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Abstract Context Patients with glucocorticoid-dependent Duchenne muscular dystrophy (DMD) have increased fracture risk and reduced bone mineral density (BMD), often precipitating mobility loss. Objective To investigate use of zoledronic acid (ZA) in DMD in improving BMD. Methods Two arm, parallel, randomized controlled trial, set in pediatric hospitals across Australia and New Zealand. Sixty-two (31 per arm) boys with glucocorticoid-dependent DMD between 6 and 16 years were included. Five ZA infusions (0.025 mg/kg at months 0, and 3, and 0.05 mg/kg at months 6, 12, and 18), plus calcium and vitamin D, were compared with calcium and vitamin D alone. The main outcome measures were change in lumbar spine (LS) BMD raw and Z-score by dual energy absorptiometry x-ray (DXA) at 12 and 24 months, secondary outcomes assessing mobility, fracture incidence, bone turnover, peripheral quantitative computerized (pQCT) and pain scores. Results At 12 and 24 months, mean difference in changes of LS BMD Z-score from baseline was 1.2 SD (95% CI 0.9-1.5), higher by 19.3% (14.6-24.0) and 1.4 SD (0.9-1.9), higher by 26.0% (17.4-34.5) in ZA than control arms respectively (both P < .001). Five controls developed Genant 3 vertebral fractures, 0 in the ZA arm. Mobility, pain, and bone turnover markers were similar between arms at 12 and 24 months. Trabecular BMC and vBMD pQCT at radius and tibia were greater at 12 months in the ZA cohort than control; the evidence for this difference remained at 24 months for radius but not tibia. Conclusion ZA improved BMD in glucocorticoid-dependent DMD boys. Although the small cohort precluded demonstrable fracture benefit, improved BMD might reduce incident vertebral fracture.

X-linked hypophosphatemia (XLH) is a rare, X-linked dominant condition with a high burden of both physical and psychosocial disease. This study aimed to describe the experience and burden of disease for children and adults living with XLH in Australia by inviting affected individuals and their carers to complete an online questionnaire. Of the 46 responses, half were completed by a person with XLH, and half by carers. Thirty percent were male, 33% were aged less than 18 yr. Median age at diagnosis was 2 yr (IQR 1.5-3.0). There was a high burden of surgical intervention: 59% reported 5 or more surgeries and 33% (15) had major dental procedures. Bone deformities and painful bones/joints were rated as the most impactful symptoms for both children and adults with XLH with 54% of participants rating emotional and physical burden of disease as equally impactful. Participants reported experiencing many psychosocial and financial challenges, including mental health disorders (including depression, anxiety, suicidal ideation, and self-harm), discrimination, and social isolation. Seventy percent reported it was difficult or very difficult living with XLH. Over 80% percent strongly agreed that lack of XLH awareness impacts on support services and health funding and agreed or strongly agreed that it is hard living with a condition that most Australians have never heard of. X-linked hypophosphatemia imparts a high physical, emotional, psychosocial, and mental toll on affected individuals. While the most impactful reported symptoms were musculoskeletal features, this survey emphasizes the degree of social and psychological challenges that individuals with XLH face. Some of these difficulties appear to be worsened by a lack of awareness. Patient advocacy and improving knowledge of rare diseases such as XLH is a key role of health professionals and should improve overall experience for affected individuals.

