel of human tumor cell lines harboring different defects in the PI3K-AKT signaling pathway. Supplementary Table 4. Summary of the pharmacokinetics of AT13148 in mouse plasma and tissues following iv or oral administration

In some patients undergoing radioembolization, lung toxicity is a limiting factor when calculating their dose. At the same time, it is known that the lung shunt fraction (LSF) is overestimated by the mapping exam. Furthermore, there are multiple methods to measure LSF. Planar measurement is both the most commonly utilized and easiest to perform, however new dosimetry software provides the ability to use more advanced 3D techniques. This paper reviews the different LSF calculation methods and elucidates the available data comparing the techniques, clinical relevance, and dose calculation.

Understanding ecosystem service change necessitates an understanding of the social and ecological dimensions of ecosystem services and how they contribute to the well‐being of different people. These empirical research gaps persist across the tropics and in coastal environments, posing a challenge for small island states that depend on ecosystem services associated with near‐shore ecosystems like coral reefs. Perception‐based approaches allow for a rapid appraisal of what constitutes ecosystem service change, providing insights into why these changes matter, and how experiences of change differ between individuals. To capture perceptions of change in four ecosystem services associated with coral reefs (habitat, fishery, coastal protection and recreation services), we conducted 41 semi‐structured interviews with coral reef fishers from Seychelles, where reef ecosystems have been severely impacted by climate disturbance. We gathered quantitative and qualitative data to understand (a) if and what changes in reef‐associated ecosystem services have been perceived; (b) if fishers’ characteristics are associated with differences in perceived changes and (c) which changes matter most in fishers’ lives. Using a three‐dimensional approach to well‐being, we sought to identify whether reasons behind the importance of change connect to fishers’ well‐being. There have been noticeable changes across all four ecosystem services investigated. Changes include social, ecological and behavioural dynamics. Every fisher perceived at least one ecosystem service change but fishers who dive/snorkel or work from larger boats perceived a higher number of ecosystem services to have changed. Education, age and participation in snorkelling/diving were associated with fishers who identified changing habitat services as most important, whereas fishers from families with fewer livelihood alternatives and from smaller islands identified changing fishery services as most important. Different aspects of the subjective, relational and material dimensions of well‐being were implicated in why changing services matter. Despite known ecological shifts in reef condition, this research is one of few studies to empirically show how changes across multiple ecosystem services are being perceived. These perceived changes are complex, engage both the social and ecological dimensions of services, and connect in multiple ways to how fishers feel about their lives, their relationships and material well‐being. A free Plain Language Summary can be found within the Supporting Information of this article.

Optical biopsies bring the microscope to the patient rather than the tissue to the microscope, and may complement or replace the tissue-harvesting component of the traditional biopsy process with its associated risks. In general, optical biopsies are limited by the lack of endogenous tissue contrast and the small number of clinically approved

AIM To determine patient/carer expectations of continuous glucose monitoring (CGM) and short-term satisfaction, to assess the efficacy of CGM in improving: fear of hypoglycaemia and glycaemic control (HbA1c , ketosis, hypoglycaemia) and to determine time requirements of diabetes clinic staff in commencing and administering CGM. METHODS We assessed CGM-naive patients starting on CGM at a Sydney Diabetes Centre following the introduction of a nationwide government subsidy for CGM. A standardised questionnaire was administered collecting demographic and glycaemic information in addition to Likert scale assessment of expectations and satisfaction. Clinic staff reported time dedicated to CGM education, commencement and follow-up. RESULTS A total of 55 patients or parents/carers completed baseline questionnaires, with 37 completing a 3-month follow-up questionnaire. There were high expectations of CGM prior to commencement and high satisfaction ratings on follow-up. CGM improved fear of hypoglycaemia, and total daily insulin dose increased after commencement of CGM. There was a trend towards lower HbA1c that was not statistically significant and no statistically significant reduction in ketosis or hypoglycaemia. Comments were mostly positive, with some concern raised regarding technical issues and a lack of subsidy after 21 years of age. Staff time requirements were substantial, with an estimated average of 7.7 h per patient per year. CONCLUSIONS Patients and families have high expectations of CGM, and satisfaction levels are high in the short term. Total insulin delivery increased after CGM commencement. Time requirements by staff are substantial but are worthwhile if families' overall satisfaction levels are high.

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.

