Prevalence of type 2 diabetes risk factors, including overweight and obesity, among youth attending hospital-based paediatric care in Western Melbourne.

AIM: To determine the prevalence of risk factors for type 2 diabetes in overweight and obese adolescents attending hospital-based paediatric care in Western Melbourne. METHODS: One hundred overweight and obese adolescents (aged 10-17 years) who attended an outpatient clinic at Sunshine Hospital between May 2019 and May 2020 were randomly selected following a retrospective chart review of 10-17 years old for whom a height and weight had been documented. Additional risk factors for type 2 diabetes were ascertained via structured telephone interview. Data were analysed to determine the overall prevalence of risk factors for type 2 diabetes, and to evaluate for associations between each parameter with body mass index and the number of risk factors. RESULTS: Of the 487 adolescents who had height and weight data recorded, 45% were overweight or obese. 77% of those who were interviewed had an additional risk factor for type 2 diabetes. No association between the number of risk factors and body mass index standard deviation score was found. Additionally, there was no association between the number of risk factors for type 2 diabetes and either family history of type 2 diabetes or ethnicity. CONCLUSIONS: This paediatric subpopulation had a high rate of risk factors for type 2 diabetes in addition to overweight and obesity, and are at risk of premature mortality and chronic morbidity should they develop type 2 diabetes.

Accelerometer-based osteogenic indices, moderate-to-vigorous and vigorous physical activity, and bone traits in adolescents.

OBJECTIVES: We investigated the associations of accelerometry-derived osteogenic indices (OIs), moderate-to-vigorous (MVPA), and vigorous intensity physical activity (VPA) with peripheral quantitative computed tomography (pCQT) parameters in 99 adolescents aged 10-13 years. METHODS: Bone parameters were assessed at the distal (4%) and shaft (66%) of the tibia using pQCT. Accelerometers were worn on the right hip for 7 consecutive days. OIs were calculated based on acceleration peak histograms either using all of the peaks (OI) or peaks with acceleration ≥5.2 g (HOI). MVPA and VPA were defined using previously published cut-points. RESULTS: HOI was positively associated with total area (Partial correlation= 0.22, 95% CI=0.01 to 0.41), cortical area (CoA) (0.33, 95% CI=0.13 to 0.50), and stress strain index (SSI) (0.29, 95% CI=0.09 to 0.47) of tibial shaft and with total density at the distal tibia (0.23, 95% CI=0.02 to 0.42). OI was positively associated with CoA (0.31, 95% CI=0.11 to 0.49) and SSI (0.26, 95% CI=0.05 to 0.44) of tibial shaft. MVPA was positively associated with CoA (0.28, 95% CI=0.07 to 0.46) of the tibial shaft. CONCLUSIONS: OI and HOI were positively associated with pQCT parameters while MVPA and VPA demonstrated less consistent associations with them.

Clinical practice guidelines for paediatric X-linked hypophosphataemia in the era of burosumab.

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.

Proinsulin C-peptide is an autoantigen in people with type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells, found within the islets of Langerhans in the pancreas, are destroyed by islet-infiltrating T cells. Identifying the antigenic targets of beta-cell reactive T cells is critical to gain insight into the pathogenesis of T1D and develop antigen-specific immunotherapies. Several lines of evidence indicate that insulin is an important target of T cells in T1D. Because many human islet-infiltrating CD4+ T cells recognize C-peptide-derived epitopes, we hypothesized that full-length C-peptide (PI33-63), the peptide excised from proinsulin as it is converted to insulin, is a target of CD4+ T cells in people with T1D. CD4+ T cell responses to full-length C-peptide were detected in the blood of: 14 of 23 (>60%) people with recent-onset T1D, 2 of 15 (>13%) people with long-standing T1D, and 1 of 13 (<8%) HLA-matched people without T1D. C-peptide-specific CD4+ T cell clones, isolated from six people with T1D, recognized epitopes from the entire 31 amino acids of C-peptide. Eighty-six percent (19 of 22) of the C-peptide-specific clones were restricted by HLA-DQ8, HLA-DQ2, HLA-DQ8trans, or HLA-DQ2trans, HLA alleles strongly associated with risk of T1D. We also found that full-length C-peptide was a much more potent agonist of some CD4+ T cell clones than an 18mer peptide encompassing the cognate epitope. Collectively, our findings indicate that proinsulin C-peptide is a key target of autoreactive CD4+ T cells in T1D. Hence, full-length C-peptide is a promising candidate for antigen-specific immunotherapy in T1D.

