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Background Orchestration of tooth movement necessitates an equilibrium of bone synthesis and resorption. Vitamin D, through receptor-mediated actions, regulates the differentiation and maturation of osteoblasts and also induces osteoclastogenesis, maintaining this equilibrium. Objective To analyze the impact of vitamin D in orthodontic tooth movement (OTM). Search method A comprehensive exploration of the existing literature was conducted by systematic search through seven e-databases. Selection criteria The criteria for inclusion were established using the PICO format: Orthodontic patients treated with fixed appliance (P), administered with vitamin D3 (I), collated with appropriate control groups (C), with tooth movement as the primary outcome and root resorption, anchorage loss, gingival crevicular fluid (GCF) volume, pain perception, and alveolar bone density as the secondary outcome (O). Data collection and analysis After an extensive database search, 251 articles were obtained. Six articles were chosen following a stringent selection using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The critical appraisal of randomized control trials (RCTs) involved the meticulous application of the RoB 2 tool. The quantitative synthesis incorporated a subset of six articles only. Results In the meta-analysis investigating the influence of vitamin D on OTM, a notable disparity was evident between the vitamin D and control groups. Specifically, the standardized mean difference (SMD) stood at 1.43, accompanied by a 95% confidence interval (CI) ranging from 0.691 to 2.169 (P  = .00154). For root resorption, the SMD was recorded at −0.51, with a 95% CI spanning from −3.051 to 2.031 (P  = .11). Conclusions The rate of tooth movement was enhanced by systemic and local administration of vitamin D. However, the inadequacy of available data is a hindrance in determining conclusively the impact of vitamin D on the extent of root resorption. The resolution of this quandary needs future human studies devoted toward investigating the influence of vitamin D in the realms of OTM and associated root resorption, thereby providing a definitive elucidation. Registration details Prospero- CRD42023491783 [ABSTRACT FROM AUTHOR]

The 6th International Conference, "Controversies in Vitamin D," was convened to discuss controversial topics, such as vitamin D metabolism, assessment, actions, and supplementation. Novel insights into vitamin D mechanisms of action suggest links with conditions that do not depend only on reduced solar exposure or diet intake and that can be detected with distinctive noncanonical vitamin D metabolites. Optimal 25-hydroxyvitamin D (25(OH)D) levels remain debated. Varying recommendations from different societies arise from evaluating different clinical or public health approaches. The lack of assay standardization also poses challenges in interpreting data from available studies, hindering rational data pooling and meta-analyses. Beyond the well-known skeletal features, interest in vitamin D's extraskeletal effects has led to clinical trials on cancer, cardiovascular risk, respiratory effects, autoimmune diseases, diabetes, and mortality. The initial negative results are likely due to enrollment of vitamin D-replete individuals. Subsequent post hoc analyses have suggested, nevertheless, potential benefits in reducing cancer incidence, autoimmune diseases, cardiovascular events, and diabetes. Oral administration of vitamin D is the preferred route. Parenteral administration is reserved for specific clinical situations. Cholecalciferol is favored due to safety and minimal monitoring requirements. Calcifediol may be used in certain conditions, while calcitriol should be limited to specific disorders in which the active metabolite is not readily produced in vivo. Further studies are needed to investigate vitamin D effects in relation to the different recommended 25(OH)D levels and the efficacy of the different supplementary formulations in achieving biochemical and clinical outcomes within the multifaced skeletal and extraskeletal potential effects of vitamin D. [ABSTRACT FROM AUTHOR]

Aim The gut microbiota plays a key role in host health. An intake of omega-3 and vitamin D3 in a separate manner is vital for maintaining good health of gut microbiota and controlling some illness manifestations. The aim of this study is to investigate the potential change in biodiversity of the gut microbiome in healthy rats supplemented with vitamin D3, omega-3 alone and their combination and to reflect onto the triglyceride levels in serum and fecal samples. Methods and results Using the 16S rRNA gene Miseq Illumina NGS, and monitoring triglyceride levels in serum and fecal samples coupled with several clinical parameters, we examined the effect of orally taken combination of omega-3 and vitamin D3 alongside the separate intake of supplements on gut microbiota in 24 healthy white Wistar rats for six weeks. The study findings showed that combination treatment encouraged the growth of opportunistic Clostridia class during day 21 and 42 of treatment by 7.7 and 7.4 folds, respectively, exhibited incomplete absorption levels for both supplements when used concomitantly, demonstrated a damaging effect on the gut intestinal lining wall thickness (126 µm) when compared to control group (158  µm), increasing lumen diameter (400 µm), and showed higher triglyceride level in fecal samples. Conclusions These findings indicate that omega-3 and vitamin D3 supplements as combination intake reveal unfavorable effects, thus, it is advised to conduct further in-depth studies to clarify the presence or absence of any chemical interaction between both supplements' molecules and to investigate based on human model to attain a superior perspective. [ABSTRACT FROM AUTHOR]

Context Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder in women of reproductive age. Vitamin D supplementation is a promising complementary therapy for PCOS, yet there is no consensus on an optimal dose, leading to a lack of evidence-based supplementation guidelines. Objective The objective of this study was to conduct a vitamin D dose–response meta-analysis among women with PCOS. Data sources MEDLINE, CINAHL, and EMBASE databases from inception to November 2022 were searched for relevant articles. Data extraction Study screening and bias assessment were conducted by 2 independent reviewers. Eight relevant studies were identified; data for serum 25(OH)D (nmol/L) at baseline and at 12 weeks in each intervention group (mean ± SD) and vitamin D dose were extracted. Data analysis Estimates across studies were used to create a pooled curve, using restricted cubic splines with knots at the 10th, 50th, and 90th percentiles of the distribution of doses, to estimate the mean difference in effect for serum 25(OH)D at each dose compared with 0 IU/day. Sensitivity analyses were conducted fixing knots at 4000 IU/day and 7000 IU/day, which were a priori identified as potentially important thresholds, and to assess model fit and estimate heterogeneity. The pooled analysis demonstrated strong evidence of a dose–response relationship (P < .001), suggesting an increasing effect with increasing dose. An initial increase in serum 25(OH)D was evident until doses of approximately 3000 IU/day; this was followed by a plateau in effect between approximately 3000 IU/day and 5000 IU/day. The effect of supplementation with >5000 IU/day was unclear, given the minimal data at higher doses. The curve produced robust results for moderate doses (3000 IU/day to 4000 IU/day), which were not sensitive to model specification. Conclusion Women with PCOS are responsive to vitamin D supplementation, but the benefit of providing doses of >3000 IU/day appears minimal. Further data is required to determine dose–response at doses of >5000 IU/day, and whether higher intakes provide a clinically meaningful advantage in this population. Systematic Review Registration PROSPERO registration no. CRD42021259396. [ABSTRACT FROM AUTHOR]

Background Patients with erythropoietic protoporphyria experience lifelong painful photosensitivity resulting in a lack of sunlight exposure. Previous studies have shown that 47–63% of patients with EPP suffer from vitamin D deficiency and a high prevalence of osteoporosis. An effective treatment for EPP has been available since 2016: the α-melanocyte stimulating hormone analogue afamelanotide. So far, studies on vitamin D levels in EPP have only investigated patients who have not been treated with afamelanotide. Objectives To investigate the effects of afamelanotide treatment on vitamin D levels in EPP. Methods A multicentre observational cohort study in adults with EPP from the Erasmus Medical Centre, the Netherlands, and the University Hospital Düsseldorf, Germany, was carried out. Routinely collected vitamin D levels between 2005 and 2021 were used for analysis. Patient exposure to cholecalciferol or afamelanotide was categorized into four treatment groups: untreated, cholecalciferol, afamelanotide and combined treatment. A linear mixed model for longitudinal data was applied to measure the effect of the treatment groups compared with the untreated groups on vitamin D levels. Results A total of 230 patients and 1774 vitamin D measurements were included. The prevalence of vitamin D deficiency and severe deficiency remained high despite afamelanotide treatment (< 50 nmol L–1 in 71.8% of patients and < 30 nmol L–1 in 48.1%, respectively). Afamelanotide treatment alone did not lead to a significant average increase in vitamin D levels [β = 0.5, 95% confidence interval (CI) –3.2 to 4.2]. In contrast, cholecalciferol and combined therapy with afamelanotide led to a significant increase in vitamin D levels [β = 11.6 (95% CI 7.2–15.9) and β = 15.2 (95% CI 12.3–18.1), respectively]. Conclusions Cholecalciferol remains essential for the treatment of vitamin D deficiency in EPP, irrespective of new treatment options like afamelanotide. Afamelanotide treatment did not affect vitamin D levels. We suggest that future guidelines include continuous monitoring of vitamin D and a prescription for cholecalciferol in all patients with EPP, including those treated with afamelanotide. [ABSTRACT FROM AUTHOR]

