Search

Purpose: Observational studies have suggested negative associations between maternal 25-hydroxyvitamin D (25(OH)D) status and risk of hypertensive disorders of pregnancy [pregnancy-induced hypertension (PIH) and preeclampsia (PET)]. Data from intervention studies are limited. We hypothesised that vitamin D supplementation would lower maternal blood pressure (BP) during pregnancy and reduce the incidence of hypertensive disorders of pregnancy., Methods: The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a randomised placebo-controlled trial. Pregnant women with a baseline 25(OH)D of 25-100 nmol/l were randomized to either 1000 IU/day cholecalciferol or placebo from 14 to 17 weeks' gestation until delivery. BP recordings documented during routine clinical pregnancy care were obtained from clinical records and grouped into gestational windows based on the schedule for routine antenatal care in the United Kingdom (23 +0 -24 +6 , 27 +0 -28 +6 , 33 +0 -35 +6 , 37 +0 -38 +6 , 39 +0 -40 +6 and ≥ 41 +0  weeks +days ). Systolic and diastolic BP measurements in these gestational windows were compared between randomisation groups. Diagnoses of PIH or PET (in accordance with national guidelines) and the use of antihypertensive agents were also noted and compared between groups., Results: Data for 734 women (366 cholecalciferol, 368 placebo) were included. Maternal mean systolic and diastolic BP did not differ between the randomization groups at any of the gestations studied. The incidences of PIH (placebo 1.6%, cholecalciferol 3.6%, p = 0.10) and PET (placebo 3.3%, cholecalciferol 3.8%, p = 0.68) were similar between the two groups., Conclusions: Gestational vitamin D supplementation with 1000 IU/day from 14 to 17 weeks gestation did not lower maternal BP or reduce the incidences of PIH or PET in this trial., Competing Interests: Declarations. Conflict of interest: KMG has received reimbursement for speaking at conferences sponsored by companies selling nutritional products and is part of an academic consortium that has received research funding from Bayer, Nestec, BenevolentAI Bio Ltd. and Danone, outside the submitted work. CC reports personal fees from ABBH, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier and Takeda, outside the submitted work. NCH reports personal fees, consultancy, lecture fees and honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Servier, Theramex, Shire, Consilient Healthcare, Kyowa Kirin and Internis Pharma, outside the submitted work. RJM has received travel bursaries from Kyowa Kirin unrelated to this work. NLC-C, SRC and SD declare no conflicts of interest related to the submitted work. Ethical approval: The original MAVIDOS trial, from which this data analysis was performed on, was conducted in accordance with the Declaration of Helsinki guidelines and was approved by the Southampton and South-West Hampshire Research Ethics Committee and full approval from UK Medicines and Healthcare products Regulatory Agency (MHRA) was granted. All women gave written informed consent to participate in the pregnancy phase of the study. MAVIDOS was registered on the International Standard Randomised Controlled Trial registry, ISRCTN 82927713, and the European Clinical Trials Database, EudraCT 2007–001716–23 [18]., (© 2025. The Author(s).)

Background: Findings from the Maternal Vitamin D Osteoporosis Study (MAVIDOS) trial demonstrated a positive effect of gestational cholecalciferol supplementation on offspring bone mineral density (BMD) at age 4 y. Demonstrating the persistence of this effect is important to understanding whether maternal vitamin D supplementation could be a useful public health strategy to improving bone health., Objectives: We investigated whether gestational vitamin D supplementation increases offspring BMD at ages 6-7 y in an exploratory post-hoc analysis of an existing trial., Methods: In the MAVIDOS randomized controlled trial, pregnant females <14 wk' gestation with a singleton pregnancy and serum 25-hydroxyvitamin D 25-100nmol/l at 3 United Kingdom hospitals (Southampton, Sheffield, and Oxford) were randomly assigned to either 1000 IU/d cholecalciferol or placebo from 14 to 17-wk gestation until delivery. Offspring born at term to participants recruited in Southampton were invited to the childhood follow-up at ages 4 and 6-7 y. The children had a dual-energy X-ray absorptiometry (DXA, Hologic discovery) scan of whole-body-less-head (WBLH) and lumbar spine, from which bone area, bone mineral content (BMC), BMD, and bone mineral apparent density (BMAD) were derived. Linear regression was used to compare the 2 groups adjusting for age, sex, height, weight, duration of consumption of human milk, and vitamin D use at 6-7 y., Results: A total of 454 children were followed up at ages 6-7 y, of whom 447 had a usable DXA scan. Gestational cholecalciferol supplementation resulted in higher WBLH BMC [0.15 SD, 95% confidence interval (CI): 0.04, 0.26], BMD (0.18 SD, 95% CI: 0.06, 0.31), BMAD (0.18 SD, 95% CI: 0.04, 0.32), and lean mass (0.09 SD, 95% CI: 0.00, 0.17) compared with placebo. The effect of pregnancy cholecalciferol on bone outcomes was similar at ages 4 and 6-7 y., Conclusions: Supplementation with cholecalciferol 1000 IU/d during pregnancy resulted in greater offspring BMD and lean mass in mid-childhood compared with placebo in this exploratory post-hoc analysis. These findings suggest that pregnancy vitamin D supplementation may be an important population health strategy to improve bone health., Trial Registration Number: This trial was registered at the ISRCTN (https://doi.org/10.1186/ISRCTN82927713) as 82927713 and EUDRACT (https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-001716-23/results) as 2007-001716-23., Competing Interests: Conflict of interest RJM has received travel bursaries from Kyowa Kirin unrelated to this work. EMC has received travel bursaries or lecture fees from Eli Lilly, Pfizer, Thornton and Ross, and UCB, unrelated to this work. KMG has received reimbursement for speaking at conferences sponsored by companies selling nutritional products, and is part of an academic consortium that has received research funding from Abbott Nutrition, Nestec, BenevolentAI Bio Ltd., and Danone, outside the submitted work. MKJ reports consultancy and speaker fees from UCB, Amgen, and Kyowa Kirin. CC reports personal fees from ABBH, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, and Takeda, outside the submitted work. NCH reports personal fees, consultancy, lecture fees and honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Servier, Theramex, Shire, Consilient Healthcare, Kyowa Kirin, and Internis Pharma, outside the submitted work. KAW received Honoraria from Abbott Nutrition unrelated to this work. IS, SRC, and SD declare no conflicts of interest related to the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Poor cognitive function and osteoporosis commonly co-exist in later life. In women, this is often attributed to post-menopausal estrogen loss. However, a common early life origin for these conditions and the associations between cognitive function and bone mineral density (BMD) in childhood have not previously been explored. We examined these relationships at age 6-7 years in the Southampton Women's Survey (SWS) mother-offspring cohort., Methods: Child occipitofrontal circumference (OFC), a proxy for brain volume, intelligence quotient (IQ) [Wechsler Abbreviated Scale of Intelligence] and visual recognition and working memory [CANTAB® Delayed Matching to Sample (DMS) and Spatial Span Length (SSP), respectively] were assessed. Whole-body-less-head (WBLH) and lumbar spine dual-energy X-ray absorptiometry [Hologic Discovery] (DXA) were performed to measure bone area (BA), bone mineral content (BMC), BMD and bone mineral apparent density (BMAD). Linear regression was used to examine associations between age and sex standardized variables (β represent standard deviation (SD) difference per SD of cognitive function)., Results: DXA was performed in 1331 children (mean (SD) age 6.8 (0.33) years, 51.5 % male), with OFC, IQ, DMS and SSP assessed in 1250, 551, 490 and 460, respectively. OFC (β = 0.25 SD/SD, 95%CI 0.20,0.30), IQ (β = 0.11 SD/SD, 95%CI 0.02,0.19), and DMS (β = 0.11, SD/SD, 95%CI 0.01,0.20) were positively associated with WBLH BA, with similar associations for lumbar spine BA. OFC and DMS were also positively associated with WBLH BMC, but only OFC was associated with BMD (WBLH: β = 0.38 SD/SD, 95%CI 0.33,0.43; LS: β = 0.19 SD/SD, 95%CI 0.13,0.24)., Conclusion: Childhood brain volume was positively associated with measures of skeletal size and BMD, whereas IQ and memory were associated only with skeletal size. These findings suggest that common early life determinants for skeletal growth and BMD and cognitive function should be explored to identify potential early-life approaches to preventing osteoporosis and cognitive decline., Competing Interests: Declaration of competing interest RJM has received travel bursaries from Kyowa Kirin unrelated to this work. KMG has received reimbursement for speaking at conferences sponsored by companies selling nutritional products, and is part of an academic consortium that has received research funding from Abbott Nutrition, Nestec, BenevolentAI Bio Ltd. and Danone, outside the submitted work. JHD has received travel bursaries from Novo Nordisk, SANDOZ and Pfizer unrelated to this work. CC reports personal fees from ABBH, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier and Takeda, outside the submitted work. NCH reports personal fees, consultancy, lecture fees and honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Servier, Shire, UCB, Kyowa Kirin, Consilient Healthcare and Internis Pharma, outside the submitted work. SD, CG, MF and SRC declare no potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: None declared.