The skeletal maturity of Australian children aged 10-13 years in 2016.

Skeletal maturity can be used as a biological indicator of the tempo of growth in children and adolescents. We present a description of skeletal maturity from a cohort of white Australian children and describe variation in skeletal maturity based on child age. Participants (n = 71; age 10.5-13.9 years) were recruited from the 'Healthy, Active Preschool & Primary Years (HAPPY)' study. Left hand-wrist radiographs were used to determine skeletal maturity using the Tanner-Whitehouse III (TW3) RUS technique. In boys, the mean skeletal maturity offset (bone age - chronological age) was -0.12 ± 0.19 years and 57.9% had delayed skeletal maturity compared to chronological age. Among those with delayed skeletal maturity, the average delay was 0.99 years (range 0.02-2.54 years). In girls, skeletal age was advanced, on average, compared to chronological age by 0.32 ± 0.20 years. Among the 39.4% of girls with delayed skeletal maturity, the average delay was 0.48 years (range: 0.01-2.28). Four children in the sample exhibited a delay in skeletal maturity greater than 2 years. In the context of secular trends towards advanced skeletal maturity observed globally, delayed skeletal maturation in this white, economically privileged cohort are surprising and warrant further exploration.

Global consensus on nutritional rickets: Implications for Australia.

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.

Validity of hip-worn inertial measurement unit compared to jump mat for jump height measurement in adolescents.

Jump tests assess lower body power production capacity, and can be used to evaluate athletic ability and development during growth. Wearable inertial measurement units (IMU) seem to offer a feasible alternative to laboratory-based equipment for jump height assessments. Concurrent validity of these devices for jump height assessments has only been established in adults. Therefore, the purpose of this study was to evaluate the concurrent validity of IMU-based jump height estimate compared to contact mat-based jump height estimate in adolescents. Ninety-five adolescents (10-13 years-of-age; girls N = 41, height = 154 (SD 9) cm, weight = 44 (11) kg; boys N = 54, height = 156 (10) cm, weight = 46 (13) kg) completed 3 counter-movement jumps for maximal jump height on a contact mat. Inertial recordings (accelerations, rotations) were concurrently recorded with a hip-worn IMU (sampling at 256 Hz). Jump height was evaluated based on flight time. The mean IMU-derived jump height was 27.1 (SD 3.8) cm, and the corresponding mean jump-mat-derived value was 21.5 (3.4) cm. While a significant 26% mean difference was observed between the methods (5.5 [95% limits of agreement 2.2 to 8.9] cm, P = 0.006), the correspondence between methods was excellent (ICC = 0.89). The difference between methods was weakly positively associated with jump height (r = 0.28, P = 0.007). Take-off velocity-derived jump height was also explored but produced only fair congruence. In conclusion, IMU-derived jump height exhibited excellent congruence to contact mat-based jump height and therefore presents a feasible alternative for jump height assessments in adolescents.

Consensus guidelines on the use of bisphosphonate therapy in children and adolescents.

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.

Vitamin D in newborns. A randomised controlled trial comparing daily and single oral bolus vitamin D in infants.