Background Numerous studies demonstrate associations between serum concentrations of 25-hydroxyvitamin D (25[OH]D) and a variety of common disorders, including musculoskeletal, metabolic, cardiovascular, malignant, autoimmune, and infectious diseases. Although a causal link between serum 25(OH)D concentrations and many disorders has not been clearly established, these associations have led to widespread supplementation with vitamin D and increased laboratory testing for 25(OH)D in the general population. The benefit-risk ratio of this increase in vitamin D use is not clear, and the optimal vitamin D intake and the role of testing for 25(OH)D for disease prevention remain uncertain. Objective To develop clinical guidelines for the use of vitamin D (cholecalciferol [vitamin D3] or ergocalciferol [vitamin D2]) to lower the risk of disease in individuals without established indications for vitamin D treatment or 25(OH)D testing. Methods A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and prioritized 14 clinically relevant questions related to the use of vitamin D and 25(OH)D testing to lower the risk of disease. The panel prioritized randomized placebo-controlled trials in general populations (without an established indication for vitamin D treatment or 25[OH]D testing), evaluating the effects of empiric vitamin D administration throughout the lifespan, as well as in select conditions (pregnancy and prediabetes). The panel defined "empiric supplementation" as vitamin D intake that (a) exceeds the Dietary Reference Intakes (DRI) and (b) is implemented without testing for 25(OH)D. Systematic reviews queried electronic databases for publications related to these 14 clinical questions. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and guide recommendations. The approach incorporated perspectives from a patient representative and considered patient values, costs and resources required, acceptability and feasibility, and impact on health equity of the proposed recommendations. The process to develop this clinical guideline did not use a risk assessment framework and was not designed to replace current DRI for vitamin D. Results The panel suggests empiric vitamin D supplementation for children and adolescents aged 1 to 18 years to prevent nutritional rickets and because of its potential to lower the risk of respiratory tract infections; for those aged 75 years and older because of its potential to lower the risk of mortality; for those who are pregnant because of its potential to lower the risk of preeclampsia, intra-uterine mortality, preterm birth, small-for-gestational-age birth, and neonatal mortality; and for those with high-risk prediabetes because of its potential to reduce progression to diabetes. Because the vitamin D doses in the included clinical trials varied considerably and many trial participants were allowed to continue their own vitamin D–containing supplements, the optimal doses for empiric vitamin D supplementation remain unclear for the populations considered. For nonpregnant people older than 50 years for whom vitamin D is indicated, the panel suggests supplementation via daily administration of vitamin D, rather than intermittent use of high doses. The panel suggests against empiric vitamin D supplementation above the current DRI to lower the risk of disease in healthy adults younger than 75 years. No clinical trial evidence was found to support routine screening for 25(OH)D in the general population, nor in those with obesity or dark complexion, and there was no clear evidence defining the optimal target level of 25(OH)D required for disease prevention in the populations considered; thus, the panel suggests against routine 25(OH)D testing in all populations considered. The panel judged that, in most situations, empiric vitamin D supplementation is inexpensive, feasible, acceptable to both healthy individuals and health care professionals, and has no negative effect on health equity. Conclusion The panel suggests empiric vitamin D for those aged 1 to 18 years and adults over 75 years of age, those who are pregnant, and those with high-risk prediabetes. Due to the scarcity of natural food sources rich in vitamin D, empiric supplementation can be achieved through a combination of fortified foods and supplements that contain vitamin D. Based on the absence of supportive clinical trial evidence, the panel suggests against routine 25(OH)D testing in the absence of established indications. These recommendations are not meant to replace the current DRIs for vitamin D, nor do they apply to people with established indications for vitamin D treatment or 25(OH)D testing. Further research is needed to determine optimal 25(OH)D levels for specific health benefits. [ABSTRACT FROM AUTHOR]

Background efficacy of therapeutic cholecalciferol supplementation for severe COVID-19 is sparingly studied. Objective effect of single high-dose cholecalciferol supplementation on sequential organ failure assessment (SOFA) score in moderate-to-severe COVID-19. Methods participants with moderate to severe COVID-19 with PaO2/FiO2 ratio < 200 were randomized to 0.6 million IU cholecalciferol oral (intervention) or placebo. Outcomes primary outcome was change in Day 7 SOFA score and pre-specified secondary outcomes were SOFA and 28-day all-cause mortality. Results in all, 90 patients (45 each group) were included for intention-to-treat analysis. 25(OH)D3 levels were 12 (10–16) and 13 (12–18) ng/ml (P  = 0.06) at baseline; and 60 (55–65) ng/ml and 4 (1–7) ng/ml by Day 7 in vitamin D and placebo groups, respectively. The SOFA score on Day 7 was better in the vitamin D group [3 (95% CI, 2–5) versus 5 (95% CI, 3–7), P  = 0.01, intergroup difference − 2 (95% CI, −4 to −0.01); r  = 0.4]. A lower all-cause 28-day mortality [24% compared to 44% (P  = 0.046)] was observed with vitamin D. Conclusions single high-dose oral cholecalciferol supplementation on ICU admission can improve SOFA score at Day 7 and reduce in-hospital mortality in vitamin D-deficient COVID-19. ClinicalTrials.gov   id: NCT04952857 registered dated 7 July 2021. What is already known on this topic —vitamin D has immunomodulatory role. Observational and isolated intervention studies show some benefit in COVID-19. Targeted therapeutic vitamin D supplementation improve outcomes in severe COVID-19 is not studied in RCTs. What this study adds —high-dose vitamin D supplementation (0.6 Million IU) to increase 25(OH)D > 50 ng/ml is safe and reduces sequential organ failure assessment score, in-hospital mortality in moderate to severe COVID-19. How this study might affect research, practice or policy— vitamin D supplementation in vitamin D-deficient patients with severe COVID-19 is useful may be practiced. [ABSTRACT FROM AUTHOR]

Background Among individuals with vitamin D deficiency, daily vitamin D supplementation appears to lower risk of acute respiratory infection. However, recent trials, in different populations and using different regimens, have yielded null results. We investigated the effect of daily vitamin D supplementation (vs placebo) on risk of upper respiratory infection (URI) in older adults. Methods The VITamin D and OmegA-3 TriaL (VITAL) is a randomized, double-blind, placebo-controlled trial of supplemental vitamin D and/or omega-3 fatty acids in generally healthy men (age ≥50 years) and women (age ≥55 years). This prespecified analysis focuses on vitamin D3 (2000 IU/day) versus placebo in the 15 804 (61%) participants with baseline serum total 25-hydroxyvitamin D level. The primary outcome was self-report of a recent URI at 1-year follow-up. Results Participants had a mean age of 68 years and 51% were women; 76% were non-Hispanic White, 16% Black, and 8% other race/ethnicity. The mean 25-hydroxyvitamin D level at baseline was 31 (standard deviation, 10) ng/mL, with <12 ng/mL in 2.4%. The overall effect of vitamin D supplementation on recent URI was nonsignificant (odds ratio [OR], 0.96 [95% confidence interval {CI},.86–1.06]). In the prespecified subgroup of primary interest (<12 ng/mL and denied taking concurrent vitamin D), which had only 255 participants, vitamin D supplementation was nonsignificant (OR, 0.60 [95% CI,.28–1.30]). Statistical power to assess effect modification in other subgroups was limited. Conclusions In older adults not selected for vitamin D deficiency, supplemental vitamin D did not lower URI risk overall. Whether effects differ in subgroups requires further study. Clinical Trials Registration. NCT01169259. [ABSTRACT FROM AUTHOR]

Context Chronic kidney disease (CKD) leads to alterations in fibroblast growth factor 23 (FGF23) and the renal-bone axis. This may be partly driven by altered inflammation and iron status. Vitamin D supplementation may reduce inflammation. Objective and methods Older adults with early CKD (estimated glomerular filtration rate (eGFR) 30–60 ml/min/1.73 m2; CKDG3a/b; n  = 35) or normal renal function (eGFR >90 ml/min/1.73 m2; CKDG1; n  = 35) received 12,000, 24,000 or 48,000 IU D3/month for 1 year. Markers of the renal-bone axis, inflammation and iron status were investigated pre- and post-supplementation. Predictors of c-terminal and intact FGF23 (cFGF23; iFGF23) were identified by univariate and multivariate regression. Results Pre-supplementation, comparing CKDG3a/b to CKDG1, plasma cFGF23, iFGF23, PTH, sclerostin and TNFα were significantly higher and Klotho, 1,25-dihydroxyvitamin D and iron were lower. Post-supplementation, only cFGF23, 25(OH)D and IL6 differed between groups. The response to supplementation differed between eGFR groups. Only in the CKDG1 group, phosphate decreased, cFGF23, iFGF23 and procollagen type I N-propeptide increased. In the CKDG3a/b group, TNFα significantly decreased, and iron increased. Plasma 25(OH)D and IL10 increased, and carboxy-terminal collagen crosslinks decreased in both groups. In univariate models cFGF23 and iFGF23 were predicted by eGFR and regulators of calcium and phosphate metabolism at both time points; IL6 predicted cFGF23 (post-supplementation) and iFGF23 (pre-supplementation) in univariate models. Hepcidin predicted post-supplementation cFGF23 in multivariate models with eGFR. Conclusion Alterations in regulators of the renal-bone axis, inflammation and iron status were found in early CKD. The response to vitamin D3 supplementation differed between eGFR groups. Plasma IL6 predicted both cFGF23 and iFGF23 and hepcidin predicted cFGF23. [ABSTRACT FROM AUTHOR]

Background High-resolution metabolomics (HRM) is an innovative tool to study challenging infectious diseases like leprosy, where the pathogen cannot be grown with standard methods. Here, we use HRM to better understand associations between disease manifestations, nutrition, and host metabolism. Methods From 2018 to 2019, adults with leprosy and controls were recruited in Minas Gerais, Brazil. Plasma metabolites were detected using an established HRM workflow and characterized by accurate mass, mass to charge ratio m/z and retention time. The mummichog informatics package compared metabolic pathways between cases and controls and between multibacillary (MB) and paucibacillary (PB) leprosy. Additionally, select individual metabolites were quantified and compared. Results Thirty-nine cases (62% MB and 38% PB) and 25 controls were enrolled. We found differences (P <.05) in several metabolic pathways, including fatty acid metabolism, carnitine shuttle, retinol, vitamin D3, and C-21 steroid metabolism, between cases and controls with lower retinol and associated metabolites in cases. Between MB and PB, leukotrienes, prostaglandins, tryptophan, and cortisol were all found to be lower in MB (P <.05). Discussion Metabolites associated with several nutrient-related metabolic pathways appeared differentially regulated in leprosy, especially MB versus PB. This pilot study demonstrates the metabolic interdependency of these pathways, which may play a role in the pathophysiology of disease. [ABSTRACT FROM AUTHOR]

Monogenic forms of rickets are being increasingly recognized. However, vitamin D-dependent rickets 1b (VDDR1b) due to CYP2R1 gene mutation is exceedingly rare. We report a 4.5-year-old girl and her younger sibling who presented with clinical, radiological, and biochemical features suggestive of nutritional rickets that did not resolve despite repeated therapeutic doses of vitamin D3. This led to evaluation for resistant rickets, which revealed a novel homozygous CYP2R1 c.50_51insTCGGCGGCGC; p.Leu18ArgfsTer79 variant in the affected siblings. The children were treated with oral calcium and cholecalciferol, dose titrated to maintain serum alkaline phosphatase, 25 hydroxy vitamin D, and parathyroid hormone levels in the normal range, with good clinical and radiological response. This case highlights the importance of genetic evaluation in patients with suspected nutritional rickets who have a family history of similar illness and require higher than usual doses of vitamin D for healing or relapse on stopping treatment. To the best of our knowledge this is the first case of VDDR1b reported from Asia. [ABSTRACT FROM AUTHOR]