The present work relates to the synthesis of iron and iron oxide based particles via Aerosol Spray Pyrolysis; a continuous and scalable aerosol synthesis method. Different process parameters included the temperature of reactor synthesis, flow rate/type of carrier gas and post treatment temperature as well as precursor solution chemistry, concentration, solvent and reactant type and such parameters are evaluated with respect to their effect on the synthesized particles crystallinity, morphology, iron oxidation state and mean particle diameter of produced powders. Three different iron precursor sources are employed: chloride, nitrate and a dispersible gel derived from a steel industry byproduct. Iron nitrate and chloride aqueous solutions were sprayed at four different concentrations in order to evaluate the effect of the nature of the iron precursor salt on the main attributes of the particle synthesized. Particle diameter was calculated theoretically based on models from the literature describing nucleation at the droplet level, while mean diameter of the synthesized particles was experimentally measured on line at the exit of the reactor. Ex situ TEM characterization provided the necessary morphological data to elaborate on the mechanisms of produced particles formation and explain observed deviations from the theoretically calculated mean particle diameter values.

In 2016, a global consensus on the prevention, diagnosis and management of nutritional rickets was published. The bone and mineral working group of the Australasian Paediatric Endocrine Group provides a summary and highlights differences to previous Australian and New Zealand (ANZ) guidelines on vitamin D deficiency and their implications for clinicians. Key points are: (i) The International Consensus document is focused on nutritional rickets, whereas the ANZ guidelines were focused on vitamin D deficiency. (ii) Definitions for the interpretation of 25-hydroxy vitamin D (25OHD) levels do not differ between statements. (iii) The global consensus recommends that routine 25OHD screening should not be performed in healthy children and recommendations for vitamin D supplementation are not based solely on 25OHD levels. The Australasian Paediatric Endocrine Group bone and mineral working group supports that screening for vitamin D deficiency should be restricted to populations at risk. (iv) Recommendations from the global consensus for vitamin D dosages for the therapy of nutritional rickets (diagnosed based on history, physical examination, biochemical testing and a confirmation by X-rays) are higher than in ANZ publications. (v) The global consensus recommends the implementation of public health strategies such as universal supplementation with vitamin D from birth to 1 year of age and food fortification. We conclude that updated global recommendations for therapy of nutritional rickets complement previously published position statements for Australia and New Zealand. Screening, management and the implementation of public health strategies need to be further explored for Australia.

1. Coral reefs underpin a range of ecosystem goods and services that contribute to the well-being of millions of people. However, tropical coral reefs in the Anthropocene are likely to be functionally different from reefs in the past. In this perspective piece, we ask, what does the Anthropocene mean for the provision of ecosystem services from coral reefs? 2. First, we provide examples of the provisioning, regulating, cultural and supporting services underpinned by coral reef ecosystems. We conclude that coral reef ecosystem service research has lagged behind multidisciplinary advances in broader ecosystem services science, such as an explicit recognition that interactions between social and ecological systems underpin ecosystem services. 3. Second, drawing on tools from functional ecology, we outline how these social–ecological relationships can be incorporated into a mechanistic understanding of service provision and how this might be used to anticipate future changes in coral reef ecosystem services. 4. Finally, we explore the emergence of novel reef ecosystem services, for example from tropicalized coastlines, or through changing technological connections to coral reefs. Indeed, when services are conceived as coming from social–ecological system dynamics, novelty in services can emerge from elements of the interactions between people and the ecosystem. 5. This synthesis of the coral reef ecosystem services literature suggests the field is poorly prepared to understand the changing service provision anticipated in the Anthropocene. A new research agenda is needed that better connects reef functional ecology to ecosystem service provision. This research agenda should embrace more holistic approaches to ecosystem service research, recognizing them as co-produced by ecosystems and society. Importantly, the likelihood of novel ecosystem service configurations requires further conceptualization and empirical assessment. As with current ecosystem services, the loss or gain of services will not affect all people equally and must be understood in the context in which they occur. With the uncertainty surrounding the future of coral reefs in the Anthropocene, research exploring how the benefits to people change will be of great importance.

Additional exploratory results not shown in manuscript

Vitamin D deficiency is common in children with inflammatory bowel disease (IBD). The aim of this study was to determine the safety and efficacy of stoss therapy on vitamin D levels during a period of 6 months in children with IBD and vitamin D deficiency (50 nmol/L).A retrospective chart review was undertaken, focusing upon children managed in the IBD clinic at Sydney Children's Hospital between 2006 and 2010. Those with a 25-hydroxyvitamin D (25-OHD) level50 nmol/L and those who received stoss therapy were included in this study.A total of 76 children received stoss therapy. There was a significant and sustained increase in 25-OHD levels at all of the time points compared with baseline (40.8 ± 7.5 nmol/L), 1 month (145.6 ± 51.8 nmol/L), 3 months (87.1 ± 28.4 nmol/L), and 6 months 69.2 ± 31.3 nmol/L). There were no significant changes in serum calcium, phosphate, or parathyroid hormone at any time points.Stoss therapy safely and effectively achieved and maintained a level of 25-OHD50 nmol/L during 6 months in these children with IBD. Further prospective studies are now required to confirm this finding and establish whether this intervention has other benefits.

