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Purpose: 1. To determine the effect of vitamin D supplementation on bone age (BA), a marker of skeletal maturity, and Bone Health Index (BHI), a surrogate marker of bone density. 2. To characterise the differences in nutritional intake and anthropometry between children with advanced vs. delayed BA. Methods: The current study is a post hoc analysis of radiographs obtained as part of a randomised controlled trial. In this double-blind, placebo-controlled trial, deprived Afghan children (n = 3046) aged 1–11 months were randomised to receive six doses of oral placebo or vitamin D3 (100,000 IU) every 3 months for 18 months. Dietary intake was assessed through semi-quantitative food frequency questionnaires at two time points. Anthropometric measurements were undertaken at baseline and 18 months. Serum 25OHD was measured at five time points on a random subset of 632 children. Knee and wrist radiographs were obtained from a random subset (n = 641), of which 565 wrist radiographs were digitised for post-hoc analysis of BA and BHI using BoneXpert version 3.1. Results: Nearly 93% (522, male = 291) of the images were analysable. The placebo (n = 258) and vitamin D (n = 264) groups were comparable at baseline. The mean (± SD) age of the cohort was 2 (± 0.3) years. At study completion, there was no difference in mean 25-hydroxy vitamin D concentrations [47 (95% CI 41, 56) vs. 55 (95% CI 45, 57) nmol/L, p = 0.2], mean (± SD) BA SDS [− 1.04 (1.36) vs. − 1.14 (1.26) years, p = 0.3] or mean (± SD) BHI SDS [− 0.30 (0.86) vs. − 0.31 (0.80), p = 0.8] between the placebo and vitamin D groups, respectively. Children with advanced skeletal maturity (BA SDS ≥ 0) when compared to children with delayed skeletal maturity (BA SDS < 0), had consumed more calories [mean (± SD) calories 805 (± 346) vs 723 (± 327) kcal/day, respectively, p < 0.05], were significantly less stunted (height SDS − 1.43 vs. − 2.32, p < 0.001) and underweight (weight SDS − 0.82 vs. − 1.45, p < 0.001), with greater growth velocity (11.57 vs 10.47 cm/ year, p < 0.05). Conclusion: Deprived children have significant delay in skeletal maturation but no substantial impairment in bone health as assessed by BHI. BA delay was influenced by total calorie intake, but not bolus vitamin D supplementation. [ABSTRACT FROM AUTHOR]

Defective mineralization of the growth plate and preformed osteoid result in rickets and osteomalacia, respectively. The leading cause of rickets worldwide is solar vitamin D deficiency and/or dietary calcium deficiency collectively termed as nutritional rickets. Vitamin D deficiency predominates in high-latitude countries in at-risk groups (dark skin, reduced sun exposure, infants and pregnant and lactating women) but is emerging in some tropical countries due to sun avoidance behaviour. Calcium deficiency predominates in tropical countries, especially in the malnourished population. Nutritional rickets can have devastating health consequences beyond bony deformities (swollen wrist and ankle joints, rachitic rosary, soft skull, stunting and bowing) and include life-threatening hypocalcaemic complications of seizures and, in infancy, heart failure due to dilated cardiomyopathy. In children, diagnosis of rickets (always associated with osteomalacia) is confirmed on radiographs (cupping and flaring of metaphyses) and should be suspected in high risk individuals with the above clinical manifestations in the presence of abnormal blood biochemistry (high alkaline phosphatase and parathyroid hormone, low 25-hydroxyvitamin D and calcium and/or low phosphate). In adults or adolescents with closed growth plates, osteomalacia presents with non-specific symptoms (fatigue, malaise and muscle weakness) and abnormal blood biochemistry, but only in extreme cases, it is associated with radiographic findings of Looser's zone fractures. Bone biopsies could confirm osteomalacia at earlier disease stages, for definitive diagnosis. Treatment includes high-dose cholecalciferol or ergocalciferol daily for a minimum of 12 wk or stoss therapy in exceptional circumstances, each followed by lifelong maintenance supplementation. In addition, adequate calcium intake through diet or supplementation should be ensured. Preventative approaches should be tailored to the population needs and incorporate multiple strategies including targeted vitamin D supplementation of at-risk groups and food fortification with vitamin D and/or calcium. Economically, food fortification is certainly the most cost-effective way forward. [ABSTRACT FROM AUTHOR]