Background Apolipoprotein E (APOE)-ε4 allele is associated with cognitive decline; however, its potential to modify effects of vitamin D3 and omega-3s supplementation on later-life cognition is unclear. Our objectives were to estimate among the in-clinic subset of a randomized trial: (1) associations between APOE-ε4 and global and domain-specific cognitive change, with exploration of potential sex and race differences; and (2) modification by APOE-ε4 of effects of vitamin D3 and omega-3s supplementation on cognitive change. Methods From an ancillary study of depression prevention within a completed 2 × 2 factorial trial testing vitamin D3 (2 000 IU per day), omega-3s (1 g per day), and/or placebos, we included 743 older adults with baseline in-person neuropsychiatric assessments and APOE genotyping data. The primary outcome was change in global cognition (averaging z -scores of 9 tests) over 2 years. Secondarily, episodic memory and executive function/attention z -scores were examined. General linear models of response profiles with multiplicative interaction terms were constructed; stratified results were reported. Results Mean age (standard deviation) was 67.1 (5.3) years; 50.6% were females; 24.9% were APOE-ε4 carriers. Compared to noncarriers, APOE-ε4 carriers had worse 2-year change in global cognition and episodic memory; differences were more apparent among females than males. There was no variation by race in APOE-ε4 associations with cognition. APOE-ε4 did not significantly modify effects of vitamin D3 or omega-3s, compared to placebo, on change in global cognition, episodic memory, or executive function/attention. Conclusions APOE-ε4 was associated with worse cognition but did not modify overall effects of vitamin D3 or omega-3 supplementation on cognition over 2 years. [ABSTRACT FROM AUTHOR]

Randomized controlled trials (RCTs) to determine the influence of vitamin D on BMC and fracture risk in children of Black African ancestry are lacking. We conducted a sub-study (n  = 450) nested within a phase 3 RCT of weekly oral supplementation with 10 000 IU vitamin D3 vs placebo for 3 yr in HIV-uninfected Cape Town schoolchildren aged 6–11 yr. Outcomes were BMC at the whole body less head (WBLH) and LS and serum 25-hydroxyvitamin D3 (25(OH)D3), PTH, alkaline phosphatase, C-terminal telopeptide, and PINP. Incidence of fractures was a secondary outcome of the main trial (n  = 1682). At baseline, mean serum 25(OH)D3 concentration was 70.0 nmol/L (SD 13.5), and 5.8% of participants had serum 25(OH)D3 concentrations <50 nmol/L. Among sub-study participants, end-trial serum 25(OH)D3 concentrations were higher for participants allocated to vitamin D vs placebo (adjusted mean difference [aMD] 39.9 nmol/L, 95% CI, 36.1 to 43.6) and serum PTH concentrations were lower (aMD −0.55 pmol/L, 95% CI, −0.94 to −0.17). However, no interarm differences were seen for WBLH BMC (aMD −8.0 g, 95% CI, −30.7 to 14.7) or LS BMC (aMD −0.3 g, 95% CI, −1.3 to 0.8) or serum concentrations of bone turnover markers. Fractures were rare among participants in the main trial randomized to vitamin D vs placebo (7/755 vs 10/758 attending at least 1 follow-up; adjusted odds ratio 0.70, 95% CI, 0.27 to 1.85). In conclusion, a 3-yr course of weekly oral vitamin D supplementation elevated serum 25(OH)D3 concentrations and suppressed serum PTH concentrations in HIV-uninfected South African schoolchildren of Black African ancestry but did not influence BMC or serum concentrations of bone turnover markers. Fracture incidence was low, limiting power to detect an effect of vitamin D on this outcome. [ABSTRACT FROM AUTHOR]

Background Kidney stones are frequent in industrialized countries with a lifetime risk of 10 to 15%. A high percentage of individuals experience recurrence. Calcium-containing stones account for more than 80% of kidney stones. Diet, environmental factors, behavior, and genetic variants contribute to the development of kidney stones. Osteocytes excrete the 21 kDa glycoprotein sclerostin, which inhibits bone formation by osteoblasts. Animal data suggests that sclerostin might directly or indirectly regulate calcium excretion via the kidney. As hypercalciuria is one of the most relevant risk factors for kidney stones, sclerostin might possess pathogenic relevance in nephrolithiasis. Methods We performed a prospective cross-sectional observational controlled study in 150 recurrent kidney stone formers (rKSF) to analyse the association of sclerostin with known stone risk factors and important modulators of calcium-phosphate metabolism. Serum sclerostin levels were determined at the first visit. As controls, we used 388 non-stone formers from a large Swiss epidemiological cohort. Results Sclerostin was mildly increased in rKSF in comparison to controls. This finding was more pronounced in women compared to men. Logistic regression indicated an association of serum sclerostin with rKSF status. In hypercalciuric individuals, sclerostin levels were not different from normocalciuric patients. In Spearman correlation analysis we found a positive correlation between sclerostin, age, and BMI and a negative correlation with eGFR. There was a weak correlation with iPTH and intact FGF 23. In contrast, serum sclerostin levels were not associated with 25-OH Vitamin D3, 1,25-dihydroxy-Vitamin D3, urinary calcium and phosphate or other urinary lithogenic risk factors. Conclusion This is the first prospective controlled study investigating serum sclerostin in rKSF. Sclerostin levels were increased in rKSF independent of hypercalciuria and significantly associated with the status as rKSF. It appears that mechanisms other than hypercalciuria may be involved and thus further studies are required to elucidate underlying pathways. [ABSTRACT FROM AUTHOR]

Context Skeletal fragility is observed in 30% to 60% of acromegaly patients, representing an emerging complication of the disease that increases disability. Despite several studies having investigated the clinical and hormonal prognostic factors for the occurrence of vertebral fractures (VFs) in acromegaly, very few data are available on their prevention/treatment including the effect of vitamin D (VD) supplementation, which has been reported to have a fracture-protective effect in several studies in patients with osteoporosis. Objective We aimed to investigate the role of cholecalciferol (D3) supplementation in the prevention of incident VFs (i-VFs) in acromegaly. Methods A longitudinal, retrospective and multicenter study was performed on 61 acromegaly patients treated and untreated with D3 supplementation. Results Twenty-six patients were treated with D3 supplementation according to clinical guidelines. The median D3 weekly dosage was 8500 IU (interquartile range [IQR]: 3900). The median duration of D3 supplementation was 94 months (IQR: 38). At last follow-up, i-VFs were diagnosed in 14 patients (23%). I-VFs were less prevalent in patients on D3 supplementation (14.3% of cases) compared to patients not treated with D3 (85.7%; P =.02). The final level of serum V25OH-D was significantly lower in patients who developed i-VFs (28.6 ng/mL, IQR: 4.1) compared to patients who did not develop i-VFs (34.2 ng/mL, IQR: 9.6; P =.05). The logistic regression confirmed the protective role of D3 supplementation on the occurrence of i-VFs (odds ratio: 0.16; 95% CI, 0.03-0.79; P =.01). Conclusion It is likely that D3 supplementation could lead to a reduction in i-VFs in acromegaly. [ABSTRACT FROM AUTHOR]

Fahr syndrome is a rare neurologic disorder, usually affecting young and middle-aged adults, that can present with symptoms ranging from extrapyramidal to neuropsychiatric abnormalities. Pseudohypoparathyroidism (PHP), characterized by parathyroid hormone (PTH)-resistance or PTH-unresponsiveness at target organs, is associated with Fahr syndrome and typically presents with hypocalcemia. The following case presents a 39-year-old-woman with PHP complicated by symptomatic hypocalcemia, hypokalemia, and movement disturbances, who had computed tomography imaging showing basal ganglia calcifications consistent with Fahr syndrome. She initially presented with headache and was hospitalized for hypertensive emergency and severe hypocalcemia. Examination, including the neurologic examination, was unrevealing aside from hypertension and central adiposity. Laboratory tests were consistent with PHP, showing hypocalcemia with elevated PTH, and negative for hyperaldosteronism. Management of hypocalcemia consisted of intravenous calcium infusion, oral calcium carbonate, oral vitamin D3, and oral calcitriol. Patients with severe hypocalcemia and elevated PTH who present with new neurological symptoms despite normal general neurologic examination may warrant consideration for brain imaging to evaluate for Fahr syndrome. Further investigations are necessary to determine the prevalence of Fahr syndrome and hypokalemia in patients with PHP, explore if these findings are significantly associated with PHP-1b subtype, and ultimately inform potential new screening pathways for these patients. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What metabolic pathways and metabolites in the serum and follicular fluid are associated with peak estradiol levels and the number of mature oocytes? SUMMARY ANSWER In the serum metabolome, mostly fatty acid and amino acid pathways were associated with estradiol levels and mature oocytes while in the follicular fluid metabolome, mostly lipid, vitamin, and hormone pathways were associated with peak estradiol levels and mature oocytes. WHAT IS KNOWN ALREADY Metabolomics has identified several metabolic pathways and metabolites associated with infertility but limited data are available for ovarian stimulation outcomes. STUDY DESIGN, SIZE, DURATION A prospective cohort study of women undergoing IVF from 2009 to 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 125 women undergoing a fresh IVF cycle at a fertility clinic in the Northeast United States who provided a serum and follicular fluid sample. Untargeted metabolomics profiling was conducted using liquid chromatography with high-resolution mass spectrometry in two chromatography columns (C18 and hydrophilic interaction chromatography (HILIC)). The main ovarian stimulation outcomes were peak serum estradiol levels and number of mature oocytes. We utilized adjusted generalized linear regression models to identify significant metabolic features. Models were adjusted for age,BMI, initial infertility diagnosis, and ovarian stimulation protocol. We then conducted pathway analysis using mummichog and metabolite annotation using level-1 evidence. MAIN RESULTS AND ROLE OF CHANCE In the serum metabolome, 480 and 850 features were associated with peak estradiol levels in the C18 and HILIC columns, respectively. Additionally, 437 and 538 features were associated with mature oocytes in the C18 and HILIC columns, respectively. In the follicular fluid metabolome, 752 and 929 features were associated with peak estradiol levels in the C18 and HILIC columns, respectively, Additionally, 993 and 986 features were associated with mature oocytes in the C18 and HILIC columns, respectively. The most common pathways associated with peak estradiol included fatty acids (serum and follicular fluid), hormone (follicular fluid), and lipid pathways (follicular fluid). The most common pathways associated with the number of mature oocytes retrieved included amino acids (serum), fatty acids (serum and follicular fluid), hormone (follicular fluid), and vitamin pathways(follicular fluid). The vitamin D3 pathway had the strongest association with both ovarian stimulation outcomes in the follicularfluid. Four and nine metabolites were identified using level-1 evidence (validated identification) in the serum and follicular fluid metabolomes, respectively. LIMITATIONS, REASONS FOR CAUTION Our sample was majority White and highly educated and may not be generalizable to thewider population. Additionally, residual confounding is possible and the flushing medium used in the follicular fluid could have diluted our results. WIDER IMPLICATIONS OF THE FINDINGS The pathways and metabolites identified by our study provide novel insights into the biologicalmechanisms in the serum and follicular fluid that may underlie follicular and oocyte development, which could potentially be used to improve ovarian stimulation outcomes. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the following grants from the National Institute of Environmental Health Sciences (P30-ES019776, R01-ES009718, R01-ES022955, P30-ES000002, R00-ES026648, and T32-ES012870), and National Institute of Diabetes and Digestive and Kidney Diseases (P30DK046200). The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Autophagy is a complex process of lysosomal-dependent degradation of unwanted cellular material. In response to endogenous or exogenous stimuli, autophagy is induced and regulated by two kinases: the AMP activated kinase and the mammalian target of rapamycin (mTOR). Cells activated by Unc-51-like kinase 1 form a double membrane complex that sequesters the cargo (phagophore) and elongates producing spherical vesicles (autophagosomes). These reach and fuse with lysosomes, which degrade the cargo (autolysosomes). The resulting macromolecules are released back and recycled in the cytosol for reuse. In the podocyte, autophagy is a homeostatic mechanism that contributes to the formation and preservation of the morphological and functional integrity of actin cytoskeleton. Podocytes, fenestrated endothelial cells and glomerular basement membrane compose the glomerular filtration barrier. Podocyte damage may cause dysfunction of the glomerular barrier, proteinuria and glomerulosclerosis in different glomerular diseases and particularly in so-called podocytopathies, namely minimal change disease and focal segmental glomerulosclerosis. Several drugs and molecules may activate autophagic function in murine models. Among them, aldosterone inhibitors, mineralocorticoid inhibitors and vitamin D3 were proven to protect podocyte from injury and reduce proteinuria in clinical studies. However, no clinical trial with autophagy regulators in podocytopathies has been conducted. Caution is needed with other autophagy activators, such as mTOR inhibitors and metformin, because of potential adverse events. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective Second fractures at the cemented vertebrae (SFCV) are often seen after percutaneous kyphoplasty, especially at the thoracolumbar junction. Our study aimed to develop and validate a preoperative clinical prediction model for predicting SFCV. Methods A cohort of 224 patients with single-level thoracolumbar osteoporotic vertebral fractures (T11–L2) from 3 medical centers was analyzed between January 2017 and June 2020 to derive a preoperative clinical prediction model for SFCV. Backward-stepwise selection was used to select preoperative predictors. We assigned a score to each selected variable and developed the SFCV scoring system. Internal validation and calibration were conducted for the SFCV score. Results Among the 224 patients included, 58 had postoperative SFCV (25.9%). The following preoperative measures on multivariable analysis were summarized in the 5-point SFCV score: bone mineral density (≤–3.05), serum 25-hydroxy vitamin D3 (≤17.55 ng/mL), standardized signal intensity of fractured vertebra on T1-weighted images (≤59.52%), C7–S1 sagittal vertical axis (≥3.25 cm), and intravertebral cleft. Internal validation showed a corrected area under the curve of 0.794. A cutoff of ≤1 point was chosen to classify a low risk of SFCV, for which only 6 of 100 patients (6%) had SFCV. A cutoff of ≥4 points was chosen to classify a high risk of SFCV, for which 28 of 41 (68.3%) had SFCV. Conclusion The SFCV score was found to be a simple preoperative method for identification of patients at low and high risk of postoperative SFCV. This model could be applied to individual patients and aid in the decision-making before percutaneous kyphoplasty. [ABSTRACT FROM AUTHOR]

