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In people with chronic kidney disease (CKD), the physiology of vitamin D is altered and leads to abnormalities in bone and mineral metabolism which contribute to CKD mineral and bone disorder (CKD-MBD). Observational studies show an association between vitamin D deficiency and increased risk of mortality, cardiovascular disease and fracture in CKD. Although vitamin D therapy is widely prescribed in people with CKD, clinical trials to date have failed to demonstrate a clear benefit of either nutritional vitamin D supplementation or active vitamin D therapy in improving clinical outcomes in CKD. This review provides an updated critical analysis of recent trial evidence on vitamin D therapy in people with CKD. [ABSTRACT FROM AUTHOR]

Deep learning–based mammographic evaluations could noninvasively assess response to breast cancer chemoprevention. We evaluated change in a convolutional neural network–based breast cancer risk model applied to mammograms among women enrolled in SWOG S0812, which randomly assigned 208 premenopausal high-risk women to receive oral vitamin D3 20 000 IU weekly or placebo for 12 months. We applied the convolutional neural network model to mammograms collected at baseline (n = 109), 12 months (n = 97), and 24 months (n = 67) and compared changes in convolutional neural network-based risk score between treatment groups. Change in convolutional neural network-based risk score was not statistically significantly different between vitamin D and placebo groups at 12 months (0.005 vs 0.002, P  = .875) or at 24 months (0.020 vs 0.001, P  = .563). The findings are consistent with the primary analysis of S0812, which did not demonstrate statistically significant changes in mammographic density with vitamin D supplementation compared with placebo. There is an ongoing need to evaluate biomarkers of response to novel breast cancer chemopreventive agents. [ABSTRACT FROM AUTHOR]

Although clinical guidelines recommend measuring total plasma 25-hydroxyvitamin D (25[OH]D) to assess vitamin D (VitD) status, this index does not account for 3-fold inter-individual variation in VitD binding protein (VDBP) level. We present 3 individuals with total plasma 25(OH)D levels of 10.8 to 12.3 ng/mL (27-30.7 nmol/L). Because Endocrine Society guidelines define VitD deficiency as 25(OH)D = 20 ng/mL (50 nmol/L), all 3 would be judged to be VitD deficient. VitD3 supplementation increased 25(OH)D to the range of 31.7 to 33.8 ng/mL (79.1-84.4 nmol/L). Patient #1 exhibited secondary hyperparathyroidism; VitD3 supplementation decreased parathyroid hormone (PTH) by 34% without a clinically significant change in PTH levels in the other 2 individuals. Thus, 25(OH)D level did not distinguish between the 1 patient who had secondary hyperparathyroidism and the 2 who did not. We therefore inquired whether VitD metabolite ratios (which are VDBP-independent) might distinguish among these 3 individuals. Of all the assessed ratios, the 1,25(OH)2D/24,25(OH)2D ratio was the most informative, which had a value of 102 pg/ng in the individual with secondary hyperparathyroidism but lower values (41 and 20 pg/ng) in the other 2 individuals. These cases illustrate the value of the 1,25(OH)2D/24,25(OH)2D ratio to provide clinically relevant information about VitD status. [ABSTRACT FROM AUTHOR]

Background There is a lack of data regarding the effect of vitamin D supplements in patients with I131-induced hypothyroidism. The primary aim of this study was to investigate the effect of vitamin D supplements on muscle function, and the secondary aim was to observe the effect on body composition, insulin resistance, and quality of life (QOL) in patients with I131-induced hypothyroidism. Methods In this pilot randomized placebo-controlled trial, patients with I131-induced hypothyroidism on a stable dose of levothyroxine were enrolled and allocated into 2 groups to receive oral vitamin D 20 000 IU weekly or placebo for 24 weeks. Baseline biochemical values, body composition, handgrip strength, the 5 times sit-to-stand test (5TSTS), homeostatic model assessment for insulin resistance (HOMA-IR), and QOL were measured before intervention and after 3 and 6 months in both groups. Mixed model regression analysis was used to compare the outcomes between the 2 groups. Significance was set at P value of < .05. Results There were 20 participants in each group. The time taken for 5TSTS in the vitamin D group was significantly lower than the placebo group at 3 (P =.032) and 6 months (P =.006). Other outcomes, including handgrip strength, body composition, HOMA-IR, and QOL, showed no significant difference between the 2 groups. Conclusion A supplement of vitamin D2 at 20 000 IU per week for 24 weeks could help improve performance in 5TSTS in patients with I131-induced hypothyroidism. [ABSTRACT FROM AUTHOR]