AIM: There are no published data to demonstrate the efficacy of bolus dose vitamin D in newborn infants. The study sought to evaluate this alternative approach of supplementation. METHODS: This single centre, open randomised controlled trial was conducted from August 2013 to May 2014. It compared the efficacy and safety of daily (400 IU) versus a bolus dose (50 000 IU) of cholecalciferol in newborn infants of vitamin D deficient mothers. The primary outcome measure was the rate of 25 hydroxyvitamin D (25OHD) repletion-defined as 25OHD greater than 50 nmol/L. The secondary objective was determining safety using adjusted total serum calcium. RESULTS: Of 70 eligible infants, 36 received a daily dose and 34 received a single high-dose cholecalciferol. Mean 25OHD in the bolus group (154 nmol/L, 95% confidence interval (CI) 131-177) was higher than the daily group (48 nmol/L, 95% CI 42-54) at 1-2 weeks of age. This was reversed at 3-4 months, (65 nmol/L, 95% CI 59-71) compared with the daily group (81 nmol/L, 95% CI 77-85). More infants in the single bolus group achieved vitamin D repletion (100 vs. 31%) at 1-2 weeks. By 3-4 months, both groups achieved similar vitamin D repletion rates (91 vs. 89%). Mean adjusted total serum calcium in the bolus group were normal at 1-2 weeks (2.73 mmol/L) and 3-4 months (2.55 mmol/L). CONCLUSION: Single bolus dosing of 50 000 IU cholecalciferol achieves higher 25OHD repletion rates at 1-2 weeks of age compared with daily dosing, but repletion rates were similar by 3-4 months. There was no hypercalcaemia documented with single bolus dosing in this study.

Effect of Polyester and Plaster of Paris Casts on Determination of Volumetric Bone Mineral Density Assessed by Peripheral Quantitative Computed Tomography (pQCT).

Peripheral quantitative computed tomography (pQCT) is a non-invasive, low-radiation tool for measuring volumetric bone mineral density. It has potential for use in fracture healing applications; however, the unknown attenuation effects of cast material on peripheral quantitative computed tomography have contributed to its limited use in this area. The effect of two common cast materials, polyester and Plaster of Paris was investigated by performing both in vitro and in vivo studies. The in vitro study tested the effect of increasing layers of cast material on bone density measurements performed on a hydroxyapatite phantom. Cast thickness was directly associated with a reduction in bone mineral density, with twelve layers of polyester and Plaster of Paris resulting in a 0.55 and 2.21 % decrease in bone density measurements. Precision error in situ with polyester cast material was 0.71 %, and 2.31 % with Plaster of Paris cast material. The in vivo study comprised a prospective trial with 28 healthy adult participants to evaluate the effect of the two cast materials. Trabecular bone mineral density was increased by 0.5 % in the presence of a polyester cast and decreased by 4.22 % in the presence of a Plaster of Paris cast. Cortical bone mineral density was decreased by 3.46 and 5.54 % for polyester and Plaster of Paris, respectively. This study quantified the effects of orthopaedic casts on pQCT-derived bone parameters. The results suggest applicability of commonly utilised cast materials in combination with pQCT to assess fracture healing.

Low vitamin D is associated with hypertension in paediatric obesity.

AIM: The aim of this paper was to investigate the relationship between circulating 25-hydroxyvitamin D (25(OH)D) and cardio-metabolic risk factors in a large cohort of obese youth attending tertiary paediatric obesity services. METHODS: We conducted a retrospective cross-sectional study. Data were retrospectively collected from all new consultations of children and adolescents attending obesity outpatient clinics between 2008 and 2011 at the two major paediatric hospitals in Melbourne, Australia. Information collected included demographics, anthropometry, blood pressure, pubertal staging, body composition and fasting serum levels of 25(OH)D, glucose, insulin, cholesterol, triglyceride, high-density lipoprotein, liver function, calcium and phosphate. RESULTS: 25(OH)D data were available in 229 patients (age 3-18 years; 116 men; mean (standard deviation) body mass index ( BMI) Z-score 2.5 (0.5) ). One hundred four (45%) participants were 25(OH)D deficient (<50 nmol/L). Lower serum 25(OH)D levels were associated with higher BMI Z-score (P-trend = 0.001), total fat mass (P-trend = 0.009), systolic (P-trend = 0.03) and diastolic blood pressures(P-trend = 0.009). In multivariable-adjusted regression analysis, 25(OH)D was significantly lower in those with elevated blood pressure after adjustment for BMI(P-trend = 0.004) or total fat mass (P-trend = 0.01). CONCLUSION: Overweight and obese youth attending specialist obesity services have a high prevalence of vitamin D deficiency. In this population, lower levels of vitamin D were seen in those with greater adiposity, and independent of this, in those who had higher blood pressure.