Cytochrome P450 3A4 (CYP3A4) is involved in first-pass metabolism in the small intestine and is heavily implicated in oral drug bioavailability and pharmacokinetics. We previously reported that vitamin D3 (VD3), a known CYP enzyme inducer, induces functional maturation of iPSC-derived enterocyte-like cells (iPSC-ent). Here, we identified a Notch activator and CYP modulator valproic acid (VPA), as a promotor for the maturation of iPSC-ent. We performed bulk RNA sequencing to investigate the changes in gene expression during the differentiation and maturation periods of these cells. VPA potentiated gene expression of key enterocyte markers ALPI, FABP2, and transporters such as SULT1B1. RNA-sequencing analysis further elucidated several function-related pathways involved in fatty acid metabolism, significantly upregulated by VPA when combined with VD3. Particularly, VPA treatment in tandem with VD3 significantly upregulated key regulators of enterohepatic circulation, such as FGF19, apical bile acid transporter SLCO1A2 and basolateral bile acid transporters SLC51A and SLC51B. To sum up, we could ascertain the genetic profile of our iPSC-ent cells to be specialized toward fatty acid absorption and metabolism instead of transporting other nutrients, such as amino acids, with the addition of VD3 and VPA in tandem. Together, these results suggest the possible application of VPA-treated iPSC-ent for modelling enterohepatic circulation. [ABSTRACT FROM AUTHOR]

Context There is still controversy over the effect of vitamin D3 supplementation on bone health. Objective The effects of vitamin D3 supplementation on bone mineral density (BMD) and markers of bone turnover, as well as the dose-response relationship between vitamin D3 and bone health in adults, were evaluated. Data Sources The PubMed, Scopus, Cochrane, Web of Science, and AGRIS databases were searched for articles published through April 30, 2022. Thirty-nine of the 6409 records identified met the inclusion criteria Data Extraction Data were extracted from articles by 2 authors, and data extraction was cross-checked independently. A random-effects model was used to estimate the pooled effect size and the associated 95%CI for the effect of vitamin D3 for each outcome. A one-stage random-effects dose-response model was used to estimate the dose-response relationship between vitamin D3 supplementation and BMD. Data Analysis Results of meta-analysis showed a beneficial effect of vitamin D3 at the lumbar spine (standardized mean difference [SMD] = 0.06; 95%CI, 0.01–0.12) and femoral neck (SMD = 0.25; 95%CI, 0.09–0.41). Dose-response analysis revealed a linear relationship between vitamin D3 supplementation doses and BMD at the femoral neck, lumbar spine, and total hip sites. No significant effect of vitamin D3 supplementation on whole-body or total hip BMD was observed (P  >   0.05). Vitamin D3 supplementation significantly decreased BMD at both proximal and distal forearm (SMD = −0.16; 95%CI, −0.26 to −0.06). The variables of ethnicity, age, baseline 25-hydroxyvitamin D (25[OH]D), menopause status, vitamin D3 dosing frequency, and bone health status (P interaction = 0.02) altered the effect of vitamin D3 supplementation on BMD. Additionally, a nonlinear relationship between vitamin D3 supplement doses and markers of bone turnover was found. Conclusion A protective effect of vitamin D3 supplementation on BMD of the lumbar spine, femoral neck, and total hip is implicated. Systematic Review Registration PROSPERO registration number CRD42017054132. [ABSTRACT FROM AUTHOR]

Vitamin D plays a major role in bone health and probably also in multiple extraskeletal acute and chronic diseases. Although supplementation with calcifediol, a vitamin D metabolite, has demonstrated efficacy and safety in short‐term clinical trials, its effects after long‐term monthly administration have been studied less extensively. This report describes the results of a 1‐year, phase III‐IV, double‐blind, randomized, controlled, parallel, multicenter superiority clinical trial to assess the efficacy and safety of monthly calcifediol 0.266 mg versus cholecalciferol 25,000 IU (0.625 mg) in postmenopausal women with vitamin D deficiency (25(OH)D < 20 ng/mL). A total of 303 women were randomized and 298 evaluated. Patients were randomized 1:1:1 to calcifediol 0.266 mg/month for 12 months (Group A1), calcifediol 0.266 mg/month for 4 months followed by placebo for 8 months (Group A2), and cholecalciferol 25,000 IU/month (0.625 mg/month) for 12 months (Group B). By month 4, stable 25(OH)D levels were documented with both calcifediol and cholecalciferol (intention‐to‐treat population): 26.8 ± 8.5 ng/mL (Group A1) and 23.1 ± 5.4 ng/mL (Group B). By month 12, 25(OH)D levels were 23.9 ± 8.0 ng/mL (Group A1) and 22.4 ± 5.5 ng/mL (Group B). When calcifediol treatment was withdrawn in Group A2, 25(OH)D levels decreased to baseline levels (28.5 ± 8.7 ng/mL at month 4 versus 14.4 ± 6.0 ng/mL at month 12). No relevant treatment‐related safety issues were reported in any of the groups. The results confirm that long‐term treatment with monthly calcifediol in vitamin D‐deficient patients is effective and safe. The withdrawal of treatment leads to a pronounced decrease of 25(OH)D levels. Calcifediol presented a faster onset of action compared to monthly cholecalciferol. Long‐term treatment produces stable and sustained 25(OH)D concentrations with no associated safety concerns. © 2023 Faes Farma SA. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Nearly half of adult fracture patients are vitamin D deficient (serum 25‐hydroxyvitamin D [25(OH)D] levels <20 ng/mL). Many surgeons advocate prescribing vitamin D supplements to improve fracture healing outcomes; however, data supporting the effectiveness of vitamin D3 supplements to improve acute fracture healing are lacking. We tested the effectiveness of vitamin D3 supplementation for improving tibia and femur fracture healing. We conducted a single‐center, double‐blinded phase II screening randomized controlled trial with a 12‐month follow‐up. Patients aged 18–50 years receiving an intramedullary nail for a tibia or femoral shaft fracture were randomized 1:1:1:1 to receive (i) 150,000 IU loading dose vitamin D3 at injury and 6 weeks (n = 27); (ii) 4000 IU vitamin D3 daily (n = 24); (iii) 600 IU vitamin D3 daily (n = 24); or (iv) placebo (n = 27). Primary outcomes were clinical fracture healing (Function IndeX for Trauma [FIX‐IT]) and radiographic fracture healing (Radiographic Union Score for Tibial fractures [RUST]) at 3 months. One hundred two patients with a mean age of 29 years (standard deviation 8) were randomized. The majority were male (69%), and 56% were vitamin D3 deficient at baseline. Ninety‐nine patients completed the 3‐month follow‐up. In our prespecified comparisons, no clinically important or statistically significant differences were detected in RUST or FIX‐IT scores between groups when measured at 3 months and over 12 months. However, in a post hoc comparison, high doses of vitamin D3 were associated with improved clinical fracture healing relative to placebo at 3 months (mean difference [MD] 0.90, 80% confidence interval [CI], 0.08 to 1.79; p = 0.16) and within 12 months (MD 0.89, 80% CI, 0.05 to 1.74; p = 0.18). The study was designed to identify potential evidence to support the effectiveness of vitamin D3 supplementation in improving acute fracture healing. Vitamin D3 supplementation, particularly high doses, might modestly improve acute tibia or femoral shaft fracture healing in healthy adults, but confirmatory studies are required. The Vita‐Shock trial was awarded the Orthopaedic Trauma Association's (OTA) Bovill Award in 2020. This award is presented annually to the authors of the most outstanding OTA Annual Meeting scientific paper. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