Background: Observational studies relating maternal 25-hydroxyvitamin D status to timing and mode of delivery have reported inconsistent results. We assessed the effect of antenatal cholecalciferol supplementation on the incidence of preterm birth, delivery mode and post-partum haemorrhage (PPH)., Methods: MAVIDOS was a randomized, double-blind, placebo-controlled trial of 1000 IU/day cholecalciferol from 14 weeks' gestation until delivery. Gestational age, mode of delivery [categorized as spontaneous vaginal delivery (SVD), instrumental (including forceps and vacuum extraction) or Caesarean section] and PPH (>500 ml estimated blood loss) were determined from medical records., Results: A total of 965 women participated in the study until delivery. Gestation at birth and incidence of preterm birth (cholecalciferol 5.7%, placebo 4.5%, P = 0.43) were similar between the two treatment groups. SVD (versus instrumental or Caesarean delivery) was more likely in women randomized to cholecalciferol [Relative Risk (RR) 1.13, 95% confidence interval (CI) 1.02,1.25] due to lower instrumental (RR 0.68, 95%CI 0.51,0.91) but similar risk of Caesarean delivery (RR 0.94, 95%CI 0.74,1.19). PPH was less common in women randomized to cholecalciferol [32.1% compared with placebo (38.1%, P = 0.054) overall], but similar when stratified by delivery mode., Conclusions: Antenatal cholecalciferol supplementation did not alter timing of birth or prevalence of preterm birth but demonstrated a possible effect on the likelihood of SVD., (© The Author(s) 2022. Published by Oxford University Press on behalf of Faculty of Public Health.)

Objectives: Performing wedge resection rather than lobectomy for primary lung cancer remains controversial. Recent studies demonstrate no survival advantage for non-anatomical resection compared to lobectomy in patients with early-stage lung cancer. The objective of this study was to investigate whether in patients with T1 tumours, non-anatomical wedge resection is associated with equivalent survival to lobectomy., Methods: This was a retrospective cohort study of patients who underwent lung resection at the Lancashire Cardiac Centre between April 2005 and April 2018. Patients were subjected to multidisciplinary team discussion. The extent of resection was decided by the team based on British Thoracic Society guidelines. The primary outcome was overall survival. Propensity matching of patients with T1 tumours was also performed to determine whether differences in survival rates exist in a subset of these patients with balanced pre-operative characteristics., Results: There were 187 patients who underwent non-anatomical wedge resection and 431 patients who underwent lobectomy. Cox modelling demonstrated no survival difference between groups for the first 1.6 years then a risk of death 3-fold higher for wedge resection group after 1.6 years (HR 3.14, CI 1.98-4.79). Propensity matching yielded 152 pairs for which 5-year survival was 66.2% for the lobectomy group and 38.5% for the non-anatomical wedge group (SMD = 0.58, p = 0.003)., Conclusions: Non-anatomical wedge resection was associated with significantly reduced 5-year survival compared to lobectomy in matched patients. Lobectomy should remain the standard of care for patients with early-stage lung cancer who are fit enough to undergo surgical resection., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Context: Children born to parents who are overweight or obese have a high risk of adult obesity, but it is unclear if transgenerational associations relating to unfavorable body composition differ by parent., Objective: To examine differential mother-offspring and father-offspring associations in body composition in early childhood., Methods: A total of 240 mother-father-offspring trios from a prospective UK population-based pre-birth cohort (Southampton Women's Survey) were included for anthropometry and dual-energy x-ray absorptiometry assessment of whole-body-less-head body composition in the offspring at 3 different ages (4, 6-7, and 8-9 years) and in the mother and father at the 8- to 9-year offspring visit. Associations were assessed using linear regression adjusting for the other parent., Results: Positive associations between mother-daughter body mass index (BMI) and fat mass were observed at ages 6 to 7 (BMI: β = .29 SD/SD, 95% CI = .10, .48; fat mass β = .27 SD/SD, 95% CI = .05, .48) and 8 to 9 years (BMI: β = .33 SD/SD, 95% CI = .13, .54; fat mass β = .31 SD/SD, 95% CI = .12, .49), with similar associations at age 4 years but bounding the 95% CI. The mother-son, father-son, and father-daughter associations for BMI and fat mass were weaker at each of the ages studied., Conclusion: A strong association between the fat mass of mothers and their daughters but not their sons was observed. In contrast, father-offspring body composition associations were not evident. The dimorphic parent-offspring effects suggest particular attention should be given to early prevention of unfavorable body composition in girls born to mothers with excess adiposity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This narrative review summarises the recommendations of a Working Group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) for the conduct and reporting of real-world evidence studies with a focus on osteoporosis research., Purpose: Vast amounts of data are routinely generated at every healthcare contact and activity, and there is increasing recognition that these real-world data can be analysed to generate scientific evidence. Real-world evidence (RWE) is increasingly used to delineate the natural history of disease, assess real-life drug effectiveness, understand adverse events and in health economic analysis. The aim of this work was to understand the benefits and limitations of this type of data and outline approaches to ensure that transparent and high-quality evidence is generated., Methods: A ESCEO Working Group was convened in December 2022 to discuss the applicability of RWE to osteoporosis research and approaches to best practice., Results: This narrative review summarises the agreed recommendations for the conduct and reporting of RWE studies with a focus on osteoporosis research., Conclusions: It is imperative that research using real-world data is conducted to the highest standards with close attention to limitations and biases of these data, and with transparency at all stages of study design, data acquisition and curation, analysis and reporting to increase the trustworthiness of RWE study findings., (© 2023. The Author(s).)

Purpose of Review: Increasing bone mineral accrual during childhood might delay the onset of osteoporosis. We discuss the scientific evidence for early life approaches to optimising skeletal health., Recent Findings: There is an ever-growing body of evidence from observational studies suggesting associations between early life exposures, particularly during foetal development, and bone mineral density (BMD). The findings of such studies are often heterogeneous, and for some exposures, for example, maternal smoking and alcohol intake in pregnancy or age at conception, intervention studies are not feasible. The most frequently studied exposures in intervention studies are calcium or vitamin D supplementation in pregnancy, which overall suggest positive effects on offspring childhood BMD. Maternal calcium and/or vitamin D supplementation during pregnancy appear to have positive effects on offspring BMD during early childhood, but further long-term follow-up is required to demonstrate persistence of the effect into later life., (© 2023. The Author(s).)

