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Access to published research has always been difficult for researchers and clinicians in low- and middle-income countries, because of the cost of and lack of access to the relevant publications. The dramatic recent increase in electronic research publications has resulted in a marked improvement in reader access to these publications through their mainly Open Access policies, however the costs of processing of submissions and publication have now become the burden of the researchers wishing to publish, rather than the readers. For many researchers working in LMIC, the Article Processing Charges (APC) are prohibitive, hampering the publication of research being conducted in and relevant to these countries. A number of grant funding agencies and international not-for-profit organizations are trying to address these issues by including funding for article publications in their grants, or by supporting publishing entities by subsiding the cost of publication, but more needs to be done by major journal publishers through markedly reducing the APC being charged to researchers in LMIC for open access facilities., (© 2023. The Author(s).)

Competing Interests: We declare no competing interests.

Objectives: There's paucity of longitudinal studies assessing the role of adolescent growth on adult body composition in developing countries. The aims of this study were to assess the association between adolescent change in height, weight and BMI and early adult height, weight, body fat and lean mass., Methods: Magnitude, timing and intensity of height, weight and BMI growth were modelled for participants from the Birth to Thirty (Bt30) cohort (7-23 years). Early adult height, weight, BMI and DXA-derived body composition were obtained 1881 black participants (21-24 years). Linear regression analyses were used to assess associations., Results: Adolescents with an earlier onset of puberty were heavier in childhood and had an earlier timing and faster weight gain velocity in late adolescence. The intensity of adolescent weight gain was positively associated with adult BMI and fat mass index (FMI) in females. Early timing of adolescent BMI gain was associated with increased weight and BMI in adult females and FMI in adult males. Achieving peak weight velocity around age at peak height velocity was associated with lower BMI and fat mass in both sexes., Conclusion: This study confirms the adverse consequences of excessive weight gain prior to puberty, which is associated with an earlier and faster resurgence in weight gain velocity in early adulthood. Factors that contribute to an asynchronous timing of ages of peak weight and peak height velocities may accentuate the risk of adult obesity., (© 2023. The Author(s).)

Background: A multivariable logistic regression model resulting from a case-control study of nutritional rickets in Nigerian children suggested that higher levels of serum 25(OH)D may be required to prevent nutritional rickets in populations with low-calcium intakes., Objectives: This current study evaluates if adding serum 1,25-dihydroxyvitamin D [1,25(OH) 2 D] to that model shows that increased levels of serum 1,25(OH) 2 D are independently associated with risk of children on low-calcium diets having nutritional rickets., Methods: Multivariable logistic regression analysis was used to model the association between serum 1,25(OH) 2 D and risk of having nutritional rickets in cases (n = 108) and controls (n = 115) after adjusting for age, sex, weight-for age z-score, religion, phosphorus intake and age began walking and the interaction between serum 25(OH)D and dietary calcium intake (Full Model)., Results: Serum 1,25(OH) 2 D levels were significantly higher (320 pmol/L vs. 280 pmol/L) (P = 0.002), and 25(OH)D levels were lower (33 nmol/L vs. 52 nmol/L) (P < 0.0001) in children with rickets than in control children. Serum calcium levels were lower in children with rickets (1.9 mmol/L) than in control children (2.2 mmol/L) (P < 0.001). Dietary calcium intakes were similarly low in both groups (212 mg/d) (P = 0.973). In the multivariable logistic model, 1,25(OH) 2 D was independently associated with risk of having rickets [coefficient = 0.007 (95% confidence limits: 0.002-0.011)] after adjusting for all variables in the Full Model., Conclusions: Results confirmed theoretical models that in children with low dietary calcium intake, 1,25(OH) 2 D serum concentrations are higher in children with rickets than in children without rickets. The difference in 1,25(OH) 2 D levels is consistent with the hypothesis that children with rickets have lower serum calcium concentrations which prompt the elevation of PTH levels resulting in an elevation of 1,25(OH) 2 D levels. These results support the need for additional studies to identify dietary and environmental risks for nutritional rickets., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: Vitamin D deficiency and anemia impact the health of women of reproductive age. Evidence suggests an inverse relationship between serum vitamin D (25-hydroxyvitamin D [25(OH)D]) and anemia/iron deficiency, but less is known about these associations in women of reproductive age, in particular in a setting with a combined burden of micronutrient deficiency, food insecurity, and obesity., Objective: We aimed to assess the associations between 25(OH)D and biomarkers of iron and anemia in a cohort of women of reproductive age from Soweto, South Africa. The prevalence of vitamin D deficiency was also assessed., Methods: In this cross-sectional substudy of the Healthy Life Trajectories Initiative (HeLTI) South Africa pilot trial, 25(OH)D, iron markers (ferritin and soluble transferrin receptor [sTFR]), and altitude-adjusted hemoglobin (Hb) were measured in 493 women aged 18 to 25 years. Associations between iron deficiency/anemia and vitamin D status were evaluated using multivariable logistic regression, adjusting for confounders including fat mass index (FMI). Structural equation modeling (SEM) was performed to evaluate direct and indirect pathways between 25(OH)D, iron and anemia markers, and covariates., Results: Of 493 participants, 136 (27.6%) had vitamin D insufficiency (25(OH)D ≥12-20 ng/mL), whereas 28 (5.6%) had vitamin D deficiency (<12 ng/mL). Anemia and iron deficiency were not significantly associated with vitamin D category (25(OH)D<20 ng/mL compared with ≥20 ng/mL) in multivariable logistic regression analyses. In SEM, log-transformed 25(OH)D was not significantly associated with Hb, ferritin, or sTFR, but it was significantly associated with season of data collection, hormonal contraceptive use, and FMI (total effects: B = 0.17, 95% CI: 0.104, 0.236, P < 0.001; B: 0.10, 95% CI: 0.041, 0.154, P < 0.001; B: -0.01, 95%CI: -0.016, -0.003, P = 0.003, respectively)., Conclusion: No significant association between vitamin D (25(OH)D), anemia (Hb), and iron markers was found. The inverse relationship between FMI and vitamin D status emphasizes the overlap between adiposity and micronutrient deficiencies in young South African women, exacerbating their risk of disease development., (© 2023 The Authors.)

Inadequate dietary calcium intake is a global public health problem that disproportionately affects low- and middle-income countries. However, the calcium status of a population is challenging to measure, and there are no standard methods to identify high-risk communities even in settings with an elevated prevalence of a disease caused or exacerbated by low calcium intake (e.g., rickets). The calcium status of a population depends on numerous factors, including intake of calcium-rich foods; the bioavailability of the types of calcium consumed in foods and supplements; and population characteristics, including age, sex, vitamin D status, and genetic attributes that influence calcium retention and absorption. The aim of this narrative review was to assess candidate indicators of population-level calcium status based on a range of biomarkers and measurement methods, including dietary assessment, calcium balance studies, hormonal factors related to calcium, and health outcomes associated with low calcium status. Several promising approaches were identified, but there was insufficient evidence of the suitability of any single indicator to assess population calcium status. Further research is required to develop and validate specific indicators of calcium status that could be derived from the analysis of data or samples that are feasibly collected in population-based surveys., (© 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences.)

Dietary calcium deficiency is considered to be widespread globally, with published estimates suggesting that approximately half of the world's population has inadequate access to dietary calcium. Calcium is essential for bone health, but inadequate intakes have also been linked to other health outcomes, including pregnancy complications, cancers, and cardiovascular disease. Populations in low- and middle-income countries (LMICs) are at greatest risk of low calcium intakes, although many individuals in high-income countries (HICs) also do not meet recommendations. Paradoxically, many LMICs with lower calcium intakes show lower rates of osteoporotic fracture as compared with HICs, though data are sparse. Calcium intake recommendations vary across agencies and may need to be customized based on other dietary factors, health-related behaviors, or the risk of calcium-related health outcomes. The lack of standard methods to assess the calcium status of an individual or population has challenged efforts to estimate the prevalence of calcium deficiency and the global burden of related adverse health consequences. This paper aims to consolidate available evidence related to the global prevalence of inadequate calcium intakes and associated health outcomes, with the goal of providing a foundation for developing policies and population-level interventions to safely improve calcium intake and status where necessary., (© 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences.)