BACKGROUND Left ventricular hypertrophy (LVH) and vitamin D deficiency have been linked to hypertension (HTN) and cardiovascular disease, particularly in African Americans (AAs). Our objective was to determine if the addition of vitamin D to antihypertensive therapy would lead to greater regression of LV mass index (LVMI) as determined by cardiac magnetic resonance (CMR) after 1 year in vitamin D deficient AA patients with uncontrolled HTN and LVH. METHODS This study was a randomized, double-blind, placebo-controlled, single-center study. AA patients with HTN (systolic blood pressure [BP] >160 mm Hg), increased LVMI, and vitamin D deficiency (<20 ng/ml) were randomized. All patients received antihypertensive therapy combined with biweekly 50,000 IU vitamin D3 (vitamin D group, n = 55) or placebo (placebo group, n = 58). RESULTS At 1 year, there were no statistical differences between the vitamin D and placebo groups in LVMI (−14.1 ± 14.6 vs. −16.9 ± 13.1 g/m2; P = 0.34) or systolic BP (−25.6 ± 32.1 vs. −25.7 ± 25.6 mm Hg; P = 0.99) reduction, respectively. Serum vitamin D levels increased significantly in the vitamin D group compared with placebo (12.7 ± 2.0 vs. 1.8 ± 8.2 ng/ml; P < 0.001). CONCLUSIONS In this high-risk cohort of AAs we did not find an association between vitamin D supplementation and differential regression of LVMI or reduction in systolic BP. However, our study suffered from a small sample size with low statistical power precluding a definitive conclusion on the therapeutic benefit of vitamin D in such patients. CLINICAL TRIALS REGISTRATION Trial Number NCT01360476. Full trial protocol is available from corresponding author. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Hypoparathyroidism is a rare metabolic disease. In addition to symptoms of hypocalcemia, chronic hypoparathyroidism can result in brain calcifications leading to Fahr syndrome. Hypoparathyroidism most commonly results as a postsurgical complication, with autoimmune disease the second most common etiology. Here we report a 48-year-old man with symptoms of chronic hypocalcemia who presented with status epilepticus following severe coronavirus disease 2019 (COVID-19) infection. In addition to severe hypocalcemia, he was found to have an inappropriately low serum parathyroid hormone level and basal ganglia calcifications visualized on head computed tomography scan. He was treated with intravenous calcium infusion prior to transition to orally administered calcium, calcitriol, and high-dose cholecalciferol (vitamin D3). [ABSTRACT FROM AUTHOR]

Background: HIV infection is still a serious public health issue globally. Suboptimal vitamin D status is highly prevalent in HIV-infected children and adolescents throughout the world.Objectives: To evaluate the outcome of vitamin D supplementation on CD4 count in HIV-infected children and adolescents with suboptimal vitamin D status.Methods: Vitamin D level of HIV-infected children and adolescents were measured at enrolment. Suboptimal vitamin D level was defined as 25(OH)D < 30 ng/ml. Vitamin D insufficiency and deficiency were defined as 21-29 and <20 ng/ml, respectively. Children with suboptimal vitamin D levels were supplemented with vitamin D.Results: This was a single-centre, non-randomized comparative study enrolling 50 eligible participants. There were 20 patients who were vitamin D sufficient, 7 were vitamin D insufficient and 23 were found to be vitamin D deficient at enrolment. However, after supplementation, the status of sufficient remained same and 7 insufficient become sufficient, whereas in 23 deficient, 18 (78.3%) become sufficient and 5 (21.7%) become insufficient and this change was found statistically significant among the groups (χ2 = 6.52, p = 0.038). There was a significant improvement of CD4 count from baseline to 4 months in deficient group on vitamin D supplementation (p value < 0.001; 1.2-fold rise). No significant change was seen in vitamin D insufficient (p value = 0.791) and sufficient groups (p value = 0.168).Conclusion: Vitamin D should be supplemented in HIV-infected children on ART with low CD4 counts. [ABSTRACT FROM AUTHOR]

Background: Vitamin D supplementation may reduce the risk or severity of infection, but this has been investigated in few large population-based trials. We analyzed data from the D-Health Trial, using prescription of antibiotics as a surrogate for infection.Methods: The D-Health Trial is a randomized, double-blind, placebo-controlled trial in which 21 315 Australians aged 60-84 years were randomized to 60 000 IU of supplementary vitamin D3 or placebo monthly for 5 years. For this analysis, the primary outcome was the number of antibiotic prescription episodes; secondary outcomes were total number of prescriptions, repeat prescription episodes, and antibiotics for urinary tract infection. We estimated incidence rate ratios (IRRs) using negative binomial regression, and odds ratios using logistic regression.Results: Vitamin D supplementation slightly reduced the number of prescription episodes (IRR, 0.98; 95% confidence interval [CI], .95-1.01), total prescriptions (IRR, 0.97; 95% CI, .93-1.00), and repeat prescription episodes (IRR, 0.96; 95% CI, .93-1.00). There was stronger evidence of benefit in people predicted to have insufficient vitamin D at baseline (prescription episodes IRR, 0.93; 95% CI, .87-.99).Conclusions: Vitamin D may reduce the number of antibiotic prescriptions, particularly in people with low vitamin D status. This supports the hypothesis that vitamin D has a clinically relevant effect on the immune system.Clinical Trials Registration: Australian New Zealand Clinical Trials Registry: ACTRN12613000743763. https://www.anzctr.org.au/. [ABSTRACT FROM AUTHOR]

Skeletal muscle growth is largely dependent on the proliferation and differentiation of muscle-specific stem cells known as satellite cells (SC). Previous work has shown that dietary inclusion of the vitamin D3 metabolite, 25-hydroxycholecalciferol (25OHD3), also called calcidiol, can promote skeletal muscle growth in post-hatch broiler chickens. Improving vitamin D status of broiler breeder hens by feeding 25OHD3 in addition to vitamin D3 has also been shown to positively impact progeny. Yet, whether combined pre- and post-hatch supplementation with 25OHD3 produces an additive or synergistic SC-mediated, skeletal muscle growth response remains unanswered. To evaluate the effect of combined maternal and post-hatch dietary 25OHD3 supplementation on the growth and SC mitotic activity of the Pectoralis major (PM) muscles in broiler chickens, a randomized complete block design experiment with the main effects of maternal diet (MDIET) and post-hatch diet (PDIET) arranged in a 2 × 2 factorial treatment structure was conducted. From 25 to 36 wk of age, broiler breeder hens were fed 1 of 2 MDIET formulated to provide 5,000 IU D3 (MCTL) or 2,240 IU of D3 + 2,760 IU of 25OHD3 per kg of feed (M25OHD3). Their male broiler chick offspring (n = 400) hatched from eggs collected from 35 to 36 wk of age were reared in raised floor pens. Broilers were fed 1 of 2 PDIET formulated to provide 5,000 IU of D3 per kg of feed (PCTL) or 2,240 IU of D3 + 2,760 IU of 25OHD3 per kg of feed (P25OHD3). Muscle was collected at days 4, 8, 15, 22, and 29 and stored until immunofluorescence analysis. Data were analyzed as a 2-way ANOVA with SAS GLIMMIX. Dietary 25OHD3 was effectively transferred from hen plasma to egg yolks (P = 0.002) and to broiler progeny plasma (days 4 to 22; P ≤ 0.044). Including 25OHD3 in either MDIET or PDIET altered PM hypertrophic growth prior to day 29 (P ≥ 0.001) and tended to reduce Wooden Breast severity (P ≤ 0.089). Mitotic SC populations were increased in PM of MCTL:P25OHD3 and M25OHD:PCTL-fed broilers at d 4 (P = 0.037). At d 8, the PM mitotic SC populations were increased 33% by P25OHD3 (P = 0.054). The results of this study reveal that combined maternal and post-hatch 25OHD3 supplementation does not produce additive or synergistic effects on SC-mediated broiler muscle growth. However, vitamin D status improvement through dietary 25OHD3 inclusion in either the maternal or post-hatch diet stimulated broiler breast muscle growth by increasing proliferating SC populations. [ABSTRACT FROM AUTHOR]

Objective: To observe the association between serum vitamin D level and disease activity in juvenile idiopathic arthritis (JIA). Methods: The observational study was conducted at a tertiary care hospital during 2017-2019. Patients suffered from JIA were recruited through purposive sampling which was stratified by the disease activity based on the Juvenile Arthritis Disease Activity Score 27 (JADAS27) criteria. Serum vitamin D was estimated alongside other laboratory parameters. The numerical and categorical variables were analysed with appropriate statistical tests. Results: 40 subjects were studied where inactive disease was observed in nine subjects (22.5%), five subjects (12.5%) were found to be in low disease activity and moderate disease activity groups each, and twenty-one subjects (52.5%) had high disease activity. Considering the total sample size of the study, the mean (SD) JADAS27 score and serum vitamin D level were observed to be 12.02 (11.31) and 23.10 (5.93) respectively. A negative correlation was found between the JADAS27 score and serum vitamin D (r= -0.67). The corrected Chi-square test had revealed significant association between the status of serum vitamin-D and disease activity groups (=16.28; p < .001). Conclusions: In JIA, higher grade of disease activity was found to be significantly associated with lower serum vitamin D. [ABSTRACT FROM AUTHOR]

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/cm2; placebo group: 0.470 (95% CI, 0.466–0.475) g/cm2, 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. [ABSTRACT FROM AUTHOR]