Identification of 70 calcium-sensing receptor mutations in hyper- and hypo-calcaemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites.

The calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that has an extracellular bilobed venus flytrap domain (VFTD) predicted to contain five calcium (Ca(2+))-binding sites. To elucidate the structure-function relationships of the VFTD, we investigated 294 unrelated probands with familial hypocalciuric hypercalcaemia (FHH), neonatal severe primary hyperparathyroidism (NSHPT) or autosomal dominant hypocalcaemic hypercalciuria (ADHH) for CaSR mutations and performed in vitro functional expression studies and three-dimensional modelling of mutations involving the VFTD. A total of 70 different CaSR mutations were identified: 35 in FHH, 10 in NSHPT and 25 in ADHH patients. Furthermore, a CaSR variant (Glu250Lys) was identified in FHH and ADHH probands and demonstrated to represent a functionally neutral polymorphism. NSHPT was associated with a large proportion of truncating CaSR mutations that occurred in the homozygous or compound heterozygous state. Thirty-four VFTD missense mutations were identified, and 18 mutations were located within 10 Å of one or more of the predicted Ca(2+)-binding sites, particularly at the VFTD cleft, which is the principal site of Ca(2+) binding. Mutations of residues 173 and 221, which are located at the entrance to the VFTD cleft binding site, were associated with both receptor activation (Leu173Phe and Pro221Leu) and inactivation (Leu173Pro and Pro221Gln), thereby highlighting the importance of these residues for entry and binding of Ca(2+) by the CaSR. Thus, these studies of disease-associated CaSR mutations have further elucidated the role of the VFTD cleft region in Ca(2+) binding and the function of the CaSR.

Vitamin D and health in pregnancy, infants, children and adolescents in Australia and New Zealand: a position statement.

• The recommended level for serum 25-hydroxyvitamin D (25(OH)D) in infants, children, adolescents and during pregnancy and lactation is ≥ 50 nmol/L. This level may need to be 10-20 nmol/L higher at the end of summer to maintain levels ≥ 50 nmol/L over winter and spring. • Sunlight is the most important source of vitamin D. The US recommended dietary allowance for vitamin D is 600 IU daily in children aged over 12 months and during pregnancy and lactation, assuming minimal sun exposure. • Risk factors for low vitamin D are: lack of skin exposure to sunlight, dark skin, southerly latitude, conditions affecting vitamin D metabolism and storage (including obesity) and, for infants, being born to a mother with low vitamin D and exclusive breastfeeding combined with at least one other risk factor. • Targeted measurement of 25(OH)D levels is recommended for infants, children and adolescents with at least one risk factor for low vitamin D and for pregnant women with at least one risk factor for low vitamin D at the first antenatal visit. • Vitamin D deficiency can be treated with daily low-dose vitamin D supplements, although barriers to adherence have been identified. High-dose intermittent vitamin D can be used in children and adolescents. Treatment should be paired with health education and advice about sensible sun exposure. Infants at risk of low vitamin D should be supplemented with 400 IU vitamin D3 daily for at least the first year of life. • There is increasing evidence of an association between low vitamin D and a range of non-bone health outcomes, however there is a lack of data from robust randomised controlled trials of vitamin D supplementation.

Insulin pump therapy in children and adolescents: changes in dietary habits, composition and quality of life.