Systematic review and meta-analysis of the effect of moderate- to high-dose vitamin D supplementation in pregnancy on offspring bone mineralisation found a positive effect of vitamin D supplementation on offspring bone mineral density (BMD) at age 4-6 years, with a smaller effect on bone mineral content., Purpose: A systematic review and meta-analysis was performed to assess the effect of pregnancy vitamin D supplementation on offspring bone mineral density (BMD) in childhood., Methods: A literature search was conducted for published RCTs of antenatal vitamin D supplementation with assessment of offspring BMD or bone mineral content (BMC) by dual-energy X-ray absorptiometry (DXA) using MEDLINE and EMBASE up to 13th July 2022. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Study findings were grouped in two age groups of offspring assessment: neonatal period and early childhood (3-6 years). Random-effects meta-analysis of the effect on BMC/BMD at 3-6 years was performed using RevMan 5.4.1, yielding standardised mean difference (SMD) (95% CI)., Results: Five RCTs were identified with offspring assessment of BMD or BMC; 3250 women were randomised within these studies. Risk of bias was low in 2 studies and "of concern" in 3. Supplementation regimes and the control used (3 studies used placebo and 2 used 400 IU/day cholecalciferol) varied, but in all studies the intervention increased maternal 25-hydroxvitamin D status compared to the control group. Two trials assessing BMD in the neonatal period (total n = 690) found no difference between groups, but meta-analysis was not performed as one trial represented 96.4% of those studied at this age. Three trials assessed offspring whole-body-less-head BMD at age 4-6 years. BMD was higher in children born to mothers supplemented with vitamin D [0.16 SD (95% confidence interval 0.05, 0.27), n = 1358] with a smaller effect on BMC [0.07 SD (95% CI - 0.04, 0.19), n = 1351]., Conclusions: There are few RCTs published to address this question, and these are inconsistent in methodology and findings. However, meta-analysis of three trials suggests moderate- to high-dose vitamin D supplementation in pregnancy might increase offspring BMD in early childhood, but further trials are required to confirm this finding. (Prospero CRD42021288682; no funding received)., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Objectives: Hypothalamic hamartoma (HH) typically presents with gonadotrophin-dependent precocious puberty and/or seizures. Other endocrine disturbances are rare. We describe an infant with syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) and a HH., Case Presentation: A 6-week-old infant presented with seizures and life-threatening hyponatremia. A HH was identified on magnetic resonance imaging. Clinical examination and biochemistry were consistent with SIADH, and serum copeptin was high during hyponatremia, further supporting this diagnosis. Tolvaptan was effective in normalizing plasma sodium and enabling liberalization of fluids to ensure sufficient nutritional intake and weight gain and manage hunger., Conclusions: Hyponatremia due to SIADH is novel at presentation of a HH, and can be challenging to diagnose and manage. Successful management of hyponatremia in this case was achieved using tolvaptan., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

We report the case of a 44-year-old gentleman who underwent coarctation repair at the age of 7 years. He was lost to follow-up and represented. Computed tomography scan demonstrated a 9.8-cm diameter aortic aneurysm involving the distal aortic arch and proximal descending aorta. Open surgery was performed to repair the aneurysm. The patient made an unremarkable recovery. He was followed up 12 weeks later, and significant improvement in preoperative symptoms was observed. This case demonstrates the importance of long-term follow-up., Competing Interests: We have no conflicts of interest to disclose related to this article., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Objective: General Medical Council (GMC) guidance describes an intimate examination as one that may be embarrassing for the patient, for example, breast or genitalia examination. Documentation of consent and use of a trained impartial observer (chaperone) is recommended. Pubertal staging is often necessitated for assessment of growth and puberty. We assessed current practice of pubertal staging by paediatricians and paediatric endocrinology nurse specialists (PENS) in the UK., Methods: An electronic survey was distributed to paediatricians (consultants and trainees) and PENS across the UK. The survey enquired about training received, confidence in and typical practice for pubertal staging examinations., Results: 235 responses were received. Low confidence in pubertal staging was commonly reported by trainees and consultants without an endocrinology interest.Most respondents consider pubertal staging to be an intimate examination for male (94.9%) and female (93.1%) patients. Consent to examination is always documented by 38.2% of respondents. 62.0% and 54.8% report always using a chaperone for male and female pubertal staging, respectively. However, many respondents use a parent as the chaperone. Few document the name of the chaperone used. Patient objections and availability of chaperones were commonly perceived barriers to chaperone use., Conclusion: Most clinicians consider pubertal staging an intimate examination, but documentation of consent and use of formal chaperones is not standard practice. The use of a parent as a chaperone was common but is not recommended by the GMC. Local chaperone policies should address these issues to protect patients and clinicians., Competing Interests: Competing interests: JHD has received travel bursaries from Novo Nordisk, honoraria from Kyowa Kirin., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Childhood osteoporosis leads to increased propensity to fracture, and thus is an important cause of morbidity, pain and healthcare utilisation. Osteoporosis in children may be caused by a primary bone defect or secondary to an underlying medical condition and/or its treatment. Primary osteoporosis is rare, but there is an increasing number of children with risk factors for secondary osteoporosis. Therefore it is imperative that all paediatricians are aware of the diagnostic criteria and baseline investigations for childhood osteoporosis to enable timely referral to a specialist in paediatric bone health. This review will discuss the approach to diagnosis, investigation and management of childhood osteoporosis, with particular consideration to advances in molecular diagnosis of primary bone disorders, and current and emerging therapies for fracture reduction.

Objectives: Bisphosphonates are used in childhood osteoporosis but can cause an acute phase reaction (APR) and hypocalcemia. We present a child with cardiac thrombosis following zoledronate, a previously unreported complication., Case Presentation: An 11-year-old with Duchenne muscular dystrophy and steroid-induced osteoporosis presented 48 h after first zoledronate infusion with fever, tachycardia, tachypnoea and hypoglycaemia. This was managed as acute adrenal crisis and possible sepsis. He also had hypocalcemia, hypophosphatemia, hyponatraemia and hypokalaemia. Echocardiography performed due to persistent chest pain and tachycardia revealed a left ventricular thrombus., Conclusions: Potential causes for intracardiac thrombosis in this patient include ventricular dysfunction due to acute adrenal crisis or electrolyte disturbance, and hypercoagulability due to the APR. Echocardiography should be considered in children with acute cardiovascular compromise following zoledronate. Stress-dose steroids to cover the APR and a reduced starting dose of zoledronate might have reduced the risk of this complication., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Evidence linking prenatal maternal vitamin D supplementation with the offspring's risk of atopic eczema is inconsistent, with most data coming from observational studies., Objectives: To examine the influence of maternal cholecalciferol supplementation during pregnancy on the risk of atopic eczema in the offspring at ages 12, 24 and 48 months., Methods: Within the UK Maternal Vitamin D Osteoporosis Study (MAVIDOS) double-blind, randomized placebo-controlled trial, we examined the relationship of maternal vitamin D supplementation during pregnancy with offspring atopic eczema at ages 12, 24 and 48 months. In MAVIDOS, pregnant women were allocated to either cholecalciferol 1000 IU per day or matched placebo, taken from around 14 weeks' gestation until delivery, with the primary outcome of neonatal whole-body bone mineral content. The prevalence of atopic eczema in the offspring was ascertained at ages 12 (n = 635), 24 (n = 610) and 48 (n = 449) months, based on the UK Working Party criteria for the definition of atopic dermatitis. The trial was registered with ISRCTN (82927713) and EudraCT (2007-001716-23)., Results: The characteristics of mothers and offspring were similar between the intervention and placebo groups, apart from longer breastfeeding duration in the intervention group. Adjusting for breastfeeding duration, offspring of mothers who received cholecalciferol 1000 IU daily had a lower odds ratio (OR) of atopic eczema at age 12 months [OR 0·55, 95% confidence interval (CI) 0·32-0·97, P = 0·04]; this effect weakened and was not statistically significant at ages 24 months (OR 0·76, 95% CI 0·47-1·23) or 48 months (OR 0·75, 95% CI 0·37-1·52). The statistical interaction of intervention and breastfeeding duration in relation to eczema at age 12 months was not significant (P = 0·41), but stratification showed reduced infantile eczema risk in the intervention group for infants breastfed for ≥ 1 month (OR 0·48, 95% CI 0·24-0·94, P = 0·03) but not in those breastfed for < 1 month (OR 0·80, 95% CI 0·29-2·17, P = 0·66)., Conclusions: Our data provide the first randomized controlled trial evidence of a protective effect of antenatal cholecalciferol supplementation on the risk of infantile atopic eczema, with the effect potentially being via increased breast milk cholecalciferol levels. The findings support a developmental influence on atopic eczema, and point to a potentially modifiable perinatal influence on atopic eczema. What is already known about this topic? There are currently no antenatal interventions proven to reduce the incidence of infantile atopic eczema in the general population. However, observational studies have led to speculation that antenatal vitamin D supplementation may be beneficial., (© 2022 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Context: Single nucleotide polymorphisms (SNPs) in vitamin D metabolism pathway genes are associated with circulating 25-hydroxyvitamin D (25(OH)D) in adults. Less is known about the relationships between mother and offspring SNPs and umbilical cord blood 25(OH)D., Objective: (1) To undertake a meta-analysis of the relationships of maternal and offspring SNPs in the vitamin D metabolism pathway and cord blood 25(OH)D in pregnant women including novel data; and (2) to examine these relationships in women who received antenatal cholecalciferol supplementation in a clinical trial., Methods: Novel data analysis from an observational mother-offspring cohort study (Southampton Women's Survey) and the MAVIDOS double-blind, randomized, placebo-controlled trial of 1000 IU/day cholecalciferol supplementation in pregnancy, and an electronic literature search of published studies in PubMed up to 31 July 2021. Studies reporting associations between rs12785878 (DHCR7), rs10741657 (CYP2R1), rs6013897 (CYP24A1), or rs2282679 (GC) and cord blood 25(OH)D. One published study was included in addition to the novel data analysis. Associations between both maternal and offspring SNPs at rs2282679 (GC) and rs12785878 (DHCR7), and cord blood 25(OH)D were identified. When maternal genotype was adjusted for offspring genotype, and vice versa, there was persisting evidence for associations with maternal rs12785878 (β [95% CI] 1.6 nmol/L [0.3, 2.8] per common allele), and offspring rs2282679 (β 3.1 nmol/L ]2.0, 4.4] per common allele). Maternal and offspring SNPs at rs1074657 and rs613897 were not associated with cord blood 25(OH)D., Result: Associations between both maternal and offspring SNPs at rs2282679 (GC) and rs12785878 (DHCR7), and cord blood 25(OH)D were identified. When maternal genotype was adjusted for offspring genotype, and vice versa, there was persisting evidence for associations with maternal rs12785878 (β [95% CI] 1.6 nmol/L [0.3, 2.8] per common allele), and offspring rs2282679 (β 3.1 nmol/L ]2.0, 4.4] per common allele). Maternal and offspring SNPs at rs1074657 and rs613897 were not associated with cord blood 25(OH)D., Conclusion: Common genetic variation in the vitamin D metabolism pathway is associated with umbilical cord blood 25(OH)D., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To investigate the association between three-dimensional (3D) skeletal variables and self-recognition of facial asymmetry in skeletal Class III patients., Materials and Methods: Questionnaires and cone beam computed tomography of 74 patients (42 men and 32 women; mean age: 22.8 ± 4.5 years) with skeletal Class III and facial asymmetry were collected retrospectively. Patients were classified into three groups: group Sy (recognition of symmetry), group NS (not sure), and group Asy (recognition of asymmetry), according to their responses to the questionnaires. To assess 3D anatomic differences in the maxillomandibular region, six 3D hard tissue variables: maxillary height, ramal length, frontal ramal inclination (FRI), lateral ramal inclination (LRI), mandibular body length (Mn BL), and mandibular body height (Mn BH) were compared among the three self-recognition groups. Six 3D hard tissue variables and Menton deviation were reduced into three factors and their association with the self-recognition of facial asymmetry was investigated., Results: Maxillary height, FRI, LRI, Mn BH, and Menton deviation demonstrated significant differences among the three self-recognition groups. The reduced factors, which consisted of transverse and vertical parameters, and vertical parameter of the mandibular corpus, demonstrated significant differences among the three self-recognition groups. The difference in Mn BH influenced the self-recognition of facial asymmetry., Conclusions: Both the transverse and vertical parameter of the skeleton were determinant in self-recognition of facial asymmetry. Identification of the skeletal difference in the lateral view involving LRI and Mn BH should be included for assessment of facial asymmetry., (© 2022 by The EH Angle Education and Research Foundation, Inc.)