Background: Tenofovir disoproxil fumarate (TDF) and intramuscular depot medroxyprogesterone acetate (DMPA-IM) are independently associated with reduced bone mineral density (BMD). We aimed to assess the combined effects of DMPA-IM use and TDF initiation on BMD in young adult women living with HIV over two years, compared with age-matched people without HIV., Methods: Th BONE: CARE study was a prospective cohort study that recruited women aged 18-35 years from 11 HIV care and general health facilities in Kampala, Uganda. The participants were classified into four groups on the basis of their combination of HIV status, TDF use, and DMPA-IM use, as follows: women living with HIV initiating TDF-containing antiretroviral therapy (ART) with DMPA-IM (HIV positive, DMPA positive, and TDF positive); women living with HIV using DMPA-IM but not eligible for ART as per local guidelines at the time of enrolment into the study (HIV positive, DMPA positive, and TDF negative); women living with HIV initiating TDF-containing ART without DMPA-IM (HIV positive, DMPA negative, and TDF positive); and controls without HIV using non-hormonal contraceptives (HIV negative, DMPA negative, and TDF negative). BMD of the lumbar spine, total hip, and femoral neck were measured using semiannual dual-energy x-ray absorptiometry at enrolment and at intervals every 6 months thereafter. We assessed percentage change in mean BMD., Findings: Between March 30, 2016, and Oct 19, 2017, we enrolled 265 women living with HIV initiating ART (159 DMPA-IM users and 106 non-hormonal contraceptive users), 187 women living with HIV using DMPA-IM but not ART, and 69 controls without HIV. Mean age was 26·1 years (SD 4·2). BMD declined significantly from baseline in women living with HIV on TDF with versus without DMPA-IM at the lumbar spine (-3·406% [95% CI -3·969 to -2·844] vs -1·111% [-1·929 to -0·293]; p<0·0001), total hip (-3·856% [-4·449 to -3·264] vs -1·714% [-2·479 to -0·949]; p=0·0002), and femoral neck (-4·422% [-5·078 to -3·766] vs -1·999% [-3·022 to -0·976]; p=0·0002), increased in controls at the lumbar spine (1·5% change), and remained unchanged at total hip and femoral neck (-0·1% change). Concurrent use of TDF and DMPA-IM resulted in significantly greater BMD decline (p<0·0001) than TDF alone (lumbar spine -2·677% [95% CI -3·743 to -1·611]; p<0·0001; total hip -2·518% [-3·575 to -1·461]; p<0·0001; and femoral neck -2·907 [-4·132 to -1·683]; p<0·0001) or than controls (lumbar spine -4·970% [-6·391 to -3·549]; p<0·0001; total hip -4·151% [-5·579 to -2·724]; p<0.0001; and femoral neck -4·773% [-6·424 to -3·122]; p<0·0001) INTERPRETATION: Concomitant DMPA-IM use resulted in a doubling of BMD loss in women living with HIV initiating TDF-containing ART. Identification of safer contraceptive and bone-sparing ART options should be prioritised for optimal care of women living with HIV., Funding: National Institute of Allergy and Infectious Diseases of the US National Institutes of Health., Competing Interests: Declaration of interests TTB has received consulting fees from Merck, ViiV Heathcare, Gilead Sciences, Janssen, and Theratecnologies. FKM has received money to her institution from Gilead Sciences. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Vitamin D regulates the master iron hormone hepcidin, and iron in turn alters vitamin D metabolism. Although vitamin D and iron deficiency are highly prevalent globally, little is known about their interactions in Africa. To evaluate associations between vitamin D and iron status we measured markers of iron status, inflammation, malaria parasitemia, and 25-hydroxyvitamin D (25(OH)D) concentrations in 4509 children aged 0.3 months to 8 years living in Kenya, Uganda, Burkina Faso, The Gambia, and South Africa. Prevalence of iron deficiency was 35.1%, and prevalence of vitamin D deficiency was 0.6% and 7.8% as defined by 25(OH)D concentrations of <30 nmol/L and <50 nmol/L, respectively. Children with 25(OH)D concentrations of <50 nmol/L had a 98% increased risk of iron deficiency (OR 1.98 [95% CI 1.52, 2.58]) compared to those with 25(OH)D concentrations >75 nmol/L. 25(OH)D concentrations variably influenced individual markers of iron status. Inflammation interacted with 25(OH)D concentrations to predict ferritin levels. The link between vitamin D and iron status should be considered in strategies to manage these nutrient deficiencies in African children.

Context: Nutritional rickets results from the interaction of low vitamin D status and limited calcium intake. Serum alkaline phosphatase (AP) activity is a biomarker of impaired mineralization in rickets., Objective: To assess the performance of serum AP activity in identifying nutritional rickets in calcium-deprived Nigerian children., Methods: We reanalyzed data from a case-control study of children with active rickets and matched control subjects without rickets, using a multivariate logistic regression to assess the odds of rickets associated with AP activity, adjusting for age, sex, and weight-for-age z-score., Results: A total of 122 children with rickets and 119 controls were included. Rachitic children had a mean (±SD) age of 54 ± 29 months, and 55 (45.1%) were male. Cases and controls had low dietary calcium intakes (216 ± 87 and 214 ± 96 mg/day, respectively). Serum AP activity levels in cases and controls were 812 ± 415 and 245 ± 78 U/L, respectively (P < 0.001). AP was negatively associated with 25-hydroxyvitamin D values (r = -0.34; P < 0.001). In the adjusted model, the odds ratio (95% CI) receiver operating characteristic curve was 0.978. AP > 350 U/L identified nutritional rickets in Nigerian children with sensitivity 0.93, specificity 0.92, positive likelihood ratio 11.3, and negative likelihood ratio 0.07., Conclusion: An AP > 350 U/L effectively discriminated between Nigerian children with and without nutritional rickets. AP is a low-cost biochemical test that could be used to screen for nutritional rickets, but cutoff values require validation in other populations, and laboratory values need to be standardized for widespread population studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Nutritional rickets is believed to result from the interaction of inadequate serum 25-hydroxyvitamin D [25(OH)D] concentration and dietary calcium intake, but this interaction has not been confirmed in children with rickets. Determining the vitamin D requirements to prevent nutritional rickets has been thwarted by inconsistent case definition, inadequate adjustment for calcium intake and other confounders, and 25(OH)D assay variability., Objectives: To model the 25(OH)D concentration associated with nutritional rickets in calcium-deprived Nigerian children, adjusted for confounding factors, and develop a general approach to define vitamin D status while accounting for calcium intake., Methods: Logistic regression was used to model the association of serum 25(OH)D with having rickets adjusted for calcium intake in a reanalysis of a case-control study in Nigerian children. The matching variables age, sex, weight-for-age z score, and 4 additional significant variables were selected [religion, age began walking, phosphorus intake, and the 25(OH)D × calcium intake interaction] using a rigorous 7-step algorithm., Results: Cases had significantly (P < 0.0001) lower mean ± SD 25(OH)D than controls (33 ± 13 compared with 51 ± 16 nmol/L, respectively), whereas cases and controls had similarly (P = 0.81) low mean dietary calcium intakes (216 ± 88 and 213 ± 95 mg/d, respectively). There was a significant interaction between 25(OH)D and calcium intake [coefficient (95% CI): -0.0006 (-0.0009, -0.0002)]. Accordingly, as calcium intake increased from 130 to 300 mg/d, the adjusted odds of having rickets decreased dramatically with increasing 25(OH)D such that at 200 mg/d, the adjusted odds of having rickets at 47.5 nmol/L was 0.80, whereas it was 0.2 at 62.5 nmol/L. Moreover, at a calcium intake of 300 mg/d, the adjusted odds was 0.16 at a 25(OH)D concentration of 47.5 nmol/L and 0.02 at 62.5 nmol/L., Conclusions: The vitamin D requirement to prevent nutritional rickets varies inversely with calcium intake and vice versa. Also, application of multivariable modeling is essential in defining vitamin D requirements., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Children living in sub-Saharan Africa have a high burden of rickets and infectious diseases, conditions that are linked to vitamin D deficiency. However, data on the vitamin D status of young African children and its environmental and genetic predictors are limited. We aimed to examine the prevalence and predictors of vitamin D deficiency in young African children., Methods: We measured 25-hydroxyvitamin D (25(OH)D) and typed the single nucleotide polymorphisms, rs4588 and rs7041, in the GC gene encoding the vitamin D binding protein (DBP) in 4509 children aged 0-8 years living in Kenya, Uganda, Burkina Faso, The Gambia and South Africa. We evaluated associations between vitamin D status and country, age, sex, season, anthropometric indices, inflammation, malaria and DBP haplotypes in regression analyses., Results: Median age was 23.9 months (interquartile range [IQR] 12.3, 35.9). Prevalence of vitamin D deficiency using 25(OH)D cut-offs of < 30 nmol/L and < 50 nmol/L was 0.6% (95% CI 0.4, 0.9) and 7.8% (95% CI 7.0, 8.5), respectively. Overall median 25(OH)D level was 77.6 nmol/L (IQR 63.6, 94.2). 25(OH)D levels were lower in South Africa, in older children, during winter or the long rains, and in those with afebrile malaria, and higher in children with inflammation. 25(OH)D levels did not vary by stunting, wasting or underweight in adjusted regression models. The distribution of Gc variants was Gc1f 83.3%, Gc1s 8.5% and Gc2 8.2% overall and varied by country. Individuals carrying the Gc2 variant had lower median 25(OH)D levels (72.4 nmol/L (IQR 59.4, 86.5) than those carrying the Gc1f (77.3 nmol/L (IQR 63.5, 92.8)) or Gc1s (78.9 nmol/L (IQR 63.8, 95.5)) variants., Conclusions: Approximately 0.6% and 7.8% of young African children were vitamin D deficient as defined by 25(OH)D levels < 30 nmol/L and < 50 nmol/L, respectively. Latitude, age, season, and prevalence of inflammation and malaria should be considered in strategies to assess and manage vitamin D deficiency in young children living in Africa.