Vitamin D is mainly made in the skin following exposure to sunlight but can also be taken in via specific natural or fortified food sources. It is essential for intestinal calcium absorption and thereby bone mineralisation. Deficiency in vitamin D, or low dietary calcium intake, therefore results in defective bone mineralisation causing osteomalacia in children and adults and rickets in growing children. The leading causes of rickets and osteomalacia worldwide are solar vitamin D deficiency and/or nutritional calcium deficiency. Long-standing severe vitamin D deficiency can lead to craniotabes, large fontanelle, leg bowing, stunted growth and obstructed labour. The deficient state in the infant is almost always acquired from the mother. Therefore, robust antenatal and infant vitamin D supplementation programmes are obligatory to prevent complications. Conversely, lack of programme monitoring and conflicting recommendations can lead to confusion among healthcare professionals and poor uptake in the population. Factors shown to improve adherence to supplementation include universal supplementation of breast- and bottle-fed infants, monitoring supplementation at antenatal/postnatal healthcare visits, providing information to families at discharge from the neonatal unit and financial family support. [ABSTRACT FROM AUTHOR]

Hypophosphatasia (HPP) is an inherited metabolic bone disease characterized by reduced mineralization due to mutations in the tissue non-specific alkaline phosphatase (ALPL) gene. HPP is clinically variable with extensive allelic heterogeneity in the ALPL gene. We report the findings of in vitro functional studies following site-directed mutagenesis in bi-allelic mutations causing extreme clinical phenotypes; severe perinatal and asymptomatic HPP. Elucidate genotype-phenotype correlation using in vitro functional studies and 3 dimensional (3D) ALP modelling. Clinical, biochemical and radiological features were recorded in two children with extreme HPP phenotypes: Subject 1 (S1): Perinatal HPP with compound heterozygous mutations (c.110T>C; c.532T>C); Subject 2 (S2): asymptomatic with homozygous missense mutation (c.715G>T). Plasmids created for mutants 1 c.110T>C (L37P), 2 c.532T>C (Y178H) and 3 c.715G>T (D239Y) using in vitro mutagenesis were transfected into human osteosarcoma (U 2 OS) cells and compared to wildtype (WT) and mock cDNA. ALP activity was measured using enzyme kinetics with p -nitrophenylphosphate. Mineral deposition was evaluated photometrically with Alizarin Red S staining after culture with mineralization medium. Western blot analysis was performed to identify the mature type protein expression (80 kDa). Mutations were located on a 3D ALP model. Co-transfection was performed to identify dominant negative effect of the mutants. Phenotype : S1, had typical perinatal HPP phenotype at birth; extremely under-mineralized bones and pulmonary hypoplasia. S2, diagnosed incidentally by laboratory tests at 4 years, had normal growth, development, dentition and radiology. All S2's siblings (3 homozygous, 1 heterozygous) were asymptomatic. All subjects had typical biochemical features of HPP (low ALP, high serum pyridoxal-5′-phosphate), except the heterozygous sibling (normal ALP). Functional assay : Mutants 1 and 2 demonstrated negligible ALP activity and mineralization was 7.9% and 9.3% of WT, respectively. Mutant 3 demonstrated about 50% ALP activity and 15.5% mineralization of WT. On Western blot analysis, mutants 1 and 2 were detected as faint bands indicating reduced expression and mutant 3 was expressed as mature form protein with 50% of WT expression. Mutant 1 was located near the Glycosylphosphatidylinositol anchor, 2 at the core structure of the ALP protein and 3 at the periphery of the protein structure. Co-transfection did not reveal a dominant negative effect in any of the mutants. Our findings expand the current knowledge of functional effect of individual mutations and the importance of their location in the ALP structure. • Genotype-phenotype correlation in two clinical extremes of HPP caused by bi-allelic ALPL mutations are reported. • Bi-allelic c.715G>T mutation displays biochemical features of HPP without clinical disease • In vitro c.715G>T mutagenesis model demonstrates reduced ALP activity (50% of WT) and mineralization ability (15.5% of WT) • Proximity of mutations to the active site on ALP structure determines clinical phenotype [ABSTRACT FROM AUTHOR]