Background: Whole-body-less-head (WBLH) is the recommended skeletal region of interest (ROI) for dual-energy X-ray absorptiometry (DXA) assessment of bone mineral density (BMD) in children. Historically it has been suggested that the skull is less responsive than the rest of the skeleton to stimuli that affect BMD but there are few published data to support this notion. We compared the associations of BMD with anthropometric, body composition, diet, and activity variables across various ROI., Methods: Children from the Southampton Women's Survey (SWS) mother-offspring cohort participated at age 6-7 years, including measurement of height, weight, and whole-body and lumbar spine (LS) BMD by DXA (Hologic Discovery). Physical activity was assessed by accelerometry (Actiheart) and diet by interviewer-led questionnaire. BMD was measured in the following skeletal ROI: whole-body, skull, WBLH and lower limbs (all derived from the whole-body scan) and LS., Results: 1218 children participated. Height z-score, weight z-score, lean mass and milk intake were associated with skull BMD, but associations were weaker than observed for other ROI; for example, the association between lean mass and skull BMD was β (95% CI) 0.11 (0.08, 0.14) SD/kg, compared with 0.32 (0.30, 0.34), 0.38 (0.37, 0.40) and 0.23 (0.21, 0.25) SD/kg for whole body, WBLH and lumbar spine, respectively. Relationships with whole-body BMD were attenuated compared with WBLH., Conclusion: Associations between skull BMD and anthropometry, body composition and dietary variables were weaker than for other DXA sites. These findings support, and importantly provide a quantitative basis for, the recommendation that the skull should be excluded from whole-body DXA analyses in children., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

In the Maternal Vitamin D Osteoporosis Study (MAVIDOS) randomized trial, vitamin D supplementation in pregnancy did not lead to greater neonatal bone mass across the trial as a whole, but, in a prespecified secondary analysis by season of birth, led to greater neonatal bone mass among winter-born babies. Demonstrating persistence of this effect into childhood would increase confidence in a long-term benefit of this intervention. We investigated whether antenatal vitamin D supplementation increases offspring bone mineralization in early childhood in a prespecified, single-center follow-up of a double-blinded, multicenter, randomized controlled clinical trial based in the UK (MAVIDOS). A total of 1123 women in early pregnancy with a baseline 25-hydroxyvitamin D level 25-100 nmol/L from three research centers (2008-2014) were randomized to 1000 IU/d cholecalciferol or matched placebo from 14 weeks of gestation to delivery. Offspring born at the Southampton, UK research center were assessed at age 4 years (2013-2018). Anthropometry and dual-energy X-ray absorptiometry (DXA) were performed (yielding whole body less head [WBLH] bone mineral content [BMC], areal bone mineral density [aBMD], bone area [BA], and body composition). Of 723 children, 564 (78.0%) children attended the 4-year visit, 452 of whom had a useable DXA. Maternal vitamin D supplementation led to greater WBLH aBMD in the children compared with placebo (mean [95% confidence interval {CI}]: supplemented group: 0.477 (95% CI, 0.472-0.481) g/cm 2 ; placebo group: 0.470 (95% CI, 0.466-0.475) g/cm 2 , p  = 0.048). Associations were consistent for BMC and lean mass, and in age- and sex-adjusted models. Effects were observed across the whole cohort irrespective of season of birth. Maternal-child interactions were observed, with a greater effect size among children with low milk intake and low levels of physical activity. Child weight, height, and body mass index (BMI) were similar by maternal randomization group. These findings suggest a sustained beneficial effect of maternal vitamin D supplementation in pregnancy on offspring aBMD at age 4 years, but will require replication in other trials. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., Competing Interests: EMC reports honoraria/travel support from Eli Lilly, Pfizer, and UCB outside the submitted work. NJB reports remuneration from Internis Pharmaceuticals Ltd, outside the submitted work. ATP reports grants from Versus Arthritis, Medical Research Council, National Institute for Health Research, Bupa Foundation, BBSRC, and EU outside the submitted work. KMG reports reimbursement for speaking at Nestle Nutrition Institute conferences, grants from Abbott Nutrition & Nestec, outside the submitted work; in addition, KMG has a patent Phenotype Prediction pending, a patent Predictive Use of CpG Methylation pending, and a patent Maternal Nutrition Composition pending, not directly related to this work. MKJ reports personal fees from Stirling Anglia, Consilient Health and Internis, outside the submitted work. RE reports grants from Amgen, grants and personal fees from IDS, grants from Alexion, grants and personal fees from Roche, personal fees from GSK Nutrition, personal fees from Mereo, personal fees from Sandoz, grants and personal fees from Nittobo, personal fees from AbbVie, personal fees from Samsung, personal fees from Haoma Medica, personal fees from Elsevier, personal fees from CL Bio, personal fees from FNIH, personal fees from Viking, personal fees from UCSF, personal fees from Biocon, from Lyramid, outside the submitted work. CC reports personal fees from ABBH, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier and Takeda, outside the submitted work. NCH reports personal fees, consultancy, lecture fees and honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Servier, Shire, UCB, Consilient Healthcare, Kyowa Kirin and Internis Pharma, outside the submitted work. RJM, SD, SRC, JSGK, SHK, RF, SVG, IS, AP, and HMI have nothing to disclose. Of the MAVIDOS group: N. Arden has received honoraria, held advisory board positions (which involved receipt of fees), and received consortium research grants, respectively, from: Merck, grants from Roche, personal fees from Smith & Nephew, Nicox, Flexion, grants from Bioiberica, Novartis, and personal fees from Bioventus and Freshfields, outside the submitted work. M.Z. Mughal has received lecture fees from Abbott Nutrition & Thornton & Ross, outside the submitted work. A. Carr, M. Clynes, E. Dennison, D. Reid, and S. Woolford have nothing to disclose., (© 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Pregnancy 25-hydroxyvitamin D [25(OH)D] concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D 3 by endocytosis, placental metabolism of 25(OH)D 3 into 24,25-dihydroxyvitamin D 3 and active 1,25-dihydroxyvitamin D [1,25(OH) 2 D 3 ], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D 3 and synthesis of 1,25(OH) 2 D 3 demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH)D 3 . We demonstrate that 25(OH)D 3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta, with widespread effects on the placenta itself. These data demonstrate a complex interplay between vitamin D and the placenta and will inform future interventions using vitamin D to support fetal development and maternal adaptations to pregnancy., Competing Interests: BA, CS, CJ, FH, JF, FR, EL, EH, LC, PM, RM, SC, HI, JH, KJ, RL, MB, JC No competing interests declared, AM AM is CSO of Proteas Bioanalytics Inc, BioLabs at the Lundquist Institute, CW Cory H White is affiliated with Merck Exploratory Science Centre, Merck Research Laboratories. The author has no financial interests to declare, SB SB part of an academic consortium that has received research funding from Abbott Nutrition, Nestec and Danone, EC EC reports honoraria/travel support from Eli Lilly, UCB, Pfizer and Amgen outside the submitted work, KG KMG has received reimbursement for speaking at conferences sponsored by companies selling nutritional products, and is part of an academic consortium that has received research funding from Abbott Nutrition, Nestec, BenevolentAI Bio Ltd. and Danone, CC CC has received lecture fees and honoraria from Amgen, Danone, Eli Lilly, GSK, Kyowa Kirin, Medtronic, Merck, Nestle, Novartis, Pfizer, Roche, Servier, Shire, Takeda and UCB outside of the submitted work, MH MH has received an honorarium for presenting to Thornton and Ross, SG SG is President and CEO/CTO of Proteas Bioanalytics Inc, BioLabs at the Lundquist Institute, NH NCH reports personal fees, consultancy, lecture fees and honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Servier, Shire, UCB, Consilient Healthcare, Kyowa Kirin and Internis Pharma, outside the submitted work, (© 2022, Ashley et al.)