Background: The role of vitamin D on muscle health is debated. Methods: An individual participant metanalysis of 4 randomized placebo-controlled trials, investigating short-term (3-9months) effects of vitamin D3 in moderate (2800 IU) to high (7000 IU) daily oral doses on muscle health and quality of life (QoL). Inclusion criteria were either obesity (n = 52), newly diagnosed primary hyperparathyroidism (n = 41), Graves’ disease (n = 86), or secondary hyperparathyroidism (n = 81). Results: Overall (n = 260) as well as in a subgroup analysis including only vitamin D insufficient [25(OH)D < 50 nmol/L] individuals (n = 176), vitamin D supplementation did not affect measures of muscle health (isometric muscle strength, Timed Up and Go test, chair rising test, body composition, and balance) or QoL. However, a beneficial effect was present on QoL (physical component score) in vitamin D deficient [25(OH) D < 25 nmol/L] individuals (n = 34). Overall, relative changes in 25(OH)D inversely affected maximum muscle strength in a dose-response manner. Stratified into body mass index 30 kg/m², vitamin D supplementation had divergent effects on isometric muscle strength, with beneficial effects in obese individuals (n = 93) at knee flexion 90° (P = 0.04), and adverse effects in nonobese individuals (n = 167) at handgrip (P = 0.02), knee extension 60° (P = 0.03) and knee flexion 60° (P < 0.01). Conclusion: Overall, short-term treatment with moderate to high daily doses of vitamin D did not affect muscle health or QoL. A potential beneficial effect was present on muscle strength in severely obese individuals and on QoL in vitamin D deficient individuals. Subgroup analyses, however, suggested negative effects of large relative increases in p-25(OH)D. [ABSTRACT FROM AUTHOR]

Background: Liver transplantation is one of the most efficient life-saving treatments for various end-stage hepatic diseases. However, hepatic ischemic reperfusion injury (IRI) remains a major problem in liver surgeries morbidities and mortalities. Stem cells (SCs) have been recently received increasing attention for cell-based therapy, especially in regenerative medicine, including liver diseases. Aim: to investigate the effect of vitamin D and Bone Marrow Mesenchymal Stem Cells (BM- MSCs) solely or combined on hepatic IR injury. Methods: Sixty adult male Wister rats were allocated into 5 groups; Sham, IR: underwent hepatic IR, vit. D-IR: received vit. D in a dose of 500IU/Kg/day, by gavage, 5 days/week for 2 weeks, then subjected to hepatic IR, Stem cell-IR: received single IV injection of 1 x 106 BM-MSCs prior to hepatic IR and Combined- IR: received both vit. D and BM-MSCs prior to hepatic IR. All rats were subjected to estimation of Liver index (LI), assessment of serum levels of alanine, aspartate transaminases (ALT, AST) and vitamin D, hepatic tissue levels of Malondialdehyde (H.MDA), Superoxide dismutase (H.SOD), Interleukin-2, 10 (H.IL-2, H.IL-10), Caspase-3 (H.Casp-3), H.LC3B and hepatocyte growth factor (H.HGF), as well as histopathological liver examination and scoring. Results: Hepatic IR resulted in significant elevation of ALT, AST and H.MDA, H.IL-2, H. Casp- 3 as well as significant reduction in LI, vit. D, H.SOD, H.IL-10, H.LC3B and H.HGF with evident hepatic sinusoidal congestion, cytoplasmic vacuolation and cellular necrosis. Treatment either solely or in combination mitigate these changes with the combined treatment showed the best results compared to the individual use. Conclusion: In vivo coadministration of vitamin D and BM- MSCs prior to hepatic IR attenuated hepatocellular damage through preventing oxidative stress and inflammatory response, augmenting autophagic, regenerative capacity and anti-apoptotic effect. [ABSTRACT FROM AUTHOR]

Background: there is a controversy regarding the effect of vitamin D2 and D3 in elevating and sustaining 25-hydroxyvitamin D (25(OH)D) levels in pediatric patients. It has been suggested that vitamin D3 may be superior to vitamin D2 in raising and sustaining adequate 25(OH)D values. Aim: To study the difference between the effect of enteral vitamin D2 and vitamin D3 administration in raising and maintaining serum 25(OH)D in pediatric patients. Methods: Randomized controlled clinical trial, conducted in Pediatric Endocrinology Unit, Ain Shams University, Cairo, Egypt, where 60 participants who had vitamin D deficiency were recruited. Subjects were divided into two groups, 30 patients per group (group A received 2400 IU of oral vitamin D2 daily and group B received 2400 IU of oral vitamin D3 daily). History of sun exposure and dietary intake of calcium, assessment of anthropometric measures and Tanner staging, laboratory investigations were documented. Follow up of serum level of 25(OH)D was done every month for three consecutive months. Results: Oral vitamin D3 supplementation in group B patients resulted in significantly higher increments in 25(OH)D levels than that achieved by oral vitamin D2 supplementation in group A after 2nd, and 3rd months of the supplementation (P=0.000). Vitamin D3 supplementation resulted in a significantly greater increment in serum 25(OH)D levels from 1st to 2nd month and from 1st to 3rd month than Vitamin D2 supplementation (P=0.000). All participants in group B (100%) who received vitamin D3 reached sufficient levels (> 30 ng/ml) after 2 months while 76.7% of participants in group A who received vitamin D2 reached sufficient levels after 2 months and 23.3% of participants after 3 months (P= 0.017). Conclusion: Oral vitamin D3 supplementation was more effective in raising serum 25(OH)D status in pediatric patients than oral vitamin D2 supplementation. [ABSTRACT FROM AUTHOR]

Background: There is a controversy regarding the effect of vitamin D2 and D3 in elevating and sustaining 25(OH)D levels. Aim: This study will concentrate on the effect of parenteral administration of both vitamins on serum 25(OH)D levels. Methods: Randomized controlled clinical trial, conducted in Pediatric Endocrinology Unit, Ain Shams University, Cairo, Egypt, where 50 participants who had vitamin D deficiency were recruited. Subjects were divided into two groups, 25 patients per group (group A received a single dose of 200,000 IU of intramuscular vitamin D2 and group B received 200,000 IU of intramuscular vitamin D3). History of sun exposure and dietary intake of calcium, assessment of anthropometric measures and tanner staging, laboratory investigations were documented. Follow up of serum level of 25(OH)D was done every month for three consecutive months. Results: Parenteral vitamin D3 supplementation in group B patients resulted in significantly higher increments in 25(OH)D level than that achieved by parenteral vitamin D2 supplementation in group A after 1st, 2nd, and 3rd months of the supplement (p = 0.000). Vitamin D3 supplementation resulted in a significantly greater increment in serum 25(OH)D levels from 1st to 2nd month and from 1st to 3rd month than Vitamin D2 supplementation with a P value of 0.039 and 0.018 respectively. One hundred percent of group B participants who received vitamin D3 reached sufficient level (41.04 ± 10.04) after 1 month while 80% of participants in group A who received vitamin D2 reached a sufficient level after 1 month and 20% of participants after 2 months (P = 0.018). Conclusion: We can conclude that parenteral vitamin D3 supplementation was more effective in raising serum 25(OH)D status in pediatric patients than parenteral vitamin D2 supplementation. [ABSTRACT FROM AUTHOR]

CYP105A1 from Streptomyces griseolus converts vitamin D3 to its biologically active form, 1 α,25-dihydroxy vitamin D3. R73A/R84A mutation enhanced the 1α- and 25-hydroxylation activity for vitamin D3, while M239A mutation generated the 1α-hydroxylation activity for vitamin D2. In this study, the stability of six CYP105A1 enzymes, including 5 variants (R73A/R84A, M239A, R73A/R84A/M239A (=TriA), TriA/E90A, and TriA/E90D), was examined. Circular dichroism analysis revealed that M239A markedly reduces the enzyme stability. Protein fluorescence analysis disclosed that these mutations, especially M239A, induce large changes in the local conformation around Trp residues. Strong stabilizing effect of glycerol was observed. Nondenaturing PAGE analysis showed that CYP105A1 enzymes are prone to self-association. Fluorescence analysis using a hydrophobic probe 8-anilino-1-naphthalenesulfonic acid suggested that M239A mutation enhances self-association and that E90A and E90D mutations, in cooperation with M239A, accelerate self-association with little effect on the stability. [ABSTRACT FROM AUTHOR]

Context Foods containing vitamin D reduce the deficiency of this vitamin and improve bone turnover. Objective To discuss effects of the intake of vitamin D–fortified foods in isolated form or associated with calcium on bone remodeling in postmenopausal women. Data Sources PubMed, Lilacs, Scopus, and Bireme databases. OpenThesis and Google Scholar were searched as "grey literature". Medical subject headings or similar terms related to food fortified with vitamin D and bone in postmenopausal women were used. Data Extraction Information was collected on study methodology and characteristics of studied populations; dosage; the food matrix used as the fortification vehicle; duration of intervention; dietary intake; 25-hydroxyvitamin D [25(OH)D] levels; serum parathyroid hormone (PTH) concentrations; bone resorption and/or formation markers (ie, carboxy terminal cross-linked telopeptide of type I collagen [CTX], tartrate-resistant acid phosphatase isoform 5b [TRAP5b], and procollagen type 1 N-terminal propeptide [P1NP]); main results; and study limitations. Data Analysis Five randomized controlled trials involving postmenopausal women were included. The mean ages of participants ranged from 56.1 to 86.9 years. Daily consumption of soft plain cheese fortified with 2.5 µg of vitamin D3 and 302 mg of calcium for 4 weeks resulted in a mean increase of 0.8 ng/mL in 25(OH)D and 15.9 ng/mL in P1NP levels compared with baseline, and decreased CTX, TRAP5b, and PTH values. A similar intervention for 6 weeks, using fortified cheese, showed a reduction only in TRAP5b values (−0.64 U/L). Yogurt fortified with 10 µg of vitamin D3 and 800 mg of calcium did not change P1NP values after 8 weeks of intervention, but was associated with decreases of 0.0286 ng/mL and 1.06 U/L in PTH and TRAP5b, respectively. After 12 weeks of eating the fortified yogurt, 25(OH)D levels increased by a mean of 8.8 ng/mL and PTH levels decreased in by a mean of 0.0167 ng/mL. Conclusions The interventions contributed toward the improvement of the bone resorption process but not to the bone formation process in postmenopausal women. PROSPERO registration number CRD42019131976. [ABSTRACT FROM AUTHOR]