AIM: Continuous subcutaneous insulin infusion (CSII) can improve glycaemic control and dietary flexibility compared with conventional insulin therapies. There is little information on whether users are utilising this increased dietary flexibility, and whether dietary quality is affected. METHODS: A pre-post observational study was undertaken in 28 children and adolescents with type 1 diabetes commencing CSII. Meal pattern and dietary composition was examined from 3-day food diaries completed before and 3-6 months after CSII commencement. Participants completed the Diabetes-Specific Quality of Life for Youth Short Form, and body mass index z-score, and glycated haemoglobin were measured. A second posttest was undertaken at 18 months with those who were still on CSII and contactable (n = 18). RESULTS: Energy and macronutrient intake before and 18 months after CSII commencement were unchanged. Mean snacking events decreased significantly by 1.2 snacks per day (P = 0.009), as did the percentage energy derived from snacks (28.8%, 95% confidence interval (CI) 21.5-36.1 vs. 19.3%, 95% CI 13.2-25.4; P = 0.045). Diabetes-Specific Quality of Life for Youth Short Form score was not significantly affected by pump commencement (25.9 95% CI 18.2-33.6), and body mass index z-score remained similar before and after CSII. Glycated haemoglobin decreased by 0.5% in the 3-6 months following CSII commencement, but was similar to baseline at 18 months. CONCLUSIONS: This study demonstrates that the commencement of CSII did not lead to an abandonment of healthy eating principles, and that patients utilised the increased dietary flexibility to make changes to their snacking pattern.

Feasibility and acceptability of an online guided self-determination program to improve diabetes self-management in young adults.

Objective: Evaluate the feasibility and acceptability of an online guided self-determination (GSD) program to improve diabetes self-management skills among young adults with type 1 diabetes (YAD). Methods: An online program comprising seven structured interactive conversations was designed. A pre- and post- interventional study used a sequential, two-phase multiple method design. Phase one comprised a training program for diabetes educators (DEs). In Phase two YAD participated in program and completed pre- and post-surveys assessing motivation to self-manage, perceived competence in diabetes and communication with DEs. Both YAD and DEs provided a program evaluation. Results: The online GSD program was acceptable, feasible and effective in improving autonomous motivation in self-management and communication with DEs. Easy access and program flexibility were highly appreciated by both participant groups and perceived to assist YAD to stay motivated. Conclusion: The program had a significant impact on the diabetes self-management of YAD and was a feasible and acceptable way to engage and communicate with DEs. The GSD platform contributes to age appropriate and person-centred diabetes self-management. It can potentially reach geographically distanced populations, or with social circumstances or other barriers impeding in-person service provision.

Prevalence and characteristics of paediatric X-linked hypophosphataemia in Australia and New Zealand: Results from the Australian and the New Zealand Paediatric Surveillance Units survey.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Incidence of vitamin D deficiency rickets among Australian children: an Australian Paediatric Surveillance Unit study.

OBJECTIVE: To determine the incidence of and factors associated with vitamin D deficiency rickets in Australian children. DESIGN: 18-month questionnaire-based prospective observational study, using Australian Paediatric Surveillance Unit (APSU) data. SETTING: Australian paediatricians and child health workers, January 2006 - July 2007. PARTICIPANTS: Children aged ≤ 15 years with vitamin D deficiency rickets (25-hydroxyvitamin D [25OHD] ≤ 50 nmol/L, and elevated alkaline phosphatase levels [> 229 IU/L] and/or radiological rickets). MAIN OUTCOME MEASURES: Incidence of vitamin D deficiency rickets. Description of demographics, clinical presentation, identification and further analysis of overrepresented groups, and treatment regimens compared with best-practice guidelines. RESULTS: We identified 398 children with vitamin D deficiency (55% male; median age, 6.3 years [range, 0.2-15 years]). The overall incidence in children ≤ 15 years of age in Australia was 4.9/100 000/year. All had a low 25OHD level (median, 28 nmol/L [range, 5-50 nmol]) and an elevated alkaline phosphatase level (median, 407 IU/L [range, 229-5443 IU/L]), and 48 (12%) were hypocalcaemic. Ninety-five children had wrist x-rays, of whom 67 (71%) had rachitic changes. Most (98%) had dark or intermediate skin colour and 18% of girls were partially or completely veiled. Most children were born in Africa (252; 63%) and 75% of children were refugees. Duration of exclusive breastfeeding was inversely related to serum vitamin D levels in children < 3 years of age. Empirical vitamin D treatment was given to 4% of children before diagnosis. CONCLUSIONS: Vitamin D deficiency rickets is a significant problem in Australia among known high-risk groups. Public health campaigns to prevent, identify and tre@vitamin D deficiency, especially in high-risk groups, are essential.