Highlights • The burden of "nutritional" rickets due to solar vitamin D and dietary calcium deficiency is increasing worldwide. • Nutritional osteomalacia co-exists with rickets in children, but also affects adults/adolescents who mostly remain undiagnosed. • Nutritional osteomalacia is a growing global public health concern and yet the true disease burden remains unexplored and neglected. • There is a pressing need for non-invasive diagnostic criteria and studies exploring osteomalacia's true prevalence in vivo and post-mortem. • Further studies will inform public health policies relating to vitamin D and/or calcium supplementation and food fortification. Abstract Osteomalacia and rickets result from defective mineralization when the body is deprived of calcium. Globally, the main cause of osteomalacia is a lack of mineral supply for bone modeling and remodeling due to solar vitamin D and/or dietary calcium deficiency. Osteomalacia occurs when existing bone is replaced by unmineralized bone matrix (osteoid) during remodeling in children and adults, or when newly formed bone is not mineralized in time during modeling in children. Rickets occurs when hypomineralization affects the epiphyseal growth plate chondrocytes and adjacent bone metaphysis in growing children. Hence, osteomalacia co-exists with rickets in growing children. Several reports in the last decade highlight the resurgence of so-called "nutritional" rickets in the dark-skinned population living in high-income countries. However, very few studies have ever explored the hidden iceberg of nutritional osteomalacia in the population. Rickets presents with hypocalcaemic (seizures, tetany, cardiomyopathy), or hypophosphataemic complications (leg bowing, knock knees, rachitic rosary, muscle weakness) and is diagnosed on radiographs (cupping and fraying of metaphyses). In contrast, osteomalacia lacks distinctive, non-invasive diagnostic laboratory or imaging criteria and the clinical presentation is non-specific (general fatigue, malaise, muscle weakness and pain). Hence, osteomalacia remains largely undiagnosed, as a hidden disease in millions of dark-skinned people who are at greatest risk. Radiographs may demonstrate Looser's zone fractures in those most severely affected, however to date, osteomalacia remains a histological diagnosis requiring a bone biopsy. Biochemical features of high serum alkaline phosphatase (ALP), high parathyroid hormone (PTH) with or without low 25 hydroxyvitamin D (25OHD) concentrations are common to both rickets and osteomalacia. Here, we propose non-invasive diagnostic criteria for osteomalacia. We recommend a diagnosis of osteomalacia in the presence of high ALP, high PTH, low dietary calcium intake (<300 mg/day) and/or low serum 25OHD (<30 nmol/L). Presence of clinical symptoms (as above) or Looser's zone fractures should be used to reaffirm the diagnosis. We call for further studies to explore the true prevalence of nutritional osteomalacia in various populations, specifically the Black and Asian ethnic groups, in order to identify the hidden disease burden and inform public health policies for vitamin D/calcium supplementation and food fortification. [ABSTRACT FROM AUTHOR]

Introduction Total daily insulin required to achieve glycaemic control in type 1 diabetes ( T1D) depends on numerous factors. Correlation of insulin requirement to body mass index and waist circumference has been variably reported in the literature and that of waist-to-height ratio has not been studied. Aims To study the correlation between daily insulin requirement [total daily dose ( TDD)] and waist-to-height ratio ( WHtR) in a multiethnic population. Methods A cross-sectional study of children (5-18 years) with T1D attending a diabetes clinic in a multiethnic population in Bradford, UK was conducted. Physical measurements were undertaken in the clinic setting and data collected from case notes and patients/carers. Results Sixty nine patients with mean age 12.7(±3.1) yr, duration of diabetes 5.4(±3.5) yr and hemoglobin A1c ( HbA1c) 80(±18)mmol/mol(9.5 ± 1.6%) were recruited. Nearly 54% (n = 37) were white and 46% were non-white (29 Asian Pakistani; 1 Indian; 2 mixed White Afro-Caribbean). The two groups had similar demographics and disease profiles. Non-whites compared with whites had a higher prevalence of obesity (15 vs 5%, p < 0.01), family history of type 2 diabetes ( T2D) (49% vs. 33%), microalbuminuria (22% vs. 11%, p < 0.05) and deprivation (mean index of multiple deprivation score 42 vs. 30, p < 0.001). WHtR and TDD were poorly correlated in the whole group. There was however a significant positive correlation in Caucasians (r = 0.583, N = 37, p < 0.01) and a negative correlation in Asian Pakistanis (r = −0.472, N = 32, p < 0.01); with a significant negative correlation seen in subjects with relatives with T2D (r = −0.86, N = 6, p = 0.02). Conclusions The variation in correlations highlights that the two ethnic groups behave differently and should therefore be studied separately with regards to factors influencing insulin requirements with careful consideration to the presence of parental IR. Further prospective studies are required to explore the reasons for these differences. [ABSTRACT FROM AUTHOR]