Aim: To investigate the associations between indices of bone health in childhood and corresponding parental measures., Methods: The Southampton Women's Survey characterised 12,583 non-pregnant women aged 20-34 years; 3158 subsequently had singleton live births. In a subset, dual-energy X-ray absorptiometry (DXA) measurements of bone area (BA), bone mineral content (BMC) and areal bone mineral density (aBMD) lumbar spine and total hip were obtained in the parent/offspring (aged 8-9 years) trios. Another subset of children (aged 6-7 years), and their parents, had peripheral quantitative computed tomography (pQCT; 4% and 38% tibia) measures. Using multivariable linear regression we examined relationships between mother/father and offspring, adjusting for parental age, habitual walking speed and education; offspring age and sex; and the corresponding bone measure in the other parent (β-coefficients (95%CI) unit/unit for each bone measure)., Results: Data were available for 260 trios with DXA and 99 with pQCT. There were positive associations for BA, BMC and aBMD between either parent and offspring. Mother-child associations were of greater magnitude than father-child; for example, mother-child aBMD (β = 0.26 g·cm -2 /g·cm -2 (0.21,0.32)) and father-child aBMD (β = 0.16 g·cm -2 /g·cm -2 (0.11,0.21)), P-difference in β = 0.007. In the subset with pQCT there was a positive association for mother-offspring 4% tibial total area (β = 0.33 mm 2 /mm 2 (0.17,0.48)), but little evidence of a father-offspring association (β = -0.06 mm 2 /mm 2 (-0.17,0.06)). In contrast offspring 38% cortical density was more strongly associated with this measure in fathers (β = 0.48 mg·cm -3 /mg·cm -3 (0.15,0.82)) than mothers (β = 0.27 mg·cm -3 /mg·cm -3 (-0.03,0.56)). In general mother-father differences were attenuated by adjustment for height., Conclusions: Whilst offspring bone measures are independently associated with those of either parent, the magnitude of the association is often greater for maternal than paternal relationships. These findings are consistent with an in utero influence on offspring growth but might also reflect genetic and/or epigenetic parent of origin effects., Summary: In an established parent-offspring cohort, associations between parent and offspring bone indices were generally greater in magnitude for mother-offspring than father-offspring relationships., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The pattern of change in maternal bone turnover throughout pregnancy is poorly characterized., Objectives: We investigated changes across pregnancy in a marker of maternal bone resorption, urinary C-terminal telopeptide of type I collagen (CTX), the influence of gestational vitamin D supplementation, and associations between CTX and maternal postnatal bone indices., Methods: MAVIDOS (the Maternal Vitamin D Osteoporosis Study) is a randomized, double-blind, placebo-controlled trial of 1000 IU cholecalciferol/d compared with placebo from 14 weeks of gestation to birth. Maternal second-void urinary α- and β-CTX were measured (ELISA) at 14 and 34 weeks of gestation; DXA was performed within 2 wk postpartum. The Mann-Whitney Rank Sum test, Spearman's rank correlation, and linear regression were used to compare median CTX values within and between groups from early to late pregnancy, and associations with maternal bone outcomes., Results: In total, 372 women had CTX and 25-hydroxyvitamin D [25(OH)D] measured in early and late pregnancy. CTX at 14 and 34 weeks of gestation were correlated in both placebo (r = 0.31) and cholecalciferol (r = 0.45) groups (P < 0.0001). Median CTX increased from 14 to 34 weeks of gestation in both groups (n = 372 total) [placebo (n = 188): from 223.6 to 449.7 μg/mmol creatinine; cholecalciferol (n = 184): from 222.3 to 419.3 μg/mmol creatinine; P = 0.03 for placebo compared with cholecalciferol difference in CTX at 34 weeks of gestation]. The conditional mean ± SD increase in CTX [z-score (SD)] from early to late pregnancy was greater in the placebo group (n = 188) than in the cholecalciferol group (n = 184) (placebo: 0.16 ± 0.92; cholecalciferol: -0.16 ± 1.06; P-difference < 0.01). Higher CTX at 34 weeks of gestation was associated, similarly in both groups, with lower maternal total hip and lumbar spine bone mineral content and bone mineral density (BMD) (e.g., lumbar spine BMD: β = -0.02 g · cm-2 · SD-1 increase in CTX; 95% CI: -0.027, -0.002 g · cm-2 · SD-1; P = 0.02, n = 283)., Conclusions: Maternal urinary CTX, a bone resorption marker, rises through pregnancy, although to a lesser degree with gestational cholecalciferol supplementation, and is inversely associated with maternal bone mass postpartum.This trial was registered at www.isrctn.com as ISRCTN 82927713 and eudract.ema.europa.eu as EudraCT 2007-001716-23., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Cellulose nanomaterials (CNMs) are a class of materials that have recently garnered attention in fields as varied as structural materials, biomaterials, rheology modifiers, construction, paper enhancement, and others. As the principal structural reinforcement of biomass giving wood its mechanical properties, CNM is strong and stiff, but also nontoxic, biodegradable, and sustainable with a very large (Gton yr -1 ) source. Unfortunately, due to the relatively young nature of the field and inherent incompatibility of CNM with most man-made materials in use today, research has tended to be more basic-science oriented rather than commercially applicable, so there are few CNM-enabled products on the market today. Herein, efforts are presented for preparing and forming cellulose nanomaterial nanocomposites. The focus is on recent efforts attempting to mitigate common impediments to practical commercialization but is also placed in context with traditional efforts. The work is presented in terms of the progress made, and still to be made, on solving the most pressing challenges-getting properties that are competitive with currently used materials, removing organic solvent, solving the inherent incompatibility between CNM and polymers of interest, and incorporation into commonly used industrial processing techniques., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The rapid global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), has re-ignited interest in the possible role of vitamin D in modulation of host responses to respiratory pathogens. Indeed, vitamin D supplementation has been proposed as a potential preventative or therapeutic strategy. Recommendations for any intervention, particularly in the context of a potentially fatal pandemic infection, should be strictly based on clinically informed appraisal of the evidence base. In this narrative review, we examine current evidence relating to vitamin D and COVID-19 and consider the most appropriate practical recommendations., Observations: Although there are a growing number of studies investigating the links between vitamin D and COVID-19, they are mostly small and observational with high risk of bias, residual confounding, and reverse causality. Extrapolation of molecular actions of 1,25(OH) 2 -vitamin D to an effect of increased 25(OH)-vitamin D as a result of vitamin D supplementation is generally unfounded, as is the automatic conclusion of causal mechanisms from observational studies linking low 25(OH)-vitamin D to incident disease. Efficacy is ideally demonstrated in the context of adequately powered randomised intervention studies, although such approaches may not always be feasible., Conclusions: At present, evidence to support vitamin D supplementation for the prevention or treatment of COVID-19 is inconclusive. In the absence of any further compelling data, adherence to existing national guidance on vitamin D supplementation to prevent vitamin D deficiency, predicated principally on maintaining musculoskeletal health, appears appropriate.