Objectives: The timing and magnitude of adolescent growth may be influenced by ethnicity and early life factors. We aimed to (a) characterize ethnic differences in the magnitude, timing, and intensity of adolescent growth in height, weight, and BMI; (b) assess the effect of early childhood growth on adolescent growth in black children., Methods: Data were from the Birth to Twenty Plus cohort (Bt20+) in Johannesburg, South Africa (n = 3273). Height, weight, and BMI were modeled with ethnic comparisons using the SuperImposition by Translation and Rotation for 2089 participants who had data from 7 to 23 years. Relative weight gain and relative linear growth between 0 and 24 months and 24 and 60 months were generated. Multiple regression analyses were used to assess associations between childhood and adolescent growth., Results: White children were 5 cm (SE: 0.7) taller than black children through adolescence. Black boys had a later timing of adolescent height (0.65 years ±0.12) than white boys, which in black girls was 0.24 years (0.11) earlier than in white girls. Black girls had faster BMI velocity than white girls. Among black children, birth weight and both relative weight gain 0 to 24 and relative linear growth between 3 and 24 months and 24 and 60 months were positively associated with the magnitude of adolescent growth and negatively associated with timing., Conclusion: Sex dimorphism in ethnic differences in timing of adolescent height growth may reflect some yet unexplained drivers for rapid weight gain and obesity in black females but not black males. Rapid weight gain in early life may contribute to faster adiposity accrual in adolescence., (© 2020 Wiley Periodicals LLC.)

Most studies evaluating BMD in human immunodeficiency virus (HIV)-infected populations have focused on antiretroviral therapy (ART)-experienced patients. In this study, the association between HIV-1 and/or depot medroxyprogesterone acetate (DMPA) and BMD among untreated HIV-1-infected women in a resource-limited setting was assessed before long-term exposure to ART. The data were then compared with that of the 2005-2008 United States National Health and Nutrition Examination Survey data for non-Hispanic White and Black women. Women aged 18-35 years, recruited from health facilities in Kampala, Uganda, were classified based on their combination of HIV-1 status and DMPA use: (i) HIV-1-infected current DMPA users, (ii) HIV-1-infected previous DMPA users, (iii) HIV-1-infected nonhormonal-contraceptive users, and (iv) HIV-uninfected nonhormonal-contraceptive users. All HIV-1-infected women reported being ART-naïve at baseline. BMD was measured at the lumbar spine, total hip, and femoral neck using DXA. Multivariate linear regression was used to assess the association between HIV-1 and/or DMPA and BMD Z -scores. Baseline data were analyzed for 452 HIV-1-infected (220 nonhormonal users, and 177 current and 55 previous DMPA users) and 69 HIV-1-uninfected nonhormonal-contraceptive users. The mean age was 26.1 years (SD, 4.2) with a median duration of DMPA use among current users of 24.0 months [medians (interquartile range), 12-48]. A higher proportion of HIV-1-infected previous (12.7%) or current DMPA users (20.3%) and nonhormonal users (15.0%) had low BMD ( Z -score ≤-2 at any of the three sites) compared with age-matched HIV-1-uninfected women (2.9%). HIV-1 infection and DMPA use were independently associated with significantly lower mean BMD Z -scores at all sites, with the greatest difference being among HIV-1-infected current DMPA users (5.6%-8.0%) versus uninfected nonhormonal users. Compared with non-Hispanic White and Black women, the Ugandan local reference population had generally lower mean BMD at all sites. Newer treatment interventions are needed to mitigate BMD loss in HIV-1-infected women in resource-limited settings. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research., (© 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.)

More than two decades ago, a recessive syndromic phenotype affecting kidneys, eyes, and ears, was first described in the endogamous Afrikaner population of South Africa. Using whole-exome sequencing of DNA from two affected siblings (and their carrier parents), we identified the novel RRM2B c.786G>T variant as a plausible disease-causing mutation. The RRM2B gene is involved in mitochondrial integrity, and the observed change was not previously reported in any genomic database. The subsequent screening revealed the variant in two newly presenting unrelated patients, as well as two patients in our registry with rod-cone dystrophy, hearing loss, and Fanconi-type renal disease. All patients with the c.786G>T variant share an identical 1.5 Mb haplotype around this gene, suggesting a founder effect in the Afrikaner population. We present ultrastructural evidence of mitochondrial impairment in one patient, to support our thesis that this RRM2B variant is associated with the renal, ophthalmological, and auditory phenotype., (© 2020 Wiley Periodicals LLC.)