Background The optimal treatment regimen for correcting 25-hydroxyvitamin D (25OHD) deficiency in children with chronic kidney disease (CKD) is not known. We compared cholecalciferol dosing regimens for achieving and maintaining 25OHD concentrations ≥30 ng/mL in children with CKD stages 2–4. Methods An open-label, multicentre randomized controlled trial randomized children with 25OHD concentrations <30 ng/mL in 1:1:1 to oral cholecalciferol 3000 IU daily, 25 000 IU weekly or 100 000 IU monthly for 3 months (maximum three intensive courses). In those with 25OHD ≥30 ng/mL, 1000 IU cholecalciferol daily (maintenance course) was given for up to 9 months. Primary outcome was achieving 25OHD ≥30 ng/mL at the end of intensive phase treatment. Results Ninety children were randomized to daily (n  = 30), weekly (n  = 29) or monthly (n  = 31) treatment groups. At the end of intensive phase, 70/90 (77.8%) achieved 25OHD ≥30 ng/mL; 25OHD concentrations were comparable between groups (median 44.3, 39.4 and 39.3 ng/mL for daily, weekly and monthly groups, respectively; P = 0.24) with no difference between groups for time to achieve 25OHD ≥30 ng/mL (P = 0.28). There was no change in calcium, phosphorus and parathyroid hormone, but fibroblast growth factor 23 (P = 0.002) and klotho (P = 0.001) concentrations significantly increased and were comparable in all treatment groups. Irrespective of dosing regimen, children with glomerular disease had 25OHD concentrations lower than non-glomerular disease (25.8 versus 41.8 ng/mL; P = 0.007). One child had a 25OHD concentration of 134 ng/mL, and 5.5% had hypercalcemia without symptoms of toxicity. Conclusion Intensive treatment with oral cholecalciferol as daily, weekly or monthly regimens achieved similar 25OHD concentrations between treatment groups, without toxicity. Children with glomerular disease required higher doses of cholecalciferol compared with those with non-glomerular disease. [ABSTRACT FROM AUTHOR]

Context: The effect of daily vitamin D supplementation on the serum concentration of vitamin D (the parent compound) may offer insight into vitamin D disposition. Objective: To assess the total serum vitamin D response to vitamin D3 supplementation and whether it varies according to participant characteristics. To compare results with corresponding results for total serum 25-hydroxyvitamin D [25(OH)D], which is used clinically and measured in supplementation trials. Design: Exploratory study within a randomized trial. Intervention: 2000 International Units of vitamin D3 per day (or matching placebo). Setting: Community-based. Participants: 161 adults (mean ± SD age 70 ± 6 years; 66% males) with type 2 diabetes. Main Outcome Measures: Changes in total serum vitamin D and total serum 25(OH)D concentrations from baseline to year 2. Results: At baseline, there was a positive, nonlinear relation between total serum vitamin D and total serum 25(OH)D concentrations. Adjusted effects of supplementation were a 29.2 (95% CI: 24.3, 34.1) nmol/L increase in serum vitamin D and a 33.4 (95% CI: 27.7, 39.2) nmol/L increase in serum 25(OH)D. Among those with baseline 25(OH)D < 50 compared with ≥ 50 nmol/L, the serum vitamin D response to supplementation was attenuated (15.7 vs 31.2 nmol/L; interaction P-value = 0.02), whereas the serum 25(OH)D response was augmented (47.9 vs 30.7 nmol/L; interaction P-value = 0.05). Conclusions: Vitamin D3 supplementation increases total serum vitamin D and 25(OH) D concentrations with variation according to baseline 25(OH)D, which suggests that 25-hydroxylation of vitamin D3 is more efficient when serum 25(OH)D concentration is low. [ABSTRACT FROM AUTHOR]

Background: Vitamin D has an immunomodulatory role but the effect of therapeutic vitamin D supplementation in SARS-CoV-2 infection is not known.Aim: Effect of high dose, oral cholecalciferol supplementation on SARS-CoV-2 viral clearance.Design: Randomised, placebo-controlled.Participants: Asymptomatic or mildly symptomatic SARS-CoV-2 RNA positive vitamin D deficient (25(OH)D<20 ng/ml) individuals.Intervention: Participants were randomised to receive daily 60 000 IU of cholecalciferol (oral nano-liquid droplets) for 7 days with therapeutic target 25(OH)D>50 ng/ml (intervention group) or placebo (control group). Patients requiring invasive ventilation or with significant comorbidities were excluded. 25(OH)D levels were assessed at day 7, and cholecalciferol supplementation was continued for those with 25(OH)D <50 ng/ml in the intervention arm. SARS-CoV-2 RNA and inflammatory markers fibrinogen, D-dimer, procalcitonin and (CRP), ferritin were measured periodically.Outcome Measure: Proportion of patients with SARS-CoV-2 RNA negative before day-21 and change in inflammatory markers.Results: Forty SARS-CoV-2 RNA positive individuals were randomised to intervention (n=16) or control (n=24) group. Baseline serum 25(OH)D was 8.6 (7.1 to 13.1) and 9.54 (8.1 to 12.5) ng/ml (p=0.730), in the intervention and control group, respectively. 10 out of 16 patients could achieve 25(OH)D>50 ng/ml by day-7 and another two by day-14 [day-14 25(OH)D levels 51.7 (48.9 to 59.5) ng/ml and 15.2 (12.7 to 19.5) ng/ml (p<0.001) in intervention and control group, respectively]. 10 (62.5%) participants in the intervention group and 5 (20.8%) participants in the control arm (p<0.018) became SARS-CoV-2 RNA negative. Fibrinogen levels significantly decreased with cholecalciferol supplementation (intergroup difference 0.70 ng/ml; P=0.007) unlike other inflammatory biomarkers.Conclusion: Greater proportion of vitamin D-deficient individuals with SARS-CoV-2 infection turned SARS-CoV-2 RNA negative with a significant decrease in fibrinogen on high-dose cholecalciferol supplementation.Trial Register Number: NCT04459247. [ABSTRACT FROM AUTHOR]

Background Vitamin D3 supplementation is considered a potential intervention to prevent orthostatic hypotension (OH) based on observational evidence that vitamin D levels are inversely associated with OH. With data from The Study to Understand Fall Reduction and Vitamin D in You (STURDY), a double-blind, randomized, response-adaptive trial, we determined if higher doses of vitamin D3 reduced risk of OH. Methods STURDY tested the effects of higher (1,000+ IU/day, i.e. 1,000, 2,000, and 4,000 IU/day combined) vs. lower-dose vitamin D3 (200 IU/day, comparison) on fall risk in adults ages 70 years and older with low serum 25-hydroxyvitamin D (25(OH)D, 10–29 ng/ml). OH was determined at baseline, 3, 12, and 24 months by taking the difference between seated and standing blood pressure (BP). OH was defined as a drop in systolic or diastolic BP of at least 20 or 10 mm Hg after 1 minute of standing. Participants were also asked about OH symptoms during the assessment and the preceding month. Results Among 688 participants (mean age 77 [SD, 5] years; 44% women; 18% Black), the mean baseline systolic/diastolic BP was 130 (19)/67 (11) mm Hg, serum 25(OH)D was 22.1 (5.1) ng/ml, and 2.8% had OH. There were 2,136 OH assessments over the maximum 2-year follow-up period. Compared with 200 IU/day, 1,000+ IU/day was not associated with seated, standing, or orthostatic BP, and it did not lower risk of OH or orthostatic symptoms. Conclusions These findings do not support use of higher doses of vitamin D3 supplementation as an intervention to prevent OH. Clinical trials registration Trial Number NCT02166333. [ABSTRACT FROM AUTHOR]

Context: Vitamin D regulates glucose homeostasis pathways, but effects of vitamin D supplementation on ß-cell function remain unclear. Objective: To investigate the effects of vitamin D3 supplementation on insulin sensitivity and ß-cell function. Methods: This is a prespecified secondary analysis of the Vitamin D and Type 2 Diabetes study. Overweight/obese adults at high risk for type 2 diabetes (prediabetes) were randomly treated with vitamin D3 4000 IU or matching placebo daily for 24 months. Main Outcome: Disposition index (DI), as an estimate of ß-cell function, was calculated as the product of Homeostasis Model Assessment 2 indices derived from C-peptide values (HOMA2%Scpep) and C-peptide response during the first 30 minutes of a 75-g oral glucose tolerance test (OGTT). Results: Mean age was 60.5 ± 9.8 years and body mass index was 31.9 ± 4.4 kg/m2. Mean serum 25(OH)D level increased from 27.9 ± 10.3 ng/mL at baseline to 54.9 ng/mL at 2 years in the vitamin D group and was unchanged (28.5 ± 10.0 ng/mL) in the placebo group. The baseline DI predicted incident diabetes independent of the intervention. In the entire cohort, there were no significant differences in changes in DI, HOMA2%Scpep, or C-peptide response between the 2 groups. Among participants with baseline 25(OH)D level <12 ng/mL, the mean percent differences for DI between the vitamin D and placebo groups was 8.5 (95% CI, 0.2-16.8). Conclusions: Supplementation with vitamin D3 for 24 months did not improve an OGTTderived index of ß-cell function in people with prediabetes not selected based on baseline vitamin D status; however, there was benefit among those with very low baseline vitamin D status. [ABSTRACT FROM AUTHOR]

The objective of this experiment was to determine the effects of dietary vitamin D source on serum calcium (Ca), urinary Ca excretion, and milk production when fed in combination with a prepartum acidogenic negative dietary cation–anion difference (DCAD) diet. Nonlactating, pregnant multiparous cows (n = 15), balanced for breed (Holstein n = 9 and Jersey n = 6), and previous mature equivalent milk production, were assigned to one of three treatments (five cows/treatment), consisting of a control (PCH; positive DCAD, 8.9 mEq/100 g DM) and two negative DCAD diets (−15.4 mEq/100 g DM), one with vitamin D3 (cholecalciferol; NCH) and one with 25-hydroxyvitamin D3 (calcidiol; NCA; DSM nutritional products). The treatments were formulated to provide 1.95 mg/d of vitamin D and were fed 28 d prior to expected calving date. Delivery of vitamin D sources was accomplished by manufacture of a pellet and 2 kg of these pellets were individually fed simultaneously each day along with 2 kg of ground corn daily at 0800 hours. Negative DCAD treatments were formulated to provide 0.46 kg/d of Animate (Phibro Animal Health) and, if needed, additional Animate was top-dressed at each feeding to achieve a urine pH between 5.5 and 6.0 based on the previous day's urine pH. Close-up cows had ad libitum access to chopped bermudagrass (Cynodon dactylon L.) hay and hay intake was measured using SmartFeed Pro systems (C-Lock Inc.; Rapid City, SD). Prepartum urine and serum samples were collected weekly and serum was collected 36, 48, and 72 h post-calving. Prepartum dry matter intake (DMI) as a percent of body weight was not (P = 0.66) affected by treatments. Cows fed NCH and NCA had greater (P = 0.02) prepartum serum Ca than PCH and tended to have greater urinary Ca excretions (P = 0.10). Average postpartum serum Ca (mg/dL) was greater (P = 0.05) for cows fed NCH (8.8) compared with PCH (7.8), whereas NCA (8.4) was numerically intermediate and not (P > 0.05) different from either of the other treatments. Postpartum DMI was not affected by treatment (P = 0.39). Daily milk yield (MY) (kg/d) was greatest (P < 0.01) for NCA (37.5) compared with the other treatments and NCH (34.1) was intermediate and greater than PCH (29.9). These results suggest that an acidogenic prepartum diet in combination with vitamin D was effective in maintaining peripartum serum Ca and the 25-hydroxy form of vitamin D improved MY compared with NCH in early lactation. [ABSTRACT FROM AUTHOR]