X-linked hypophosphatemia (XLH) is an X-linked dominant condition where fibroblast growth factor-23 (FGF23) excess leads to hypophosphatemic rickets, lower limb bowing, and musculoskeletal pain. Burosumab, a monoclonal antibody against FGF23, has been shown to ameliorate the clinical phenotype of XLH and has recently been approved for use in many countries. This study aimed to evaluate patient and parental/caregiver perception of burosumab therapy and the acceptability of current management practices in Australia. Children with XLH and parents/carers were invited to respond to a survey on clinical and management information including use of telehealth, access to multidisciplinary team members, and perceptions and experience regarding burosumab therapy. This was a multi-centre, cross-sectional survey-based study involving 4 tertiary Australian children’s hospitals. A total of 21 survey responses from parents/carers were received between December 2022 and October 2023. Mean (SD) age at time of survey was 12.7 (4.1) yr and median time on burosumab was 42 mo (range 2-100). Reported side effects of burosumab were limited to local skin reactions (38%, n = 8) and injection site pain (5%, n = 1), with the majority (62%, n = 13) reporting no side effects. Logistical issues (availability from the pharmacy or medical centre holiday closure) led to most instances of missed or delayed doses, which were reported by 24% (n = 5). Most participants reported seeing their specialist both face-to-face and via telehealth (64%, n = 14). The majority saw an endocrinologist (100%, n = 21) and orthopaedic surgeon (67%, n = 14), but only a small minority saw a psychologist (10%, n = 2). Answers to Likert scale questions revealed that most parents/carers and children reported a perceived improvement in physical and psychological symptoms and function with burosumab therapy. This study supports the use of recently published local guidelines to manage children with XLH on burosumab due to high satisfaction expressed by children and parents/carers. However, logistical issues leading to delayed or missed doses should be addressed.

This study aimed to investigate the prevalence of fractures and non-fracture injuries, including associated risk factors, in children with epilepsy prescribed antiseizure medications (ASM). A controlled, cross-sectional study was conducted in a hospital outpatient setting, comparing children with epilepsy prescribed ASMs with their non-epileptic siblings. Information was collected by questionnaire included history of fractures, non-fracture injuries and epilepsy, comorbidities and ASM use. 261 participants completed the questionnaire, 133 children with epilepsy (aged 10.7 ± 3.5 years, mean ± SD) and 128 siblings (10.1 ± 3.7 years). There were 49 non-seizure-related fractures in 34 ASM patients while prescribed ASMs, compared with 21 lifetime fractures in 15 controls, giving a 2.7 (95% CI 1.3–5.3, p = 0.007) times greater fracture prevalence in children treated with ASMs compared to healthy siblings. The rates of non-fracture injuries were similar across groups, except that concussion was more common in children taking ASMs (9.0% vs 1.6%, p = 0.026). Duration of ASM use and generalized tonic–clonic seizures (GTCS) were independent predictors of fractures (OR 1.55; 95% CI 1.03–2.31, p = 0.03; OR 2.50; 95% CI 1.05–5.94, p = 0.04, respectively). Fewer than 20% of participants and/or their families were aware that ASM use was related to bone health. Children with epilepsy treated with ASMs had a higher fracture prevalence than their sibling controls. Duration of ASM treatment and GTCS were associated with fracture risk. Longitudinal prospective studies are required to further explore risk and the direct impact of epilepsy on bone health.

Although hearing impairment is often listed as a nonskeletal complication of X-linked hypophosphatemia (XLH), the prevalence, etiology, pathology, and natural history are poorly described. This review aims to summarize existing literature with a view to guide the clinical management of hearing impairment in XLH. The review was conducted by 2 researchers independently. Four databases (PubMed/Medline, EMBASE, Web of Science, and Cochrane Library) were searched between January 1, 2000 and July 31, 2024, with keywords related to “X-linked hypophosphataemic rickets” and “hearing loss” including synonyms. Identified records were screened for inclusion and exclusion criteria. Human and animal studies were included. Out of 82 records found excluding duplicates, 12 studies met the final criteria and were reviewed. Studies described both conductive and sensorineural hearing loss in 13%-76% of adults with XLH, with sensorineural hearing loss more commonly reported, with impairment developing in adulthood, affecting high and low frequencies, and may be fluctuating. Evidence suggests that endolymphatic hydrops (ELH) may be a major underlying cause of hearing loss in XLH. Individuals with XLH have generalized osteosclerosis with petrous bone thickening and narrowing of the auditory meatus. No studies have looked at burosumab, a monoclonal antibody that inhibits FGF23, and its effect on the development of hearing loss in individuals with XLH. Animal studies of XLH mouse models (Hyp and Gy) describe both conductive and sensorineural hearing impairment. Mouse models demonstrate high Auditory Brainstem Response (ABR) thresholds and signs of osteomalacia of auditory ossicles and ELH. In conclusion, there is an association between hearing loss in XLH and, most commonly, adult-onset sensorineural hearing loss. Pathogenesis of hearing loss in XLH is incompletely understood, but possible contributing factors include thickening of the temporal bones, osteomalacia of the auditory ossicles, and development of ELH. There is currently no evidence that treatment with conventional therapy or burosumab reduces the risk or severity of hearing impairment.