Objectives: A high prevalence of rickets of unknown aetiology has been reported in Chakaria, Bangladesh. Classically, rickets is caused by vitamin D deficiency but increasing evidence from Africa and Asia points towards other nutritional deficiencies or excessive exposure to some metals. The aim of this study was to investigate the aetiology of rickets in rural Bangladeshi children., Methods: 64 cases with rickets-like deformities were recruited at first presentation together with age-sex-village matched controls. Data and sample acquisition included anthropometry, radiographs, fasted plasma and urinary samples, 24 h weighed dietary intake together with a 24 h urine collection, and 13 C-breath tests to detect Helicobacter (H.) pylori infection., Results: One child had active rickets and frank hypovitaminosis D (F, n = 1) and one had deformities with radiological features of Blount disease (M, n = 1). The remaining cases were grouped into those with active rickets, defined as a radiographic Thacher score ≥1.5 (Group A, n = 24, 12M, 12F) and rickets-like bone deformities but not active rickets (Group B, n = 38, 28M, 10F). All children had a low dietary calcium intake, but this was lower in Group A than their controls (mean (SD): 156 (80) versus 323 (249) mg/day, p = 0.005). Plasma 25-hydroxyvitamin D (25OHD) was lower in Group A compared to controls; 63% of Group A and 8% of controls had a concentration <25 nmol/L (p ≤ 0.0001). There was, however, no evidence of differences in skin sunshine exposure. Group A had lower plasma calcium and phosphate and higher 1,25-dihydroxyvitamin D (1,25(OH) 2 D) and parathyroid hormone (PTH). 88% of Group A and 0% of controls had undetectable plasma intact fibroblast growth factor (iFGF23), with c-terminal FGF23 (cFGF23) concentrations in the normal range. Urinary phosphate and daily outputs of environmental metals relative to creatinine were higher and tubular maximal phosphate reabsorption per unit glomerular filtration rate (TmP/GFR) was lower in Group A compared to controls. Although less pronounced than Group A, Group B had higher alkaline phosphatase, 1,25(OH) 2 D and PTH concentrations than controls but similar calcium intake, TmP/GFR, iFGF23 and cFGF23 concentrations. Mean 25OHD concentrations were also similar to controls and there was no significant difference in the percentage <25 nmol/L (Group B: 13%, controls: 5%, p = 0.2) No group differences were seen in prevalence of anaemia, iron deficiency or H. pylori infection., Conclusion: Nutritional rickets in this region is likely to be predominantly due to low calcium intake in the context of poor vitamin D status and exposure to environmental metals, but not H. pylori infection, anaemia or iron deficiency., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Vitamin D deficiency is common worldwide and young children are among the most affected groups. Animal studies suggest a key role for vitamin D in brain development. However, studies investigating the effects of vitamin D on neurobehavioural outcomes in children are inconclusive and evidence is limited in sub-Saharan Africa. We evaluated the effect of vitamin D status on cognitive and motor outcomes using prospective data from the Entebbe Mother and Baby Study birth cohort. We analysed data from 302 Ugandan children with 25-hydroxyvitamin D (25(OH)D) measurements below five years and developmental measures at five years of age. We used multivariable linear regression, adjusted for potential confounders, to estimate the effect of 25(OH)D on cognitive and motor outcomes. Of 302 children, eight (2.7%) had 25(OH)D levels <50 nmol/L, 105 (35.8%) had levels 50-75 nmol/L and 189 (62.6%) had levels >75 nmol/L. There was no evidence that earlier vitamin D status was associated with cognitive and motor outcomes in five-year-old Ugandan children. This study adds to the sparse literature and highlights the need for further longitudinal studies on vitamin D and neurobehavioural outcomes in children living in sub-Saharan Africa.

Human immunodeficiency virus- (HIV-) infection and antiretroviral therapy (ART) exposure are associated with bone loss. African data are limited despite the region's HIV burden. Of 247 ART-naïve, premenopausal, urban, black African women aged 33.9 ± 6.6 years from Soweto, South Africa, measured at baseline, 110 underwent anthropometry, DXA, and blood and urine collections at 12 and 24 months; 39 were HIV-negative (Nref), 28 were people with HIV (PWH) not ART-exposed for the duration of the study (ART-N), and 43 were PWH who were ART-exposed within the first 12 months (ART-Y). At baseline, the ART-Y group had lower BMI and fat mass than the Nref group. Within 12 months of ART initiation, areal bone mineral density (aBMD) had decreased at the lumbar spine and at the whole body less head, despite increased weight, and hip aBMD had not increased in line with the Nref group. There was no evidence of further bone changes between 12 and 24 months. By 24 months, the ART-Y women had gained weight and fat mass, but remained lighter with less fat than the Nref women. ART initiation normalized the low serum albumin of the ART-Y group at baseline, but was associated with elevated bone turnover markers at 12 and 24 months. Vitamin D status and renal phosphate handling were normal. ART-N had similar aBMD and other characteristics to the Nref group throughout, except unlike the Nref group, weight and fat mass did not increase and serum albumin decreased. This study in African women of childbearing age demonstrated that the bone loss that had occurred in these PWH after ART initiation did not continue after 12 months and that bone loss did not occur in ART-unexposed PWH over 2 years. At 24 months, despite gains in weight and fat mass, ART-exposed women remained lighter, with lower aBMD, fat mass, and higher bone turnover than women without HIV. More studies are required to establish if the bone loss and fat gain reverse, stabilize, or continue with further ART exposure, particularly during and after menopause. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research., (© 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.)

Background: Vitamin D deficiency is associated with non-communicable and infectious diseases, but the vitamin D status of African populations is not well characterised. We aimed to estimate the prevalence of vitamin D deficiency in children and adults living in Africa., Methods: For this systematic review and meta-analysis, we searched PubMed, Web of Science, Embase, African Journals Online, and African Index Medicus for studies on vitamin D prevalence, published from database inception to Aug 6, 2019, without language restrictions. We included all studies with measured serum 25-hydroxyvitamin D (25[OH]D) concentrations from healthy participants residing in Africa. We excluded case reports and case series, studies that measured 25(OH)D only after a clinical intervention, and studies with only a meeting abstract or unpublished material available. We used a standardised data extraction form to collect information from eligible studies; if the required information was not available in the published report, we requested raw data from the authors. We did a random-effects meta-analysis to obtain the pooled prevalence of vitamin D deficiency in African populations, with use of established cutoffs and mean 25(OH)D concentrations. We stratified meta-analyses by participant age group, geographical region, and residence in rural or urban areas. The study is registered with PROSPERO, number CRD42018112030., Findings: Our search identified 1692 studies, of which 129 studies with 21 474 participants from 23 African countries were included in the systematic review and 119 studies were included in the meta-analyses. The pooled prevalence of low vitamin D status was 18·46% (95% CI 10·66-27·78) with a cutoff of serum 25(OH)D concentration less than 30 nmol/L; 34·22% (26·22-43·68) for a cutoff of less than 50 nmol/L; and 59·54% (51·32-67·50) for a cutoff of less than 75 nmol/L. The overall mean 25(OH)D concentration was 67·78 nmol/L (95% CI 64·50-71·06). There was no evidence of publication bias, although heterogeneity was high (I 2 ranged from 98·26% to 99·82%). Mean serum 25(OH)D concentrations were lower in populations living in northern African countries or South Africa compared with sub-Saharan Africa, in urban areas compared with rural areas, in women compared with men, and in newborn babies compared with their mothers., Interpretation: The prevalence of vitamin D deficiency is high in African populations. Public health strategies in Africa should include efforts to prevent, detect, and treat vitamin D deficiency, especially in newborn babies, women, and urban populations., Funding: Wellcome Trust and the DELTAS Africa Initiative., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Cardiometabolic disease is associated with chronic low-grade inflammation. While low birthweight, childhood stunting and rapid weight gain predict higher adult high-sensitivity C-reactive protein (hs-CRP) concentrations, associations between childhood infections and adulthood CRP are inconsistent. Aim: To assess the associations between sanitation, diarrhoea and a combined score of both from birth to age 2 years and hs-CRP at age 18 years, independently of early life nutrition and adult adiposity. Subjects and methods: This study collected data on sanitation and diarrhoea episodes from birth to 2 years on 756 participants of the Birth-to-Twenty Plus cohort, a birth cohort initiated in South Africa in 1990, and calculated a combined score of both variables. Anthropometry was measured at 2 years and 18 years and hs-CRP at 18 years. Results: Of the participants, 29.5% had no access to indoor flush sanitation and 38.2% experienced ≥1 diarrhoea episode between birth and 2 years. Not having access to indoor flush sanitation and experiencing ≥1 diarrhoea episodes were associated with 1.50 mg/L and 1.52 mg/L higher hs-CRP, respectively. Prevalence of both burdens in infancy was associated with a 2.18 mg/L higher hs-CRP. Conclusion: In this population, poor sanitation and diarrhoea in early life predict elevated CRP in young adulthood, independently of early life nutrition and adiposity.