Cellulose nanomaterials (CNMs), mainly including nanofibrillated cellulose (NFC) and cellulose nanocrystals (CNCs), have attained enormous interest due to their sustainability, biodegradability, biocompatibility, nanoscale dimensions, large surface area, facile modification of surface chemistry, as well as unique optical, mechanical, and rheological performance. One of the most fascinating properties of CNMs is their aqueous suspension rheology, i.e., CNMs helping create viscous suspensions with the formation of percolation networks and chemical interactions (e.g., van der Waals forces, hydrogen bonding, electrostatic attraction/repulsion, and hydrophobic attraction). Under continuous shearing, CNMs in an aqueous suspension can align along the flow direction, producing shear-thinning behavior. At rest, CNM suspensions regain some of their initial structure immediately, allowing rapid recovery of rheological properties. These unique flow features enable CNMs to serve as rheological modifiers in a wide range of fluid-based applications. Herein, the dependence of the rheology of CNM suspensions on test protocols, CNM inherent properties, suspension environments, and postprocessing is systematically described. A critical overview of the recent progress on fluid applications of CNMs as rheology modifiers in some emerging industrial sectors is presented as well. Future perspectives in the field are outlined to guide further research and development in using CNMs as the next generation rheological modifiers., (© 2021 Wiley-VCH GmbH.)

Optimisation of skeletal mineralisation in childhood is important to reduce childhood fracture and the long-term risk of osteoporosis and fracture in later life. One approach to achieving this is antenatal vitamin D supplementation. The Maternal Vitamin D Osteoporosis Study is a randomised placebo-controlled trial, the aim of which was to assess the effect of antenatal vitamin D supplementation (1000 IU/day cholecalciferol) on offspring bone mass at birth. The study has since extended the follow up into childhood and diversified to assess demographic, lifestyle and genetic factors that determine the biochemical response to antenatal vitamin D supplementation, and to understand the mechanisms underpinning the effects of vitamin D supplementation on offspring bone development, including epigenetics. The demonstration of positive effects of maternal pregnancy vitamin D supplementation on offspring bone development and the delineation of underlying biological mechanisms inform clinical care and future public-health policies., Competing Interests: Conflict of interest statement: NCH has received consultancy, lecture fees and honoraria from Alliance for Better Bone Health, Amgen, MSD, Eli Lilly, Servier, Shire, Consilient Healthcare and Internis Pharmaceuticals. CC has received consultancy, lecture fees and honoraria from Amgen, GlaxoSmithKline, Alliance for Better Bone Health, MSD, Eli Lilly, Pfizer, Novartis, Servier, Medtronic and Roche. EMC reports honoraria/travel support from Eli Lilly, UCB and Amgen outside the submitted work., (© The Author(s), 2021.)

Background: Public Health England advises 400 IU/day vitamin D supplementation for children over 1 year. Commercially available children's multivitamin and vitamin D supplements were surveyed to determine the vitamin D content., Methods: Multivitamins and vitamin D supplements marketed at children <12 years and sold by nine UK supermarkets and health supplement retailers were surveyed. Vitamin D content was determined from manufacturer's websites and product packaging., Results: 67 multivitamins were surveyed, containing 0-800 IU/day vitamin D. Only 25%-36%, depending on the child's age, provided ≥400 IU/day vitamin D. Supplements containing only vitamin D or labelled as for 'healthy bones' typically had higher vitamin D content (57%-67% contained ≥400 IU/day)., Conclusions: Few multivitamin products supply the recommended 400 IU/day vitamin D. Clinicians need to be aware of this when recommending vitamin D supplementation and advise parents/carers to choose a product that contains ≥400 IU/day vitamin D., Competing Interests: Competing interests: RJM has nothing to report. EMC reports honoraria or travel support from Eli Lilly, Pfizer and UCB, outside of the submitted work. CC reports personal fees from ABBH, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier and Takeda, outside the submitted work. NCH reports personal fees, consultancy, lecture fees and honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Servier, Shire, Consilient Healthcare and Internis Pharma, outside the submitted work. JHD has received travel bursaries received from Novo Nordisk, Pfizer and Sandoz, outside the submitted work., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To evaluate the construction reproducibility of a composite tooth model (CTM) composed of an intraoral-scanned crown and a cone-beam computed tomography (CBCT)-scanned root., Methods: The study assessed 240 teeth (30 central incisors, 30 canines, 30 second premolars, and 30 first molars in the maxillary and mandibular arches) from 15 young adult patients whose pre-treatment intraoral scan and CBCT were available. Examiner-Reference (3 years' experience in CTM construction) and Examiners-A and Examiner-B (no experience) constructed the individual CTMs independently by performing the following steps: image acquisition and processing into a three-dimensional model, integration of intraoral-scanned crowns and CBCT-scanned teeth, and replacement of the CBCT-scanned crown with the intraoral-scanned crown. The tooth axis angle in terms of mesiodistal angulation and buccolingual inclination of the CTMs constructed by the three examiners were measured. To assess the construction reproducibility of CTMs, intraclass correlation coefficient (ICC) assessments were performed., Results: The ICC values of mesiodistal angulation and buccolingual inclination among the 3 examiners showed excellent agreement (0.950-0.992 and 0.965-0.993; 0.976-0.994 and 0.973-0.995 in the maxillary and mandibular arches, respectively)., Conclusions: The CTM showed excellent construction reproducibility in mesiodistal angulation and buccolingual inclination regardless of the construction skill and experience levels of the examiners.