Introduction Survival following treatment of paediatric medulloblastomas has significantly improved over the past few decades, but as a consequence, late effects, particularly endocrine sequelae, have been recognized. The complete picture of late effects, however, has been limited by short duration of follow-up. Aim To establish the evolution of endocrine sequelae in patients treated for medulloblastoma. Methods Single-centre analysis of medulloblastoma treatment and endocrine sequelae in patients diagnosed between 1982 and 2002. Results A total of 109 patients were treated for medulloblastoma, with various treatment modalities involving radio- and chemotherapy. Only 45 (41%) patients remained alive, and details of treatment and late effects were available for 35 (25 m). The median age at diagnosis was 8 (range 2-14) years, and the median follow-up was 18 (range 10-28) years. Growth hormone deficiency ( GHD) was the most prevalent hormone deficiency (97%), followed by primary hypothyroidism (60%) and adrenocorticotrophic hormone ( ACTH) deficiency (45·5%). The median time from end of treatment to loss of growth hormone was 1·7 (range 0·7-15) years, ACTH deficiency 2·9 (range 0·75-7·5) years and hypothyroidism 4·1 (range 0·7-11·4) years. Twenty-three percentage developed hypogonadism (17% primary and 6% secondary), whilst precocious puberty was seen in 20%. Endocrinopathies appeared to be more prevalent in those treated with concomitant chemotherapy and radiotherapy. Conclusions Prevalence of endocrine sequelae in medulloblastoma survivors is high, and evolution of endocrine dysfunction can occur as late as 15 years from treatment completion; hence, long-term close monitoring of growth, puberty and gonadal function is essential. [ABSTRACT FROM AUTHOR]

Aims: With numerous and continuing attempts at adapting diabetes self-management support programmes to better account for underserved populations, its important that the lessons being learned are understood and shared. The work we present here reviews the latest evidence and best practice in designing and embedding culturally and socially sensitive, self-management support programmes. Methods: We explored the literature with regard to four key design considerations of diabetes self-management support programmes: Composition - the design and content of written materials and digital tools and interfaces; Structure - the combination of individual and group sessions, their frequency, and the overall duration of programmes; Facilitators - the combination of individuals used to deliver the programme; and Context – the influence and mitigation of a range of individual, socio-cultural, and environmental factors. Results: We found useful and recent examples of design innovation within a variety of countries and models of health care delivery including Brazil, Mexico, Netherlands, Spain, United Kingdom, and United States of America. Within Composition we confirmed the importance of retaining best practice in creating readily understood written information and intuitive digital interfaces; Structure the need to offer group, individual, and remote learning options in programmes of flexible duration and frequency; Facilitators where the benefits of using culturally concordant peers and community-based providers were described; and finally in Context the need to integrate self-management support programmes within existing health systems, and tailor their various constituent elements according to the language, resources, and beliefs of individuals and their communities. Conclusions: A number of design principles across the four design considerations were identified that together offer a promising means of creating the next generation of self-management support programme more readily accessible for underserved communities. Ultimately, we recommend that the precise configuration should be co-produced by all relevant service and patient stakeholders and its delivery embedded in local health systems. [ABSTRACT FROM AUTHOR]