Background: Low- and middle-income countries (LMIC) are experiencing a double-burden of malnutrition characterised by high prevalence of both under- and over-nutrition. We set out using data from the mixed-longitudinal Birth-to-Twenty Plus (Bt20+) birth cohort, to evaluate the patterns of malnutrition and growth in a large South African (SA) city by; (i) assessing the prevalence of undernutrition from birth to 5 years of age and overweight and obesity from ages 2 to 21 years in black and white, male and female children, and (ii) determining percentiles for height, weight, BMI, waist and hip circumferences and comparing the centiles to American and Dutch references., Methods: Height, weight, waist and hip circumferences were measured on urban black and white SA children from the Bt20+. A total of 3273 children born between April and June 1990 in the Greater Johannesburg Metropolitan area were included in the cohort. Z-scores were derived using the WHO 2006 child growth standards (0-5 years), for defining stunting, underweight and wasting. The International Obesity Task Force (IOTF) references were used to define overweight and obesity. Percentiles were developed using the lambda mu sigma (LMS) method and compared to American and Dutch references., Results: Black children were consistently shorter and black males lighter than white children and American references. The prevalence of stunting peaked at 2 years and was significantly higher in males than females and in black than white children. Black females had a greater prevalence of overweight and obesity than black males from 10 to 17 years. The percentiles for black females for weight and BMI were similar to those of South African white and American references but both black and white South African females had lower waist circumferences than American references., Conclusion: The growth percentiles show that young South African urban black females are experiencing general but not central obesity due to a secular change which is faster in weight than height. High levels of undernutrition persist alongside high levels of over-nutrition with adolescence being a critical period for the upsurge in obesity in females. Early intervention is needed to combat the rise in obesity.

The Rickets Severity Score (RSS) was used to evaluate X-linked hypophosphatemic rickets (XLH), a genetic disorder mediated by increased circulating FGF23. The reliability of the RSS was assessed using data from a randomized, phase 2 clinical trial that evaluated the effects of burosumab, a fully human anti-FGF23 monoclonal antibody, in 52 children with XLH ages 5 to 12 years. Bilateral knee and wrist radiographs were obtained at baseline, week 40, and week 64. We evaluated the relationships of the RSS to the Radiographic Global Impression of Change (RGI-C), serum alkaline phosphatase (ALP), height Z-score, 6-minute walk test (6MWT) percent predicted, and the Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument (POSNA-PODCI). The RSS showed moderate-to-substantial inter-rater reliability (weighted kappa, 0.45-0.65; Pearson correlation coefficient (r), 0.83-0.89) and substantial intra-rater reliability (weighted Kappa, 0.66; r = 0.91). Baseline RSS correlated with serum ALP (r = 0.47). Baseline RSS identified two subgroups (higher [RSS ≥1.5] and lower RSS [RSS <1.5]) that discriminated between subjects with greater and lesser rachitic disease. Higher RSS was associated with more severe clinical features, including impaired growth (Z-score, -2.12 vs -1.44) and walking ability (6MWT percent predicted, 77% vs 86%), more severe self-reported pain (29.9 [more severe] vs 45.3 [less severe]) and less physical function (29.6 [more severe] vs 40.9 [less severe]). During burosumab treatment, greater reductions in RSS corresponded to higher RGI-C global scores (r = -0.65). Improvements in RSS correlated with decreased serum ALP (r = 0.47). These results show the reliability of the RSS in XLH, and demonstrate that higher RSS values are associated with greater biochemical, clinical, and functional impairments in children with XLH., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Rickets due to dietary calcium deficiency has been well described in black African children, but less is known about this condition in black adolescents. We investigated 26 black adolescents (19 males aged 11 to 19 years and 7 females aged 12 to 15 years) with rachitic leg deformities and 20 controls by routine iliac crest undecalcified cortical bone histomorphometry for disturbances of bone turnover and for mineralization defects, including severity of osteocytic osteolysis (Ot.Olysis) and periosteocytic osteolysis (Peri.Ot.Olysis) of the lacunar-canalicular space. Serum levels of calcium (sCa), 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D (1,25(OH) 2 D), and total alkaline phosphatase (ALP) were measured. Histomorphometry showed varying degrees of severity of secondary hyperparathyroidism (2 0 HPT) characterized by hyperosteoidosis, increased erosion, and porosis. Because osteoid was neither being mineralized nor eroded (osteoclasts cannot erode osteoid), it increasingly blocked bone surface needed for osteoclastic resorption. Where osteoid covered >50% of bone surface, osteoid thickness, severity of Ot.Olysis, and extent of Peri.Ot.Olysis increased, sCa and 25OHD declined, and 1,25(OH) 2 D and ALP increased. At 80% osteoid cover, bone remodeling had all but ceased, secondary HPT had changed to osteomalacia, and serum biochemical results had deteriorated further. Disease severity was greater in males than in females, likely because males grow faster and for longer than females. In conclusion, this cross-sectional clinical case study presents cortical bone histomorphometric data of secondary HPT and its transition to osteomalacia in black adolescents with rickets attributable to dietary calcium deficiency. The bone disease was most severe in older adolescent males. Importantly, bone pathology of calcium deficiency rickets in adolescents was not confined to bone surfaces but also manifested at osteocyte level as Ot.Olysis and Peri.Ot.Olysis. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

The etiology and pathogenesis of nutritional rickets are becoming progressively clearer. Vitamin D deficiency has generally been considered the major or only player in the pathogenesis of nutritional rickets. However, recent research into calcium deficiency has now provided clinicians with reasons to investigate and manage patients with nutritional rickets more appropriately. The important question when assessing cases of nutritional rickets is: "Is it calcium or vitamin D deficiency or both that play a major role in the pathogenesis of the disease?" The case presentation in this review highlights the risk factors, clinical presentation and pathophysiology of nutritional rickets in a young South African black child from a semi-urban area in Johannesburg, a city with abundant sunshine throughout the year.

Rickets is a bone disease associated with abnormal serum calcium and phosphate levels. The clinical presentation is heterogeneous and depends on the age of onset and pathogenesis but includes bowing deformities of the legs, short stature and widening of joints. The disorder can be caused by nutritional deficiencies or genetic defects. Mutations in genes encoding proteins involved in vitamin D metabolism or action, fibroblast growth factor 23 (FGF23) production or degradation, renal phosphate handling or bone mineralization have been identified. The prevalence of nutritional rickets has substantially declined compared with the prevalence 200 years ago, but the condition has been re-emerging even in some well-resourced countries; prematurely born infants or breastfed infants who have dark skin types are particularly at risk. Diagnosis is usually established by medical history, physical examination, biochemical tests and radiography. Prevention is possible only for nutritional rickets and includes supplementation or food fortification with calcium and vitamin D either alone or in combination with sunlight exposure. Treatment of typical nutritional rickets includes calcium and/or vitamin D supplementation, although instances infrequently occur in which phosphate repletion may be necessary. Management of heritable types of rickets associated with defects in vitamin D metabolism or activation involves the administration of vitamin D metabolites. Oral phosphate supplementation is usually indicated for FGF23-independent phosphopenic rickets, whereas the conventional treatment of FGF23-dependent types of rickets includes a combination of phosphate and activated vitamin D; an anti-FGF23 antibody has shown promising results and is under further study.