The relationship between the active form of vitamin D3 (1,25‐dihydroxyvitamin D, 1,25(OH)2D) and reactive oxygen species (ROS), two integral signaling molecules of the cell, is poorly understood. This is striking, given that both factors are involved in cancer cell regulation and metabolism. Mitochondria (mt) dysfunction is one of the main drivers of cancer, producing more mitochondria, higher cellular energy, and ROS that can enhance oxidative stress and stress tolerance responses. To study the effects of 1,25(OH)2D on metabolic and mt dysfunction, we used the vitamin D receptor (VDR)‐sensitive MG‐63 osteosarcoma cell model. Using biochemical approaches, 1,25(OH)2D decreased mt ROS levels, membrane potential (ΔΨmt), biogenesis, and translation, while enforcing endoplasmic reticulum/mitohormetic stress adaptive responses. Using a mitochondria‐focused transcriptomic approach, gene set enrichment and pathway analyses show that 1,25(OH)2D lowered mt fusion/fission and oxidative phosphorylation (OXPHOS). By contrast, mitophagy, ROS defense, and epigenetic gene regulation were enhanced after 1,25(OH)2D treatment, as well as key metabolic enzymes that regulate fluxes of substrates for cellular architecture and a shift toward non‐oxidative energy metabolism. ATACseq revealed putative oxi‐sensitive and tumor‐suppressing transcription factors that may regulate important mt functional genes such as the mTORC1 inhibitor, DDIT4/REDD1. DDIT4/REDD1 was predominantly localized to the outer mt membrane in untreated MG‐63 cells yet sequestered in the cytoplasm after 1,25(OH)2D and rotenone treatments, suggesting a level of control by membrane depolarization to facilitate its cytoplasmic mTORC1 inhibitory function. The results show that 1,25(OH)2D activates distinct adaptive metabolic responses involving mitochondria to regain redox balance and control the growth of osteosarcoma cells. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Context: Experimental studies suggest that vitamin D receptor signaling may benefit the gut microbiome. In humans, whether vitamin D supplementation directly alters the gut microbiome is not well studied.Objective: To determine whether correcting vitamin D deficiency with cholecalciferol (vitamin D3, D3) or calcifediol (25-hydroxyvitamin D3, 25(OH)D3) changes gut microbiome composition.Methods: 18 adults with vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] <20 ng/mL) received 60 µg/day of D3 or 20 µg/day of 25(OH)D3 for 8 weeks. Changes in serum 25(OH)D, 1,25-diydroxyvitamin D (1,25(OH)2D), and 24,25-dihydroxyvitamin D (24,25(OH)2D) were assessed. We characterized composition of the fecal microbiota using 16S rRNA gene sequencing, and examined changes in α-diversity (Chao 1, Faith's Phylogenetic Diversity, Shannon Index), β-diversity (DEICODE), and genus-level abundances (DESeq2).Results: Vitamin D3 and 25(OH)D3 groups were similar. After 8 weeks of vitamin D3, mean 25(OH)D and 24,25(OH)2D increased significantly, but 1,25(OH)2D did not (25(OH)D: 17.8-30.1 ng/mL, P = .002; 24,25(OH)2D: 1.1 to 2.7 ng/mL, P =0.003; 1,25(OH)2D: 49.5-53.0 pg/mL, P = .9). After 8 weeks of 25(OH)D3, mean 25(OH)D, 24,25(OH)2D, and 1,25(OH)2D increased significantly (25(OH)D: 16.7-50.6 ng/mL, P < .0001; 24,25(OH)2D: 1.3-6.2 ng/mL, P = .0001; 1,25(OH)2D: 56.5-74.2 pg/mL, P = .05). Fecal microbial α-diversity and β-diversity did not change with D3 or 25D3 supplementation. Mean relative abundance of Firmicutes increased and mean relative abundance of Bacterioidetes decreased from baseline to 4 weeks, but returned to baseline by study completion. DESeq2 analysis did not confirm any statistically significant taxonomic changes.Conclusion: In a small sample of healthy adults with vitamin D deficiency, restoration of vitamin D sufficiency with vitamin D3 or 25(OH)D3 did not lead to lasting changes in the fecal microbiota. [ABSTRACT FROM AUTHOR]

The vitamin D hormone, 1,25dihydroxyvitamin D3 (1,25(OH)2D3), and related compounds derived from vitamin D3 or lumisterol as a result of metabolism via the enzyme CYP11A1, have been shown, when applied 24 hours before or immediately after UV irradiation, to protect human skin cells and skin from DNA damage due to UV exposure, by reducing both cyclobutane pyrimidine dimers (CPD) and oxidative damage in the form of 8‐oxo‐7,8‐dihydro‐2′‐deoxyguanosine (8‐OHdG). We now report that knockdown of either the vitamin D receptor or the endoplasmic reticulum protein ERp57 by small, interfering RNA (siRNA) abolished the reductions in UV‐induced DNA damage with 20‐hydroxyvitamin D3 or 24‐hydroxylumisterol3, as previously shown for 1,25(OH)2D3. Treatment with 1,25(OH)2D3 reduced oxygen consumption rates in UV‐exposed and sham‐exposed human keratinocytes and reduced phosphorylation of cyclic AMP response binding element protein (CREB). Both these actions have been shown to inhibit skin carcinogenesis after chronic UV exposure, consistent with the anticarcinogenic activity of 1,25(OH)2D3. The requirement for a vitamin D receptor for the photoprotective actions of 1,25(OH)2D3 and of naturally occurring CYP11A1‐derived vitamin D–related compounds may explain why mice lacking the vitamin D receptor in skin are more susceptible to UV‐induced skin cancers, whereas mice lacking the 1α‐hydroxylase and thus unable to make 1,25(OH)2D3 are not more susceptible. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

To elucidate the effect of early life dietary nutrient level and vitamin D source during gilt development on progeny growth performance, equal number of weaning age piglets (n = 72) were selected from each of 4 sow treatments group. All pigs were fed a common 3,000 ppm zinc diet for first two weeks postweaning to allow for accommodating the weaning process. At the beginning of week 3, pigs were sorted by sow parity and BW within gender and stratified based on maternal dietary treatments. Dietary treatments during gilt development period included two levels of dietary nutrients (Adeq: optimal growing diet that exceed NRC 2012 recommendation or Low: moderate slow growing diet that SID lys and ME levels were gradually reduced by 0.03% and 0 kcal/kg, 0.15% and 146 kcal/kg, and 0.15% and 150 kcal/kg, respectively) and two sources of vitamin D [StD: 1653 IU cholecalciferol/kg or HyD: 500 IU cholecalciferol/kg + 50 mcg calcifediol (ROVIMIX HY.D DSM Nutritional Products North America)] during development phase 1 (23 to 57 kg), 2 (57 to 91 kg), and 3 (91 until breeding). Dietary nutrient level treatment was withdrawn during gestation and lactation stages, while sows remained on their vitamin D treatments. Progeny were fed with a 6-phase feeding regimen as nursery phase 3 (14 d) and 4 (14 d), grower phase 1 (28 d) and 2 (28 d), and finisher phase 1 (28 d) and 2 (28 d). All pigs were transferred to a commercial processing plant where carcass characteristics were measured. Data were analyzed using Mixed procedure of SAS (Cary, NC) with maternal diet nutrient level, vitamin D source and the interaction as fixed effects. Progeny born from sows fed HyD diets had greater ADG in overall grower/finisher phases (P = 0.04) and during the whole trial (P = 0.03). This weight gain improvement increased the final BW, HCW, and yield percentage over StD derived progeny by 3.19 kg, 3.56 kg and 0.11% (P = 0.04, 0.02 and < 0.01), respectively. Dietary nutrient level had limited effect on progeny ADG and BW during the preslaughter period. The maternal vitamin D source did not affect progeny ADFI but overall G:F tended (P = 0.06) to be greater in pigs sourced from dams fed HyD. A maternal vitamin D by nutrient level interaction was observed for ADFI during grower/finisher phases (P = 0.05) and overall (P = 0.07) because progeny from gilts fed a low nutrient level had greater intake than cohorts from gilts fed an adequate nutrient diet, while ADFI was similar for all offspring from gilts fed HyD diets. These results indicate that manipulating nutrients during gilt development, or feeding HyD rather than StD to reproducing sows, can affect growth of their progeny to slaughter. [ABSTRACT FROM AUTHOR]

Vitamin D has shown to play a role in multiple diseases due to its skeletal and extraskeletal actions. Furthermore, vitamin D deficiency has become a worldwide health issue. Few supplementation guidelines mention calcifediol treatment, despite being the direct precursor of calcitriol and the biomarker of vitamin D status. This 1‐year, phase III–IV, double‐blind, randomized, controlled, multicenter clinical trial assessed the efficacy and safety of calcifediol 0.266 mg soft capsules in vitamin D–deficient postmenopausal women, compared to cholecalciferol. Results reported here are from a prespecified interim analysis, for the evaluation of the study's primary endpoint: the percentage of patients with serum 25‐hydroxyvitamin D (25(OH)D) levels above 30 ng/ml after 4 months. A total of 303 patients were enrolled, of whom 298 were included in the intention‐to‐treat (ITT) population. Patients with baseline levels of serum 25(OH)D <20 ng/ml were randomized 1:1:1 to calcifediol 0.266 mg/month for 12 months, calcifediol 0.266 mg/month for 4 months followed by placebo for 8 months, and cholecalciferol 25,000 IU/month for 12 months. At month 4, 35.0% of postmenopausal women treated with calcifediol and 8.2% of those treated with cholecalciferol reached serum 25(OH)D levels above 30 ng/ml (p < 0.0001). The most remarkable difference between both drugs in terms of mean change in serum 25(OH)D levels was observed after the first month of treatment (mean ± standard deviation change = 9.7 ± 6.7 and 5.1 ± 3.5 ng/ml in patients treated with calcifediol and cholecalciferol, respectively). No relevant treatment‐related safety issues were reported in any of the groups studied. These results thus confirm that calcifediol is effective, faster, and more potent than cholecalciferol in raising serum 25(OH)D levels and is a valuable option for the treatment of vitamin D deficiency. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]