Aims There is a paucity of randomized controlled trials (RCT) examining transition from pediatric to adult care in type 1 diabetes mellitus (T1DM). This study aimed to determine if transition in T1DM is more effective with a comprehensive transition program (CTP) compared with standard clinical practice (SCP). Methods This RCT recruited as young people left pediatric diabetes services. The trial co-ordinator provided CTP participants with standardized telephone communication support at week 1, and 3, 6, and 12 months post-discharge from pediatric care. SCP participants were briefly contacted at 6 and 12 months post-discharge to confirm transfer status; they received no other post-discharge contact as per usual practice. At 12 months, the primary outcomes were engagement and retention in the adult service and secondary outcomes included hemoglobin A1c (HbA1c), diabetes-related hospitalizations, microvascular complication appearance, and global self-worth. Results Most CTP participants (11/14) and all SCP (12/12) participants (P = 0.2) transferred to an adult diabetes service; the median time to transfer was 14–15 wk. Overall, participants' frequency of adult diabetes service visits was sub-optimal but their retention in adult care was high. The only group difference was a higher HbA1c at baseline and follow-up in the CTP group. However, a general linear model found that follow-up HbA1c increased by 1.2% for each percentage increase in baseline HbA1c [95% confidence interval (0.4, 1.9; P = 0.01)], independent of treatment group. Conclusions Despite the challenges in recruiting adequate numbers, these findings provide valuable insights for future T1DM transition RCTs that are needed to build a more solid evidence-base in this field.

Background: Rett syndrome is a severe genetic neurodevelopmental disorder mainly affecting females. The aim of this study was to describe pubertal development in a population-based cohort of females with Rett syndrome. Methods: To assess pubertal trajectory we used six waves of data provided by parents of girls and women, recruited through the Australian population-based Rett Syndrome Database. The age at which adrenarche, thelarche or menarche occurred was used as the parameter for time to event (survival) analysis. The relationships between BMI, mutation type and the trajectories were investigated, using Cox proportional hazards. Results: One quarter of girls reached adrenarche by 9.6 years, half by 11 years and three quarters by 12.6 years. Half reached menarche by 14 years (range 8–23). Being underweight was associated with later age at adrenarche, thelarche and menarche, while higher BMI (overweight) was associated with earlier onset. In general, girls with C-terminal deletions and early truncating mutations reached pubertal stages earlier and those with the p.R168X mutation reached them later. Conclusion: The pubertal course in Rett syndrome may be abnormal, sometimes with early adrenarche but delayed menarche. These features may be genotype dependent and may have varying relationships with growth and bone acquisition.

Cinema offers a substantial opportunity to share messages with a wide audience. However, there is little research or evidence about the potential benefits and risks of cinema for conservation. Given their global reach, cinematic representations could be important in raising awareness of conservation issues and species of concern, as well as encouraging greater audience engagement due to their heightened emotional impact on viewers. Yet there are also risks associated with increased exposure, including heightened visitor pressure to environmentally sensitive areas or changes to consumer demand for endangered species. Conservationists can better understand and engage with the film industry by studying the impact of movies on audience awareness and behavior, identifying measurable impacts on conservation outcomes, and engaging directly with the movie industry, for example, in an advisory capacity. This improved understanding and engagement can harness the industry's potential to enhance the positive impacts of movies featuring species, sites, and issues of conservation concern and to mitigate any negative effects. A robust evidence base for evaluating and planning these engagements, and for informing related policy and management decisions, needs to be built.