There are no longitudinal pQCT data of bone growth and development from sub-Saharan Africa, where rapid environmental, societal, and economic transitions are occurring, and where fracture rates are predicted to rise. The aim of this study was to compare skeletal development in black and white South African adolescents using longitudinal data from the Birth to Twenty study. The Birth to Twenty Bone Health subcohort consisted of 543 adolescents (261 [178 black] girls, 282 [201 black] boys). Annual pQCT measurements of the radial and tibial metaphysis and diaphysis were obtained between ages 12 and 22 years (distal metaphysis: cross-sectional area [CSA] and trabecular bone mineral density [BMD]; diaphysis: total and cortical CSA, cortical BMD, and polar stress-strain index [SSIp]). Age at peak height velocity (APHV) was calculated to account for differences in maturational timing between ethnic groups and sexes. Mixed-effects models were used to describe trajectories for each pQCT outcome. Likelihood-ratio tests were used to summarize the overall difference in trajectories between black and white participants within each sex. APHV (mean ± SD years) was similar in black (11.8 ± 0.8) and white (12.2 ± 1.0) girls, but delayed in black (14.2 ± 1.0) relative to white boys (13.3 ± 0.8). By 4 years post-APHV, white adolescents had significantly greater cortical CSA and SSIp than black adolescents at the radius. There were no significant differences at the radial metaphysis but there was some divergence, such that black adolescents had greater radial trabecular BMD by the end of follow-up. At the tibia, white adolescents had lower diaphyseal CSA and SSIp, and greater metaphyseal CSA. There was no ethnic difference in tibial trabecular BMD. There are ethnic differences in bone growth and development, independent of maturation, in South African adolescents. This work gives new insights into the possible etiology of childhood fractures, which occur most commonly as peripheral sites. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc., (© 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.)

To monitor the drift of the periosteal and endocortical surfaces during metacarpal growth longitudinally, radiogrammetry was carried out on hand-wrist X-rays of 572 children from the Birth to Twenty Bone Health Cohort annually from ages 9 to 21 years. This is the largest collection of longitudinal X-rays in African children. The second metacarpal bone length, bone width, and medullary width were measured using digital vernier calipers on a total of 4730 X-rays. Superimposition by Translation and Rotation (SITAR) was used to obtain age at peak metacarpal length velocity (PLV). Bone width and medullary width were modeled using SITAR against both chronological age and age from PLV. In black and white females, tempo and velocity of metacarpal length growth was synchronized. Black males, however, attained PLV 7 months later than white males (p < 0.0001). Compared to white males, black males had a longer second metacarpal (p < 0.05), and greater bone width size (p < 0.02), tempo (p < 0.0009), and velocity (p < 0.0001). Medullary width growth velocity in black participants peaked 2 years prior to attainment of PLV and exceeded that of their white peers (p < 0.0001) in whom it peaked 6 to 12 months post-PLV attainment. Black adolescents therefore had wider bones with relatively thinner cortices and wider medullary cavities than their white peers. Ethnic and sex differences also occurred in the timing of medullary width contraction that accompanied expansion in bone width and cortical thickness. In black males, medullary width contraction commenced approximately 3 years later than in black females, whereas in white males this occurred a year later than in white females. The ethnic and sex differences in bone acquisition reported in this study may differentially affect bone mass in later life. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) are associated with bone loss and poor vitamin D status in white populations, though their relative roles are not known. No previous studies have examined longitudinal changes in areal bone mineral density (aBMD), measured by dual-energy X-ray absorptiometry (DXA), or in vitamin D status in HIV-positive African women. Of 247 premenopausal, urban, black African women from Soweto, South Africa, initially recruited, 187 underwent anthropometry, DXA scanning and blood and urine collections at both baseline and 12 months. Of these, 67 were HIV-negative throughout (Nref), 60 were HIV-positive with preserved CD4 counts at baseline (Ppres), and 60 were HIV-positive with low CD4 counts at baseline, eligible for ART by South African standards of care at the time (Plow). No participant had been exposed to ART at baseline. By 12 months, 51 Plow women had initiated ART, >85% of whom took combined tenofovir disoproxil fumarate (TDF), lamivudine, and efavirenz. By 12 months, Plow and Nref, but not Ppres, increased in body weight and fat mass (group-by-timepoint p ≤ 0.001, p = 0.002, respectively). Plow had significant decreases in aBMD of 2% to 3%, before and after size adjustment, at the femoral neck (p ≤ 0.002) and lumbar spine (p ≤ 0.001), despite significant weight gain. These decreases were associated with increased bone turnover but there were no significant differences or changes over time in vitamin D status, serum phosphate concentrations, or renal phosphate handling. Excluding data from nine Plow women unexposed to ART and 11 Ppres women who had initiated ART accentuated these findings, suggesting the bone loss in Plow was related to ART exposure. This is the first study describing DXA-defined bone loss in HIV-positive Sub-Saharan African women in association with ART. Further work is required to establish if bone loss continues with ongoing ART and, if so, whether this results in increased fracture rates. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Worldwide, nutritional rickets continues to be an evolving problem with several causes. This paper provides an updated literature review characterising the prevalence, aetiology, pathophysiology and treatment of nutritional rickets worldwide. A systematic review of articles on nutritional rickets from various geographical regions was undertaken. For each region, key information was extracted, including prevalence, cause of rickets specific to the region, methods of confirming the diagnosis and current treatment and preventive measures. Calcium deficiency continues to be a major cause of rickets in Africa and Asia. Vitamin D deficiency rickets is perhaps increasing in the Americas, Europe and parts of the Middle East. There continues to be a distinct presentation of calcium-predominant versus vitamin D predominant rickets, although there are overlapping features. More careful diagnosis of rickets and reporting of 25-OHD concentrations has improved accurate knowledge of rickets prevalence and better delineated the cause. Nutritional rickets continues to be an evolving and multi-factorial problem worldwide. It is on a spectrum, ranging from isolated vitamin D deficiency to isolated calcium deficiency. Specific areas which require emphasis include a consistent community approach to screening and diagnosis, vitamin D supplementation of infants and at-risk children, prevention of maternal vitamin D deficiency and the provision of calcium in areas with low calcium diets.