Objectives. Investigate the effect of using short bursts of moderate-intensity activity between meals to lower hyperglycaemia on glucose metrics. Design and Methods. Children and young people with type 1 diabetes (CYPD) attending continuous glucose monitoring education were taught to use moderate-intensity activity to lower high glucose levels (to <10.0 mmol/L using 10–15 minlowers ∼2.0 mmol/L) between meals. Retrospective cross-sectional data analysis of CYPD at a single tertiary centre between 2019 and 2022. Data were collected on demographics and glucose metrics (HbA1c, time in range (TIR, 3.9–10.0 mmol/L), time above range (TAR, >10.0 mmol/L), time below range (TBR, <3.9 mmol/L)). Minutes of activity usually performed to lower a glucose level of 14.0 mmol/L trending steady at 6 months grouped the CYPD into low (<5 min), mild (5–10 min), or moderate (11–20 min) activity groups. Results. 125 (n = 53, 40% male) CYPD with a mean (standard deviations) age of 12.3 (±3.7) years and diabetes duration of 7.0 ± 3.7 years were included. HbA1c improved from 58.5 (±8.6) mmol/mol at baseline to 54.9 (±7.2) mmol/mol at 6 months (p < 0.001). Low, mild, and moderate activity was reported by 30% (n = 37), 34% (n = 43), and 36% (n = 45), respectively. At 6 months, HbA1c (52.0 vs. 54.3 vs. 59.4 mmol/mol, p < 0.001), TIR (68.0% vs. 59.71 vs. 51.1%, p < 0.001) and TAR (29.9% vs. 38.3% vs. 45.3%, p < 0.001) were significantly different across the moderate, mild, and low activity groups, respectively. No association was found for TBR (2.16% vs. 2.32% vs. 2.58%, p = 0.408) across groups. Conclusion. Increasing the use of moderate-intensity activity to lower hyperglycaemia between meals is associated with improved glucose control without increasing hypoglycaemia for CYPD. [ABSTRACT FROM AUTHOR]

Objectives. Investigate the effect of using short bursts of moderate-intensity activity between meals to lower hyperglycaemia on glucose metrics. Design and Methods. Children and young people with type 1 diabetes (CYPD) attending continuous glucose monitoring education were taught to use moderate-intensity activity to lower high glucose levels (to <10.0 mmol/L using 10–15 minlowers ∼2.0 mmol/L) between meals. Retrospective cross-sectional data analysis of CYPD at a single tertiary centre between 2019 and 2022. Data were collected on demographics and glucose metrics (HbA1c, time in range (TIR, 3.9–10.0 mmol/L), time above range (TAR, >10.0 mmol/L), time below range (TBR, <3.9 mmol/L)). Minutes of activity usually performed to lower a glucose level of 14.0 mmol/L trending steady at 6 months grouped the CYPD into low (<5 min), mild (5–10 min), or moderate (11–20 min) activity groups. Results. 125 (n = 53, 40% male) CYPD with a mean (standard deviations) age of 12.3 (±3.7) years and diabetes duration of 7.0 ± 3.7 years were included. HbA1c improved from 58.5 (±8.6) mmol/mol at baseline to 54.9 (±7.2) mmol/mol at 6 months (p < 0.001). Low, mild, and moderate activity was reported by 30% (n = 37), 34% (n = 43), and 36% (n = 45), respectively. At 6 months, HbA1c (52.0 vs. 54.3 vs. 59.4 mmol/mol, p < 0.001), TIR (68.0% vs. 59.71 vs. 51.1%, p < 0.001) and TAR (29.9% vs. 38.3% vs. 45.3%, p < 0.001) were significantly different across the moderate, mild, and low activity groups, respectively. No association was found for TBR (2.16% vs. 2.32% vs. 2.58%, p = 0.408) across groups. Conclusion. Increasing the use of moderate-intensity activity to lower hyperglycaemia between meals is associated with improved glucose control without increasing hypoglycaemia for CYPD. [ABSTRACT FROM AUTHOR]