The Maternal Vitamin D Osteoporosis (MAVIDOS) trial reported higher total body bone mineral content in winter-born infants of mothers receiving vitamin D supplementation [1000 IU/day cholecalciferol] compared with placebo from 14 weeks gestation until delivery. This sub-study aimed to determine whether antenatal vitamin D supplementation altered postnatal bone formation in response to mechanical stimulation. Thirty-one children born to MAVIDOS participants randomised to either placebo (n=19) or cholecalciferol (n=12) were recruited at age 4-5 years. Children received whole body vibration (WBV) for 10 minutes on 5 consecutive days. Fasting blood samples for bone homeostasis, 25 hydroxyvitamin D (25OHD), parathyroid hormone (PTH), and bone turnover markers (Pro-collagen Type 1 N-terminal propeptide, P1NP; Cross-linked C-telopeptide of Type I Collagen, CTX) were collected pre-WBV and on day 8 (D8). Mean changes (D) in P1NP (ng/ml) between baseline and D8 in the vitamin-D intervention and placebo groups were 40.6 and -92.6 respectively and mean changes (Δ) in CTX (ng/ml) were 0.034 (intervention) and -0.084 (placebo) respectively. Between-group DP1NP difference was 133.2ng/ml [95% CI 0.4, 266.0; p=0.049] and ΔCTX 0.05ng/ml (95% CI -0.159, 0.26ng/mL; p=0.62). Antenatal vitamin-D supplementation resulted in increased P1NP in response to WBV, suggesting early life vitamin D supplementation increases the anabolic response of bone to mechanical loading in children., Competing Interests: JSG-K, ASR, RCH, RJM, EMC, have nothing to disclose. CC reports personal fees from ABBH, AMGEN, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier and Takeda, outside the submitted work. NCH reports personal fees, consultancy, lecture fees and honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Servier, Shire, Consilient Healthcare and Internis Pharma, outside the submitted work. RE reports consulting fees from Amgen, AstraZeneca, Chronos, GSK, Immunodiagnostic Systems, Fonterra Brands, Ono Pharma, Lilly, Bayer, Janssen Research, Alere, CL Biosystems, Teijin Pharm, D-Star, Roche Diagnostics, Inverness Medical; grant support from Amgen, Alexion, Immunodiagnostic Systems, Roche, AstraZeneca. NJB reports personal fees from Internis, grants and personal fees from Alexion Pharma, personal fees from Mereo Biopharma, grants and personal fees from Amgen, personal fees from Novartis, outside the submitted work.

Vitamin D has important roles in calcium metabolism and in the prevention of rickets and osteomalacia; low levels of 25-hydroxyvitamin D are common in the general population and amongst pregnant women. Whilst there is a wealth of observational evidence linking vitamin D deficiency to a wide range of disease outcomes, there are currently few high-quality randomised controlled trials to confirm any causal associations, although many are currently in progress. Furthermore, currently, the vast majority of published guidelines recommend standard supplemental vitamin D doses for children and pregnant women, yet there is increasing recognition that individual characteristics and genetic factors may influence the response to supplementation. As such, future research needs to concentrate on documenting definite beneficial clinical outcomes of vitamin D supplementation, and establishing personalised dosing schedules and demonstrating effective approaches to optimising initiation and adherence.

This study focuses on understanding the effect of cellulose nanocrystals (CNCs) on glass fiber/epoxy interfacial interactions. The glass fibers (GF) were coated with solutions containing cellulose nanomaterial. The parameters that were investigated were the CNC surface chemistry, concentration, and dispersing medium, i.e., aqueous solution only versus emulsions. To determine the effect of the CNC coatings on the interfacial adhesion, specimens of a single GF in an epoxy matrix were prepared for GF coating by varying the coating formulations. The interfacial shear stress (IFSS) was determined by the single fiber fragmentation test (SFFT). Following the SFFT, the samples were investigated by cross-polarized microscopy in order to understand the fracture modes which are related to the nature of the interphase. According to the SFFT data and photoelastic fracture patterns, both the emulsion and aqueous coatings containing cellulose nanocrystals functionalized with methyl(triphenyl) phosphonium (CNCPh) improve the IFSS in comparison to coated GFs without CNCs.

Introduction: Optimising bone health might reduce the burden of both fractures in childhood and fragility fractures in later life. A number of maternal dietary and non-dietary factors have been identified that might influence offspring bone health and represent targets for intervention., Areas Covered: This article will outline the accrual of bone mineral throughout the life course and how observational and intervention studies have shown that maternal diet, in particular maternal calcium and 25-hydroxyvitamin D [25(OH)D] status, and lifestyle are associated with offspring bone mineralization. Studies examining the effects of maternal micronutrient supplementation on offspring bone mineral density (BMD) will also be discussed., Expert Commentary: There is a wealth of observational evidence relating maternal diet to offspring BMD. However, high quality randomized controlled trials, such as the ongoing MAVIDOS study, are needed before these findings can be definitively translated into public health advice.

We have previously demonstrated inverse associations between maternal 25(OH)-vitamin D status and perinatal DNA methylation at the retinoid-X-receptor-alpha (RXRA) locus and between RXRA methylation and offspring bone mass. In this study, we used an existing randomized trial to test the hypothesis that maternal gestational vitamin D supplementation would lead to reduced perinatal RXRA locus DNA methylation. The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a multicenter, double-blind, randomized, placebo-controlled trial of 1000 IU/day cholecalciferol or matched placebo from 14 weeks' gestation until delivery. Umbilical cord (fetal) tissue was collected at birth and frozen at -80°C (n = 453). Pyrosequencing was used to undertake DNA methylation analysis at 10 CpG sites within the RXRA locus (identified previously). T tests were used to assess differences between treatment groups in methylation at the three most representative CpG sites. Overall, methylation levels were significantly lower in the umbilical cord from offspring of cholecalciferol-supplemented mothers, reaching statistical significance at four CpG sites, represented by CpG5: mean difference in % methylation between the supplemented and placebo groups was -1.98% (95% CI, -3.65 to -0.32, p = 0.02). ENCODE (Encyclopedia of DNA Elements) evidence supports the functionality of this locus with strong DNase hypersensitivity and enhancer chromatin within biologically relevant cell types including osteoblasts. Enrichment of the enhancer-related H3K4me1 histone mark is also seen in this region, as are binding sites for a range of transcription factors with roles in cell proliferation, response to stress, and growth factors. Our findings are consistent with previous observational results and provide new evidence that maternal gestational supplementation with cholecalciferol leads to altered perinatal epigenetic marking, informing mechanistic understanding of early life mechanisms related to maternal vitamin D status, epigenetic marks, and bone development. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc., (© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.)

Introduction: Maternal vitamin D status in pregnancy has been linked to many health outcomes in mother and offspring. A wealth of observational studies have reported on both obstetric outcomes and complications, including pre-eclampsia, gestational diabetes, mode and timing of delivery. Many foetal and childhood outcomes are also linked to vitamin D status, including measures of foetal size, body composition and skeletal mineralization, in addition to later childhood outcomes, such as asthma., Sources of Data: Synthesis of systematic and narrative reviews., Areas of Agreement and Controversy: The findings are generally inconsistent in most areas, and, at present, there is a lack of data from high-quality intervention studies to confirm a causal role for vitamin D in these outcomes. In most areas, the evidence tends towards maternal vitamin D being of overall benefit, but often does not reach statistical significance in meta-analyses., Growing Points and Areas Timely for Developing Research: The most conclusive evidence is in the role of maternal vitamin D supplementation in the prevention of neonatal hypocalcaemia; as a consequence the UK department of health recommends that pregnant women take 400 IU vitamin D daily. High-quality randomized placebo-controlled trials, such as the UK-based MAVIDOS trial, will inform the potential efficacy and safety of vitamin D supplementation in pregnancy across a variety of outcomes.

A new family of materials comprised of cellulose, cellulose nanomaterials (CNMs), having properties and functionalities distinct from molecular cellulose and wood pulp, is being developed for applications that were once thought impossible for cellulosic materials. Commercialization, paralleled by research in this field, is fueled by the unique combination of characteristics, such as high on-axis stiffness, sustainability, scalability, and mechanical reinforcement of a wide variety of materials, leading to their utility across a broad spectrum of high-performance material applications. However, with this exponential growth in interest/activity, the development of measurement protocols necessary for consistent, reliable and accurate materials characterization has been outpaced. These protocols, developed in the broader research community, are critical for the advancement in understanding, process optimization, and utilization of CNMs in materials development. This review establishes detailed best practices, methods and techniques for characterizing CNM particle morphology, surface chemistry, surface charge, purity, crystallinity, rheological properties, mechanical properties, and toxicity for two distinct forms of CNMs: cellulose nanocrystals and cellulose nanofibrils.