Factors that affect maternal bone mineral density may be related to the risk of nutritional rickets in their offspring. Our aim was to determine the relationship between maternal areal bone mineral density (aBMD) and rickets in Nigerian children. Using a case-control design, we measured forearm aBMD in 56 and 135 mothers of children with and without nutritional rickets, respectively. Active rickets was confirmed or excluded in all children radiographically. Using logistic regression, we assessed the association of maternal aBMD, adjusted for parity, pregnancy and lactation status, duration of most recent completed lactation, age of menarche, height, body mass index, and maternal age with nutritional rickets. The median (range) age of all mothers was 30years (17-47years), and parity was 4 (1-12). A total of 36 (19%) were pregnant and 55 (29%) were currently breast feeding. Mean (±SD) metaphyseal forearm aBMDs were 0.321±0.057 and 0.316±0.053g/cm 2 in mothers of children with and without rickets, respectively (P=0.60). Diaphyseal forearm aBMDs were 0.719±0.071 and 0.715±0.072g/cm 2 , respectively (P=0.69). In an adjusted analysis, maternal forearm aBMD, bone mineral content and bone area at metaphyseal and diaphyseal sites were not associated with rickets in the child. In the adjusted analysis, rickets was associated with shorter duration of most recently completed lactation (aOR 0.91 for each additional month; 95% CI 0.83-0.99), older maternal age (aOR 1.07 for each additional year; 1.00-1.14), and less frequent maternal use of lead-containing eye cosmetics (aOR 0.20; 95% CI 0.05-0.64), without any difference in maternal blood lead levels. Maternal age, parity, age of menarche, height, and body mass index were not associated with having had a child with rickets in multivariate analysis. Nutritional rickets in Nigerian children was not associated with maternal forearm aBMD. Other unidentified maternal characteristics and practices likely contribute to the risk of rickets in Nigerian children., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Calcium supplementation is indicated for the treatment of nutritional rickets. Our aim was to determine the optimal dose of calcium for treatment of children with rickets. Sixty-five Nigerian children with radiographically confirmed rickets were randomized to daily supplemental calcium intake of 500 mg (n = 21), 1000 mg (n = 23), or 2000 mg (n = 21). Venous blood, radiographs, and forearm areal bone density (aBMD) were obtained at baseline and at 8, 16, and 24 weeks after enrollment. The primary outcome was radiographic healing, using a 10-point radiographic severity score. The radiographic severity scores improved in all three groups, but the rate of radiographic healing (points per month) was significantly more rapid in the 1000-mg (-0.29; 95% confidence interval [CI] -0.13 to -0.45) and 2000-mg (-0.36; 95% CI -0.19 to -0.53) supplementation groups relative to the 500-mg group. The 2000-mg group did not heal more rapidly than the 1000-mg group. Of those who completed treatment for 24 weeks, 12 (67%), 20 (87%), and 14 (67%) in the 2000-mg, 1000-mg, and 500-mg groups, respectively, had achieved a radiographic score of 1.5 or less (p = 0.21). Serum alkaline phosphatase decreased and calcium increased similarly in all groups. Forearm diaphyseal aBMD improved significantly more rapidly in the 2000-mg group than in the 500-mg and 1000-mg groups (p < 0.001). Daily calcium intakes of 1000 mg or 2000 mg produced more rapid radiographic healing of rickets than 500 mg, but 2000 mg did not have greater benefit than 1000 mg. Some children require longer than 24 weeks for complete healing of nutritional rickets. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Early growth is associated with blood pressure measured on one occasion, but whether early life growth patterns are associated with longitudinal blood pressure trajectories is under-researched. Therefore, we sought to examine the association between early growth and blood pressure trajectories from childhood to adulthood. Blood pressure was measured on 7 occasions between ages 5 and 18 years in the Birth to Twenty cohort study, and conditional variables for growth in infancy and mid-childhood were computed from anthropometric measures (n=1937, 52% girls). We used a group-based trajectory modeling approach to identify distinct height-adjusted blood pressure trajectories and then tested their association with growth between birth and mid-childhood adjusting for several covariates. Three trajectory groups were identified for systolic and diastolic blood pressure: lower, middle, and upper in boys and girls, separately. In boys, predictors of the middle or upper systolic blood pressure trajectories versus the lower trajectory were in birth weight (odds ratio 0.75 [95% confidence interval 0.58-0.96] per SD) and relative weight gain in infancy (4.11 [1.25-13.51] per SD). In girls, greater relative weight gain and linear growth in both infancy and mid-childhood were consistently associated with an almost 2-fold higher likelihood of being in the upper versus lower systolic blood pressure trajectory. The associations for the diastolic blood pressure trajectories were inconsistent. These findings emphasize the importance of identifying children at risk of progression to high blood pressure. Accelerated growth in infancy and mid-childhood may be a key target for early life intervention in prevention of elevated blood pressure progression., (© 2016 American Heart Association, Inc.)

Concern has been expressed about the rising incidence of nutritional rickets with its associated long-term sequelae in children globally. In order to address the condition worldwide, it is imperative that accurate figures of its incidence are available particularly in at-risk communities. In order to obtain these figures, various screening tools and diagnostic criteria have been used with no standardization of methodologies, resulting in varying prevalences which may under- or over-estimate the prevalence depending of the techniques used. This review discusses the advantages and disadvantages of various screening tests used to diagnose rickets in communities. Clinical signs characteristic of rachitic deformities have been used extensively, but are likely to over-estimate the prevalence and are dependent on the clinical skills of the observer. Biochemical tests such as alkaline phosphatase and 25-hydroxyvitamin D have also been proposed. There is no consensus on the usefulness of alkaline phosphatase as a screening tool, while there is general agreement that the measurement of vitamin D status is unhelpful in screening for rickets. Finally, the confirmation of the presence of active rickets in suspected infants and children is dependent on radiographic findings, although these may be less helpful in adolescents whose growth plates might be closed or nearly so. In order to obtain uniformity in screening for rickets globally, the is a need for consensus among public health specialists, paediatric endocrinologists and those interested in paediatric bone disease as to the best methods to be employed to determine the prevalence of rickets, particularly in communities with limited resources., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

This study aims to examine the associations between BMI, disordered eating attitude, body dissatisfaction in female adolescents, and descriptive attributes assigned to silhouettes of varying sizes in male and female adolescents, aged 11 to 15, in rural South Africa. Height and weight were measured to determine BMI. Age and sex-specific cut-offs for underweight and overweight/obesity were determined using the International Obesity Task Force cut-offs. Body image satisfaction using Feel-Ideal Discrepancy (FID) scores, Eating Attitudes Test-26 (EAT-26), and perceptual female silhouettes were collected through self-administered questionnaires in 385 adolescents from the Agincourt Health and Socio-Demographic Surveillance System (HSDSS). Participants self-reported their Tanner pubertal stage and were classified as early pubertal (< = Tanner stage 2), and mid to post pubertal (Tanner stage > 2). Mid to post pubertal boys and girls were significantly heavier, taller, and had higher BMI values than their early pubertal counterparts (all p<0.001). The prevalence of overweight and obesity was higher in the girls than the boys in both pubertal stages. The majority (83.5%) of the girls demonstrated body dissatisfaction (a desire to be thinner or fatter). The girls who wanted to be fatter had a significantly higher BMI than the girls who wanted to be thinner (p<0.001). There were no differences in EAT-26 scores between pubertal groups, within the same sex, and between boys and girls within the two pubertal groups. The majority of the boys and the girls in both pubertal groups perceived the underweight silhouettes to be "unhappy" and "weak" and the majority of girls in both pubertal groups perceived the normal silhouettes to be the "best". These findings suggest a need for policy intervention that will address a healthy body size among South African adolescents.

Additional strategies are needed to prevent and treat tuberculosis (TB). Although vitamin D may have antimycobacterial effects, it is unknown whether low vitamin D status confers a risk for active TB in African children. This case-control study assessed serum 25-hydroxyvitamin D (25(OH)D) concentration in children with and without active TB in Gaborone, Botswana. A total of 80 children under 2 years old with and without active TB, seen at hospitals and clinics in the greater Gaborone area between September 2010 and November 2012, were enrolled. Of these, 39 cases did not differ from the 41 controls in median 25(OH)D levels (P = 0.84). The 25(OH)D was < 20 ng/mL in 8/39 (21%) cases and 7/41 (17%) controls (P = 0.69, χ(2)). Univariate analyses of subject clinical characteristics (other than 25(OH)D levels) showed that any degree of weight loss was associated with a diagnosis of TB (P = 0.047). Other clinical characteristics, including age (P = 0.08) or weight below third percentile (P = 0.58), showed no association with TB. There was no significant difference in vitamin D status between children under 2 years old with and without active TB. Lower vitamin D status did not appear to be a risk factor for TB in this small Gaborone cohort., (© The American Society of Tropical Medicine and Hygiene.)