Aims: Facilitated self‐management support programmes have become central to the treatment of chronic diseases including diabetes. For many children and young people with diabetes (CYPD), the impact on glycated haemoglobin (HbA1c) and a range of self‐management behaviours promised by these programmes remain unrealised. This warrants an appraisal of current thinking and the existing evidence to guide the development of programmes better targeted at this age group. Methods: Create a narrative review of systematic reviews produced in the last 3 years that have explored the impact on CYPD of the four key elements of self‐management support programmes: education, instruction and advice including peer support; psychological counselling via a range of therapies; self‐monitoring, including diaries and telemetric devices; and telecare, the technology‐enabled follow‐up and support by healthcare providers. Results: Games and gamification appear to offer a promising means of engaging and educating CYPD. Psychological interventions when delivered by trained practitioners, appear to improve HbA1c and quality of life although effect sizes were small. Technology‐enabled interactive diaries can increase the frequency of self‐monitoring and reduce levels of HbA1c. Telecare provided synchronously via telephone produced significant improvements in HbA1c. Conclusions: The cost‐effective flexibility of increasing the reliance on technology is an attractive proposition; however, there are resource implications for digital connectivity in underserved populations. The need remains to improve the understanding of which elements of each component are most effective in a particular context, and how to optimise the influence and input of families, caregivers and peers. [ABSTRACT FROM AUTHOR]

Objectives: Compare the clinical and cost‐effectiveness of an established face to face (F2F) structured education program to a new remote (VIRTUAL) program teaching dynamic glucose management (DynamicGM) to children and young people with type 1 diabetes (CYPD) using continuous glucose monitoring (CGM). To ascertain the most effective DynamicGM strategies predicting time in range (TIR) (3.9–10.0 mmol/L) and incorporating these into a user‐friendly teaching aid. Design and methods: Effectiveness of the F2F and VIRTUAL programs were ascertained by comparing the mean change (Δ) from baseline to 6 months in HbA1c, TIR and severe hypoglycemia. Delivery cost for the two programs were evaluated. Factors predicting TIR in the combined cohort were determined and incorporated into a user‐friendly infographic. Results: First 50 graduates per group were evaluated. The mean difference in Δ HbA1c, Δ TIR and Δ episodes of severe hypoglycemia between VIRTUAL and F2F groups were 1.16 (p = 0.47), 0.76 (p = 0.78) and −0.06 (p = 0.61) respectively. Delivery cost per 50 CYPD for VIRTUAL and F2F were $5752 and $7020, respectively. The strongest predictors of TIR (n = 100) were short bursts of exercise (10–40 min) to lower hyperglycemia (p < 0.001), using trend arrow adjustment tools (p < 0.001) and adjusting pre‐meal bolus timing based on trend arrows (p < 0.01). These strategies were translated into a GAME (Stop highs), SET (Stay in target), MATCH (Prevent lows) mnemonic. Conclusion: Teaching DynamicGM VIRTUALLY is just as effective as F2F delivery and cost saving. Short bursts of exercise and using CGM trend arrows to adjust insulin dose and timing improves TIR. [ABSTRACT FROM AUTHOR]

Objectives: Create and evaluate the effectiveness of a structured education program in children and young people (CYP) with type 1 diabetes using continuous glucose monitoring (CGM). Design and methods: Step 1: CGM devices were evaluated for predetermined criteria using a composite score. Step 2: The education program was developed following review of international structured education guidance, dynamic glucose management (DynamicGM) literature, award‐winning diabetes educators' websites, and CGM user feedback. Step 3: Program effectiveness was assessed at six months by change in time below range (TBR) (<3.9mmol/L), time in range (TIR) (3.9‐10.0mmol/L), time above range level 2 (TAR2) (>13.9mmol/L), severe hypoglycemia and HbA1c using a paired T‐test. A DynamicGM score was developed to assess proactive glucose management. Factors predicting TBR and TIR were assessed using regression analysis. Results: Dexcom G6 was chosen for integrated CGM (iCGM) status and highest composite score (29/30). Progressive DynamicGM strategies were taught through five sessions delivered over two months. Fifty CYP (23 male) with a mean (±SD) age and diabetes duration of 10.2 (±4.8) and 5.2 (±3.7) years respectively, who completed the education program were prospectively evaluated. Evaluation at six months showed a significant reduction in TBR (10.4% to 2.1%, p<.001), TAR2 (14.1% to 7.3%, p<.001), HbA1c [7.4 to 7.1% (57.7 to 53.8 mmol/mol), p<.001] and severe hypoglycemic episodes (10 to 1, p<.05); TIR increased (47.4% to 57.0%, p<.001). Number of Dexcom followers (p<.05) predicted reduction in TBR and DynamicGM score (p<.001) predicted increased TIR. Conclusion: Teaching DynamicGM strategies successfully improves TIR and reduces hypoglycemia. [ABSTRACT FROM AUTHOR]