Cellulose nanocrystals (CNCs) can be attractive templates for the generation of functional inorganic/organic nanoparticles, given their fine sizes, aspect ratios, and sustainable worldwide availability in abundant quantities. Here, we present for the first time a scalable, surfactant-free, tailorable wet chemical process for converting commercially available CNCs into individual aspected gold nanoshell-bearing particles with tunable surface plasmon resonance bands. Using a rational cellulose functionalization approach, stable suspensions of positively charged CNCs have been generated. Continuous, conductive, nanocrystalline gold coatings were then applied to the individual, electrostatically stabilized CNCs via decoration with 1-3 nm diameter gold particles followed by electroless gold deposition. Optical analyses indicated that these core-shell nanoparticles exhibited two surface plasmon absorbance bands, with one located in the visible range (near 550 nm) and the other at near infrared (NIR) wavelengths. The NIR band possessed a peak maximum wavelength that could be tuned over a wide range (1000-1300 nm) by adjusting the gold coating thickness. The bandwidth and wavelength of the peak maximum of the NIR band were also sensitive to the particle size distribution and could be further refined by fractionation using viscosity gradient centrifugation.

Cellulose nanofibrils (CNF) were sulfonated and the dispersion quality was compared to unfunctionalized and 2,2,6,6-tetramethylpiperdine-1-oxyl radical (TEMPO) post-oxidation treatment of existing CNF (mechanically fibrillated pulp). A post-sulfonation treatment on existing CNF in chlorosulfonic acid and dimethylformamide (DMF) resulted in sulfonated CNF that retained a fibril-like morphology. There was a small decrease in the cellulose crystallinity index for the sulfonated CNF, but this was much lower than the reported regioselective oxidative bisulfite pretreatment method used to make sulfonated CNF. The current approach was extremely quick, and 5min of reaction time was sufficient to result in significant improvements in dispersibility compared to unfunctionalized CNF. The sulfonated CNF and TEMPO oxidized CNF had better dispersibility compared to the unfunctionalized CNF when dispersed in DMF and water, and in many cases the sulfonated CNF had better dispersibility than the TEMPO CNF. It was found that when CNF was dispersed in DMF the TEMPO CNF formed carboxyl dimethylammonium groups, while the sulfonated CNF formed formate groups., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Internet search rates for "vitamin D" were explored using Google Trends. Search rates increased from 2004 until 2010 and thereafter displayed a seasonal pattern peaking in late winter. This knowledge could help guide the timing of public health interventions aimed at managing vitamin D deficiency., Purpose: The Internet is an important source of health information. Analysis of Internet search activity rates can provide information on disease epidemiology, health related behaviors and public interest. We explored Internet search rates for vitamin D to determine whether this reflects the increasing scientific interest in this topic., Methods: Google Trends is a publically available tool that provides data on Internet searches using Google. Search activity for the term "vitamin D" from 1st January 2004 until 31st October 2016 was obtained. Comparison was made to other bone and nutrition related terms., Results: Worldwide, searches for "vitamin D" increased from 2004 until 2010 and thereafter a statistically significant (p < 0.001) seasonal pattern with a peak in February and nadir in August was observed. This seasonal pattern was evident for searches originating from both the USA (peak in February) and Australia (peak in August); p < 0.001 for both. Searches for the terms "osteoporosis", "rickets", "back pain" or "folic acid" did not display the increase observed for vitamin D or evidence of seasonal variation., Conclusion: Public interest in vitamin D, as assessed by Internet search activity, did increase from 2004 to 2010, likely reflecting the growing scientific interest, but now displays a seasonal pattern with peak interest during late winter. This information could be used to guide public health approaches to managing vitamin D deficiency.

Osteoporosis constitutes a major public health problem, through its association with age-related fractures, particularly of the hip, vertebrae, distal forearm and humerus. Substantial geographic variation has been noted in the incidence of osteoporotic fractures worldwide, with Western populations (North America, Europe and Oceania), reporting increases in hip fracture throughout the second half of the 20th century, with a stabilisation or decline in the last two decades. In developing populations however, particularly in Asia, the rates of osteoporotic fracture appears to be increasing. The massive global burden consequent to osteoporosis means that fracture risk assessment should be a high priority among health measures considered by policy makers. The WHO operational definition of osteoporosis, based on a measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA), has been used globally since the mid-1990s. However, although this definition identifies those at greatest individual risk of fracture, in the population overall a greater total number of fractures occur in individuals with BMD values above the threshold for osteoporosis diagnosis. A number of web-based tools to enable the inclusion of clinical risk factors, with or without BMD, in fracture prediction algorithms have been developed to improve the identification of individuals at high fracture risk, the most commonly used globally being FRAX®. Access to DXA, osteoporosis risk assessment, case finding and treatment varies worldwide, but despite such advances studies indicate that a minority of men and women at high fracture risk receive treatment. Importantly, research is ongoing to demonstrate the clinical efficacy and cost-effectiveness of osteoporosis case finding and risk assessment strategies worldwide. The huge burden caused by osteoporosis related fractures to individuals, healthcare systems and societies should provide a clear impetus for the progression of such approaches., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Osteoporosis constitutes a major public health problem, through its association with age-related fractures, particularly of the hip, vertebrae, distal forearm and humerus. Substantial geographic variation has been noted in the incidence of osteoporotic fractures worldwide, with Western populations (North America, Europe and Oceania), reporting increases in hip fracture throughout the second half of the 20th century, with a stabilisation or decline in the last two decades. In developing populations however, particularly in Asia, the rates of osteoporotic fracture appears to be increasing. The massive global burden consequent to osteoporosis means that fracture risk assessment should be a high priority amongst health measures considered by policy makers. The WHO operational definition of osteoporosis, based on a measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA), has been used globally since the mid-1990s. However, although this definition identifies those at greatest individual risk of fracture, in the population overall a greater total number of fractures occur in individuals with BMD values above threshold for osteoporosis diagnosis. A number of web-based tools to enable the inclusion of clinical risk factors, with or without BMD, in fracture prediction algorithms have been developed to improve the identification of individuals at high fracture risk, the most commonly used globally being FRAX ® . Access to DXA, osteoporosis risk assessment, case finding and treatment varies worldwide, but despite such advances studies indicate that a minority of men and women at high fracture risk receive treatment. Importantly, research is ongoing to demonstrate the clinical efficacy and cost-effectiveness of osteoporosis case finding and risk assessment strategies worldwide. The huge burden caused by osteoporosis related fractures to individuals, healthcare systems and societies should provide a clear impetus for the progression of such approaches., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Context: Single-nucleotide polymorphisms (SNPs) in genes related to vitamin D metabolism have been associated with serum 25-hydroxyvitamin D [25(OH)D] concentration, but these relationships have not been examined following antenatal cholecalciferol supplementation., Objective: To determine whether SNPs in DHCR7, CYP2R1, CYP24A1, and GC are associated with the response to gestational cholecalciferol supplementation., Design: Within-randomization group analysis of the Maternal Vitamin D Osteoporosis Study trial of antenatal cholecalciferol supplementation., Setting: Hospital antenatal clinics., Participants: In total, 682 women of white ethnicity (351 placebo, 331 cholecalciferol) were included. SNPs at rs12785878 (DHCR7), rs10741657 (CYP2R1), rs6013897 (CYP24A1), and rs2282679 (GC) were genotyped., Interventions: 1000 IU/d cholecalciferol from 14 weeks of gestation until delivery., Main Outcome Measure: 25(OH)D at randomization and 34 weeks of gestation were measured in a single batch (Liaison; Diasorin, Dartford, UK). Associations between 25(OH)D and the SNPs were assessed by linear regression using an additive model [β represents the change in 25(OH)D per additional common allele]., Results: Only rs12785878 (DHCR7) was associated with baseline 25(OH)D [β = 3.1 nmol/L; 95% confidence interval (CI), 1.0 to 5.2 nmol/L; P < 0.004]. In contrast, rs10741657 (CYP2R1) (β = -5.2 nmol/L; 95% CI, -8.2 to -2.2 nmol/L; P = 0.001) and rs2282679 (GC) (β = 4.2 nmol/L; 95% CI, 0.9 to 7.5 nmol/L; P = 0.01) were associated with achieved 25(OH)D status following supplementation, whereas rs12785878 and rs6013897 (CYP24A1) were not., Conclusions: Genetic variation in DHCR7, which encodes 7-dehyrocholesterol reductase in the epidermal vitamin D biosynthesis pathway, appears to modify baseline 25(OH)D. In contrast, the response to antenatal cholecalciferol supplementation was associated with SNPs in CYP2R1, which may alter 25-hydroxylase activity, and GC, which may affect vitamin D binding protein synthesis or metabolite affinity., (Copyright © 2017 Endocrine Society)