Purpose of Review: Sub-Saharan Africa and other resource-limited settings (RLS) bear the greatest burden of the HIV epidemic globally. Advantageously, the expanding access to antiretroviral therapy (ART) has resulted in increased survival of HIV individuals in the last 2 decades. Data from resource rich settings provide evidence of increased risk of comorbid conditions such as osteoporosis and fragility fractures among HIV-infected populations. We provide the first review of published and presented data synthesizing the current state of knowledge on bone health and HIV in RLS., Recent Findings: With few exceptions, we found a high prevalence of low bone mineral density (BMD) and hypovitaminosis D among HIV-infected populations in both RLS and resource rich settings. Although most recognized risk factors for bone loss are similar across settings, in certain RLS there is a high prevalence of both non-HIV-specific risk factors and HIV-specific risk factors, including advanced HIV disease and widespread use of ART, including tenofovir disoproxil fumarate, a non-BMD sparing ART. Of great concern, we neither found published data on the effect of tenofovir disoproxil fumarate initiation on BMD, nor any data on incidence and prevalence of fractures among HIV-infected populations in RLS., Summary: To date, the prevalence and squeal of metabolic bone diseases in RLS are poorly described. This review highlights important gaps in our knowledge about HIV-associated bone health comorbidities in RLS. This creates an urgent need for targeted research that can inform HIV care and management guidelines in RLS.

Objective: Social epidemiology models suggest that socioeconomic status (SES) mobility across the life course affects blood pressure. The aim of this study was to investigate the association between SES change between infancy and adolescence, and blood pressure, in young adults, and the impact of early growth on this relationship., Setting: Data for this study were obtained from a 'Birth to Twenty' cohort in Soweto, Johannesburg, in South Africa., Participants: The study included 838 Black participants aged 18 years who had household SES measures in infancy and at adolescence, anthropometry at 0, 2, 4 and 18 years of age and blood pressure at the age of 18 years., Methods: We computed SES change using asset-based household SES in infancy and during adolescence as an exposure variable, and blood pressure and hypertension status as outcomes. Multivariate linear and logistic regressions were used to investigate the associations between SES change from infancy to adolescence, and age, height and sex-specific blood pressure and hypertension prevalence after adjusting for confounders., Results: Compared to a persistent low SES, an upward SES change from low to high SES tertile between infancy and adolescence was significantly associated with lower systolic blood pressure (SBP) at the age of 18 years (β=-4.85; 95% CI -8.22 to -1.48; p<0.01; r(2)=0.1804) after adjusting for SES in infancy, small-for-gestational-age (SGA) and weight gain. Associations between SES change and SBP were partly explained by weight gain between birth and the age of 18 years. There was no association between SES mobility and diastolic blood pressure, mean arterial pressure or hypertension status., Conclusions: Our study confirms that upward SES change has a protective effect on SBP by the time participants reach young adulthood. Socioeconomic policies and interventions that address inequality may have the potential to reduce cardiovascular disease burden related to BP in later life., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication., Evidence: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describe the strength of the recommendation and the quality of supporting evidence., Process: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus., Results: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts., Conclusion: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.

Background: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication., Evidence: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describes the strength of the recommendation and the quality of supporting evidence., Process: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus., Results: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts., Conclusion: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required., (© 2016 S. Karger AG, Basel and The Endocrine Society.)

Background: To our knowledge, no studies have reported on the long-term variability of vitamin D status in adolescents., Objective: To determine whether tracking of vitamin D status occurs in healthy adolescents, we assessed the variability of 25-hydroxyvitamin D [25(OH)D] every 2 y over a 10-y period in a longitudinal cohort of adolescents living in Johannesburg, South Africa (latitude 26°S)., Design: Healthy adolescents who had blood samples available on ≥3 occasions between 11 and 20 y of age were included in the study. Of the cohort of 504 children, 99 met the criteria. The mean 25(OH)D concentration at each time point was measured, and the individual 25(OH)D z scores based on year 11 values were used as the reference. All 25(OH)D concentrations for a subject were measured in a single assay., Results: No significant correlation was found between 25(OH)D in the earlier and later years of adolescence, although significant correlations were found between year 11 and year 13 (r = 0.71, P < 0.0001) and between years 15, 17, and 20 (r ≥ 0.65, P < 0.0001). The percentage of adolescents whose 25(OH)D concentration changed by >20 nmol/L from year 11 was calculated for all age groups: 12% of the cohort had a change of >20 nmol/L at 13 y of age compared with 46% at 20 y of age. Just more than one-half (53%) of the cohort changed their category of vitamin D status between the ages of 11 and 20 y, and one-third of adolescents changed from being replete to insufficient over the same period., Conclusions: The data suggest that the measurement of 25(OH)D at a single time point does not reflect the long-term vitamin D status of an adolescent. These findings may cast doubt on the veracity of those studies that suggest an association of vitamin D status with various disease states in which vitamin D status was measured only once.

The aim of this study was to estimate the burden of childhood rickets-like bone deformity in a rural region of West Africa where rickets has been reported in association with a low calcium intake. A population-based survey of children aged 0.5-17.9 years living in the province of West Kiang, The Gambia was conducted in 2007. 6221 children, 92% of those recorded in a recent census, were screened for physical signs of rickets by a trained survey team with clinical referral of suspected cases. Several objective measures were tested as potential screening tools. The prevalence of bone deformity in children <18.0 years was 3.3%. The prevalence was greater in males (M = 4.3%, F = 2.3%, p < 0.001) and in children <5.0 years (5.7%, M = 8.3%, F = 2.9%). Knock-knee was more common (58%) than bow-leg (31%) or windswept deformity (9%). Of the 196 examined clinically, 36 were confirmed to have a deformity outside normal variation (47% knock-knee, 53% bow-leg), resulting in more conservative prevalence estimates of bone deformity: 0.6% for children <18.0 years (M = 0.9%, F = 0.2%), 1.5% for children < 5.0 years (M = 2.3%, F = 0.6%). Three of these children (9% of those with clinically-confirmed deformity, 0.05% of those screened) had active rickets on X-ray at the time of medical examination. This emphasises the difficulties in comparing prevalence estimates of rickets-like bone deformities from population surveys and clinic-based studies. Interpopliteal distance showed promise as an objective screening measure for bow-leg deformity. In conclusion, this population survey in a rural region of West Africa with a low calcium diet has demonstrated a significant burden of rickets-like bone deformity, whether based on physical signs under survey conditions or after clinical examination, especially in boys < 5.0 years., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hypertension is an emerging public health problem in South Africa. Recent evidence from longitudinal studies has shown that hypertension in adulthood can be traced back to childhood. There is scarcity of longitudinal data on paediatric blood pressure (BP) particularly in African populations. The objective of this study is to assess the prevalence of hypertension and evaluate BP tracking between childhood and late adolescence among South African black Children., Methods: This study utilized data from the Birth to Twenty cohort, which is comprised of children born in Soweto, Johannesburg in 1990 (N = 3273, 78.5% black). Data on BP and anthropometry were collected at six follow-up periods between ages 5 and 18 years. Blood pressure status was classified using the Fourth report on National High Blood pressure program in children and adolescents. Pearson correlation coefficients and relative risk ratios (RR) were used to describe tracking of BP between childhood and late adolescence., Results: The overall point prevalence ranged from 9.2 to 16.4% for prehypertension and 8.4 to 24.4% for hypertension. Tracking coefficients ranged from 0.20 to 0.57 for SBP and 0.17- 0.51 for DBP in both sexes over the 14 years of measurement. The proportion of children who maintained an elevated BP status between childhood, adolescence and age 18 years ranged from 36.1% at age 5 years to 56.3% at age 13 years. Risk of having elevated BP at 18 years ranged from; RR: 1.60 (95 % CI: 1.29-2.00) at 5 years to RR: 2.71 (95 % CI: 2.32-3.17) at 14 years of age., Conclusions: This study reports high prevalence of elevated BP which tracks from early childhood into late adolescence. These findings emphasize the importance of early identification of children at risk of developing elevated BP and related risk factors plus timely intervention to prevent hypertension in adulthood.