Woodhead et al. present results from a randomized trial of a novel reading therapy app (‘iReadMore’) coupled with anodal transcranial direct current stimulation (tDCS) in patients with post-stroke central alexia. Use of iReadMore improves reading accuracy for trained words, while concurrent tDCS facilitates training and improves generalization to untrained stimuli., Central alexia is an acquired reading disorder co-occurring with a generalized language deficit (aphasia). We tested the impact of a novel training app, ‘iReadMore’, and anodal transcranial direct current stimulation of the left inferior frontal gyrus, on word reading ability in central alexia. The trial was registered at www.clinicaltrials.gov (NCT02062619). Twenty-one chronic stroke patients with central alexia participated. A baseline-controlled, repeated-measures, crossover design was used. Participants completed two 4-week blocks of iReadMore training, one with anodal stimulation and one with sham stimulation (order counterbalanced between participants). Each block comprised 34 h of iReadMore training and 11 stimulation sessions. Outcome measures were assessed before, between and after the two blocks. The primary outcome measures were reading ability for trained and untrained words. Secondary outcome measures included semantic word matching, sentence reading, text reading and a self-report measure. iReadMore training resulted in an 8.7% improvement in reading accuracy for trained words (95% confidence interval 6.0 to 11.4; Cohen’s d = 1.38) but did not generalize to untrained words. Reaction times also improved. Reading accuracy gains were still significant (but reduced) 3 months after training cessation. Anodal transcranial direct current stimulation (compared to sham), delivered concurrently with iReadMore, resulted in a 2.6% (95% confidence interval −0.1 to 5.3; d = 0.41) facilitation for reading accuracy, both for trained and untrained words. iReadMore also improved performance on the semantic word-matching test. There was a non-significant trend towards improved self-reported reading ability. However, no significant changes were seen at the sentence or text reading level. In summary, iReadMore training in post-stroke central alexia improved reading ability for trained words, with good maintenance of the therapy effect. Anodal stimulation resulted in a small facilitation (d = 0.41) of learning and also generalized to untrained items.

This study used densitometry to investigate the areal bone mineral density (aBMD) and bone mineral content (BMC) in an Australian Rett syndrome cohort and assess how factors such as genotype, epilepsy, BMI and mobility affect these parameters. The influence of lean tissue mass (LTM) and bone area (BA) on total body BMC (TBBMC) was also investigated. Participants, recruited from the Australian Rett Syndrome Database (ARSD), had TBBMC and lumbar spine (LS) and femoral neck (FN) aBMD measured using Dual energy X-ray absorptiometry. Mean height standardised z-scores and confidence intervals for the bone outcomes were obtained from multiple regression models. The mean height z-score for the FN aBMD was low at −2.20, while the LS aBMD was −0.72. The TBBMC mean height z-score was −0.62, although once adjusted for BA and LTM the mean was above zero, suggesting that low BMC can be explained by narrow bones and decreased muscle mass, likely secondary to decreased mobility. Multiple linear regression identified the p.R168X and p.T158M mutations as the strongest predictors of low aBMC and BMD for all bone outcomes. The strong relation between genotype, BMC and aBMD, is likely underpinned by the strong relation between LTM, mobility and bone outcome measures.

Hameed S, Ellard S, Woodhead HJ, Neville KA, Walker JL, Craig ME, Armstrong T, Yu L, Eisenbarth GS, Hattersley AT, Verge CF. Persistently autoantibody negative (PAN) type 1 diabetes mellitus in children. Background: Autoantibody-negative children diagnosed with type 1 diabetes might have unrecognized monogenic or type 2 diabetes. Research design and methods: At diagnosis of type 1 diabetes (between ages 0.5 and 16.3 yr, n = 470), autoantibodies [glutamic acid decarboxylase (GAD), insulinoma-associated protein 2 (IA2), insulin autoantibodies (IAA), and/or islet cell antibody (ICA)] were positive (ab+) in 330 and negative in 37 (unknown in 103). Autoantibody-negative patients were retested at median diabetes duration of 3.2 yr (range 0.9−16.2) for autoantibodies (GAD, IA2, ZnT8), human leukocyte antigen (HLA) typing, non-fasting C-peptide, and sequencing of HNF4A, HNF1A, KCNJ11, and INS. Results: Nineteen (5% of 367) remained persistently autoantibody negative (PAN), 17 were positive on repeat testing (PORT), and 1 refused retesting. No mutations were found in PORT. One PAN was heterozygous for P112L mutation in HNF1A and transferred from insulin to oral gliclazide. Another PAN transferred to metformin and the diagnosis was revised to type 2 diabetes. The remaining 17 PAN were indistinguishable from the ab+ group by clinical characteristics. HLA genotype was at high risk for type 1 diabetes in 82% of remaining PAN and 100% of PORT. After excluding patients with diabetes duration