To describe the epidemiology and concordance of bone health in a population-based sample of Australian parent-child dyads at child age 11-12 years. Population-based cross-sectional study (the Child Health CheckPoint) nested between waves 6 and 7 of the Longitudinal Study of Australian Children (LSAC). Assessment centres in seven cities around Australia, February 2015-March 2016. of all participating CheckPoint families (n=1874), bone data were available for 1222 dyads (1271 children, 50% girls; 1250 parents, 86% mothers). Peripheral quantitative CT (pQCT) of the non-dominant leg scanned at the 4% (distal) and 66% (mid-calf) tibial sites. Stratec XCT 2000 software generated estimates of bone density, geometry and polar stress-strain index.Parent-child concordance were assessed using Pearson's correlation coefficients and multivariable linear regression models. Percentiles were determined using survey weights. Survey weights and methods accounted for LSAC's complex sampling, stratification and clustering within postcodes. Concordances were greater for the geometric pQCT parameters (periosteal circumference 0.38, 95% CI 0.33 to 0.43; endosteal circumference 0.42, 95% CI 0.37 to 0.47; total cross-sectional area 0.37, 95% CI 0.32 to 0.42) than density (cortical density 0.25, 95% CI 0.19 to 0.30). Mother-child and father-child values were similar. Relationships attenuated only slightly on adjustment for age, sex and body mass index. Percentiles and concordance are presented for the whole sample and by sex. There is strong parent-child concordance in bone geometry and, to a lesser extent, density even before the period of peak adolescent bone deposition. This geometrical concordance suggests that future intergenerational bone studies could consider using pQCT rather than the more commonly used dual X-ray absorptiometry (DXA).

BackgroundOne size rarely fits all in population health. Differing outcomes may compete for best allocations of time. Among children aged 11–12 years, we aimed to (1) describe optimal 24-hour time use for diverse physical, cognitive/academic and well-being outcomes, (2) pinpoint the ‘Goldilocks Day’ that optimises all outcomes and (3) develop a tool to customise time-use recommendations.MethodsIn 2004, the Longitudinal Study of Australian Children recruited a nationally-representative cohort of 5107 infants with biennial follow-up waves. We used data from the cross-sectional Child Health CheckPoint module (2015–2016, n=1874, 11–12 years, 51% males). Time use was from 7-day 24-hour accelerometry. Outcomes included life satisfaction, psychosocial health, depressive symptoms, emotional problems, non-verbal IQ; vocabulary, academic performance, adiposity, fitness, blood pressure, inflammatory biomarkers, bone strength. Relationships between time use and outcomes were modelled using compositional regression.ResultsOptimal daily durations varied widely for different health outcomes (sleep: 8.3–11.4 hours; sedentary: 7.3–12.2 hours; light physical activity: 1.7–5.1 hours; moderate-to-vigorous physical activity (MVPA): 0.3–2.7 hours, all models p≤0.04). In general, days with highest physical activity (predominantly MVPA) and low sedentary time were optimal for physical health, while days with highest sleep and lowest sedentary time were optimal for mental health. Days with highest sedentary time and lowest physical activity were optimal for cognitive health. The overall Goldilocks Day had 10 hours 21 min sleep, 9 hours 44 min sedentary time, 2 hours 26 min light physical activity and 1 hour 29 min MVPA. Our interactive interface allows personalisation of Goldilocks Days to an individual’s outcome priorities.Conclusion‘Goldilocks Days’ necessitate compromises based on hierarchies of priorities for health, social and economic outcomes.

11 beta-Hydroxylase deficiency is a rare form of congenital adrenal hyperplasia, resulting in virilization, glucocorticoid deficiency and hypertension. There have been no previous reports in the literature of a successful pregnancy in a severely affected female. We report the first successful pregnancy resulting in a live birth for a female with 11 beta-hydroxylase deficiency and outline management issues from preconception to successful birth. We also report 2 novel mutations in the CYP11B1 gene leading to 11 beta-hydroxylase deficiency.