Introduction: When expressed as a percentage of the average result in young adults, bone mineral content lags behind bone length before puberty. Even though this observation has led to speculation about bone fragility in children, such relationships could simply be due to scaling effects when measures with different geometrical dimensions are compared. Methods: The study population comprised 145 healthy subjects (6–25 years, 94 females). Magnetic resonance imaging and dual-energy X-ray absorptiometry were used to determine femur length, bone mineral content, cortical bone mineral density, cross-sectional bone geometry (bone diameter; cortical thickness; total, cortical and medullary areas; cross-sectional and polar moments of area; bone strength index) and muscle area at the proximal one-third site of the femur. Results were dimensionally scaled by raising two-, three- and four-dimensional variables to the power of 1/2, 1/3 and 1/4, respectively. Sex-differences were also assessed before and after functionally adjusting variables for femur length and weight or muscle size. Results: In prepubertal children, unscaled results expressed as percentages of adult values were lowest for variables with the highest dimensions (e.g., moments of area < bone mineral content < cross-sectional areas < femur length). However, when dimensionally scaled, results in children represented similar percentages of the respective average adult values, even after functional adjustments. Before puberty, there was no sex-difference in adjusted bone or muscle variables. After puberty, males had greater total and cortical bone area, bone diameter, moments of area, bone strength index and muscle area than women, both in absolute terms as well as adjusted for femur length and weight. The largest sex-difference was found for muscle area. When compared relative to muscle size, young adult women attained greater total and cortical bone area than men. Conclusions: Growth in femoral length, diameter, mass and strength appears well coordinated before puberty. Postpubertal females have narrower femora, less bone strength and muscle size than males. However, when muscle size is taken into account, females have a larger femoral bone cross-section and more cortical bone. These sex-differences likely result from a combination of mechanical and hormonal effects occurring during puberty.

Objectives We developed clinical guidelines for the management of bone health in Rett syndrome through evidence review and the consensus of an expert panel of clinicians. Methods An initial guidelines draft was created which included statements based upon literature review and 11 open-ended questions where literature was lacking. The international expert panel reviewed the draft online using a 2-stage Delphi process to reach consensus agreement. Items describe the clinical assessment of bone health, bone mineral density assessment and technique, and pharmacological and non-pharmacological interventions. Results Agreement was reached on 39 statements which were formulated from 41 statements and 11 questions. When assessing bone health in Rett syndrome a comprehensive assessment of fracture history, mutation type, prescribed medication, pubertal development, mobility level, dietary intake and biochemical bone markers is recommended. A baseline densitometry assessment should be performed with accommodations made for size, with the frequency of surveillance determined according to individual risk. Lateral spine x-rays are also suggested. Increasing physical activity and initiating calcium and vitamin D supplementation when low are the first approaches to optimizing bone health in Rett syndrome. If individuals with Rett syndrome meet the ISCD criterion for osteoporosis in children, the use of bisphosphonates is recommended. Conclusion A clinically significant history of fracture in combination with low bone densitometry findings is necessary for a diagnosis of osteoporosis. These evidence and consensus-based guidelines have the potential to improve bone health in those with Rett syndrome, reduce the frequency of fractures, and stimulate further research that aims to ameliorate the impacts of this serious comorbidity.

The present study examined the natural history of fracture and vitamin D levels in Duchenne muscular dystrophy patients, who are vulnerable to osteoporosis and fractures. Retrospective analysis of a cohort of 48 Duchenne muscular dystrophy patients revealed that 43% of patients experienced ≥1 fracture. Fracture probabilities at ages 6, 9, 12, and 15 years were 4%, 9%, 31%, and 60% respectively, accelerating around the time of ambulation loss (mean age 11.8 ± 2.7 years). Chronic corticosteroid therapy was utilized in 69% of patients and was associated with all vertebral fractures. A history of vitamin D deficiency occurred in 84%, and 35% were currently deficient. Despite chronic vitamin D supplementation, 38% remained deficient. These results demonstrate that osteoporosis and fracture remain major concerns in Duchenne muscular dystrophy. Bone health should be optimized well before loss of ambulation, however current levels of vitamin D supplementation may be inadequate given high levels of deficiency.

Background: Bone strength index (BSI) combines bone mineral and bone biomechanical properties to measure resistance to bending. This index may have greater clinical significance than the more often described markers of bone mineral content (BMC), areal density, or geometry alone and, in turn, may show a stronger relation to fracture risk. The BSI is the product of volumetric cortical bone mineral density (BMD) and cross sectional moment of inertia within a region of interest. Calculations combine dual energy x ray absorptiometry and magnetic resonance imaging technologies and provide a useful, non-invasive measure of in vivo bone strength. Objectives: ( a ) To compare BSI in adolescent female middle distance runners and age matched controls; ( b ) to examine factors predictive of BSI in adolescent girls. Methods: Twenty adolescent female middle distance runners (mean (SD) age 16 (1.7) years, physical activity 8.9 (2.1) hours a week) and 20 female controls (age 16 (1.8) years, physical activity 2.0 (0.07) hours a week) were recruited. To calculate BSI, a region of interest representing 10% of the mid-distal tibia was analysed for dual energy x ray absorptiometry derived BMC and was combined with bone geometry and biomechanical properties obtained by magnetic resonance imaging assessments. Potential predictors of BSI were also examined. Results: Independent t tests showed that BMC (p = 0.028), cortical bone volume (p = 0.002), volumetric cortical BMD (p = 0.004), cross sectional moments of inertia (p = 0.005), and BSI (p = 0.002) were higher in the distal tibia of athletes than of controls. The strongest predictor of BSI was hours of physical activity a week ( R 2 = 0.46). Conclusions: Athletes habitually exposed to high training loads displayed greater BSI at the distal tibia than controls. The results further confirm BSI as a significant and discerning marker in musculoskeletal health in adolescent girls engaged in high and low mechanical loading.

Internal jugular vein thrombosis is a rare but treatable disorder with most of the reports in the literature related to the adult population. The most common reported cause is iatrogenic trauma to the internal jugular vein and only a few cases have been reported in the paediatric population. We present a case of bilateral internal jugular venous thrombosis with pulmonary and cerebral complications in a 14-year-old girl with protein S deficiency. This problem has not been previously reported in the world literature.

The impact of high training volumes on musculoskeletal adaptations of male adolescents is poorly understood. We compared bone mineral content (BMC) of total body, lumbar spine and proximal femur using Dual X-ray Absorptiometry (Lunar Prodigy™, GE Medical Systems, Madison WI) in elite level (n=20), male adolescent middle distance runners (mean 16.8 yrs, range 14–18 yrs) and age-matched (n=20) controls. Athletes averaged 14 hrs of physical activity per week and controls reported participating in physical activity an average of two hrs per week. Total body mass was 10.97 kg less in athletes than controls (p=0.005). Within the total body mass difference, fat tissue mass of athletes was 10.93 kg less in athletes than controls (p=0.001). Multiple regression analysis identified total body lean mass and total body fat mass as the strongest predictors of total body BMC (R 2 0.71). After adjusting for lean tissue mass per kg of body weight (p=0.07), no difference in BMC was detected. Lower limb muscle strength and macronutrient intakes were also measured but no between group differences were found. The number of weeks of training and/or competition missed through injury was not associated with total body BMC (R 2 =0.19) among athletes. Our results imply high training volumes in middle distance running are not detrimental to musculoskeletal health and are associated with positive body composition profiles in elite adolescent male athletes.

In upper extremity bones, a sexual dimorphism exists in the development of periosteal and endocortical bone surfaces during growth. Little is known about developmental patterns of bone geometry at weight-bearing bones like the femur. Using MRI and dual energy X-ray absorptiometry (DXA), this study assessed the differences in mid-femoral total (TA), cortical (CA) and medullary areas (MA), cortical thickness, and cortical density (BMDcompartment) between prepuberty and young adulthood in 145 healthy subjects (94 females) 6 to 25 years old. Additionally, agreement between mid-femoral total bone volume (TV) measurements by DXA and MRI were investigated. In both sexes, TA, CA, MA, and cortical thickness were significantly larger in adults compared to prepubertal subjects (P < 0.001), and males had greater values than females. This sex difference persisted for TA, CA, and cortical thickness (P < 0.05), but not MA, after adjusting for femur length and weight. Mean (SD) cortical BMD increased from 1.05 (0.07) and 1.09 (0.10) g/cm3 in prepubertal children to 1.46 (0.14) and 1.42 (0.1) g/cm3 in young adults, females and males, respectively (P < 0.001). TV measurements by DXA were significantly greater than by MRI (P < 0.001) in young adults. In conclusion, periosteal and endocortical expansion and increasing cortical BMD are the growth processes found at the mid-femur in both sexes. Our findings contrast to that in upper extremity bones, where MA is constant in females during growth. The difference in femoral bone development may be due to higher strains caused by weight bearing and genetic factors. DXA, in contrast to MRI, is inaccurate in the determination of mid-femoral TV measures.