Hypoparathyroidism is the most common endocrinological feature in children with Sanjad-Sakati syndrome. Treatment includes active vitamin D and calcium supplementation. Here, we report a case of a newborn with Sanjad-Sakati syndrome who had severe hypocalcemia since birth who responded to PTH subcutaneous pump infusion. The child was born at 35 weeks with hypocalcemia since the first day of life. The standard medical treatment proved ineffective for the newborn, necessitating the administration of unusually high doses of oral and IV calcium and vitamin D analogue for a 2 months. As a result, intermittent subcutaneous injections of PTH were commenced, resulting in an initial improvement in calcium levels, although this proved to be short-lived. Subsequently, a switch to continuous infusion via a Medtronic Vio pump was made, which unfortunately resulted in iatrogenic hypercalcemia, requiring management of hypercalcemia. Later, calcium carbonate and alfacalcidol were resumed at a lower dosage and continued to have average requirements for patients with hypoparathyroidism. PTH subcutaneous infusion can be highly effective in refractory hypocalcemia cases and can significantly impact the treatment course and facilitate hospital discharge as seen in our case. Careful dosage and monitoring are required to avoid iatrogenic hypercalcemia. [ABSTRACT FROM AUTHOR]

Vitamin D deficiency is a global public health concern that provokes bone demineralization and weakening. In response to the decreased vitamin D level, calcium stores wear out. The homeostatic effect of compensatory hyperparathyroidism in vitamin D deficiency incites variable discrepancies in different populations. This study intends to decipher the transition point of PTH in relation to levels of vitamin D in a Nepalese population. A cross-sectional study was carried out at Tribhuvan University Teaching Hospital, Nepal. Serum calcium, phosphorus, intact PTH, and 25-hydroxy vitamin D levels were assayed in an Abbott ARCHITECT Integrated System. A correlation plot of PTH and vitamin D was analyzed in Statistical Package for Social Sciences version 22.0. Using a locally weighted scatter plot smoothing method, the relation between these variables was presented graphically. Among 281 individuals, 30.2% had vitamin D levels below 20 ng/mL. There was an archetypical transition in the PTH levels in concert with the decrease in vitamin D level marked by 2 inflection points (ie, 18.5 and 42.0 ng/mL). Our findings suggest that to augment overall health and avert weakness due to vitamin D deficiency, the levels of vitamin D should be maintained above 42.0 ng/mL in our population. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Is there a causal relationship between 25-hydroxyvitamin D (25OHD) and miscarriage? SUMMARY ANSWER In this study, little evidence of a causal relationship was found between low serum 25OHD concentration or vitamin D deficiency and the risk of miscarriages. WHAT IS KNOWN ALREADY Associations between low vitamin D levels and increased risk of miscarriage have been reported, but causality is unclear. STUDY DESIGN, SIZE, DURATION The latest and largest genome-wide association studies (GWAS) for serum 25OHD concentration (n = 417 580), vitamin D deficiency (426 cases and 354 812 controls), miscarriage (16 906 cases and 149 622 controls), and the number of miscarriages (n = 78 700) were used to explore the causal association between serum vitamin D levels and miscarriage by two-sample Mendelian randomization analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS This study was based on summary GWAS results from the FinnGen database and the UK Biobank. The random-effect inverse-variance weighted method was regarded as the primary analysis; MR-Egger, weighted median, weighted mode, simple mode, and MR-pleiotropy residual sum and outlier (MR-PRESSO) were further employed as complementary methods. MR-Egger intercept analysis and MR-PRESSO were employed to test pleiotropy, and Cochran's Q statistic and leave-one-out sensitivity analysis were used to determine the heterogeneity and robustness of the overall estimates, respectively. MAIN RESULTS AND THE ROLE OF CHANCE There was insufficient evidence of causal associations between serum 25OHD concentration and miscarriage (odds ratio (OR) = 0.995, 95% CI: 0.888 to 1.114, P  = 0.927), or the number of miscarriages (β = –0.004, 95% CI: –0.040 to 0.032, P  = 0.829). Furthermore, little evidence of causality between genetically determined vitamin D deficiency to miscarriage (OR = 0.993, 95% CI: 0.966 to 1.021, P  = 0.624), or the number of miscarriages (β = 0.001, 95% CI: −0.009 to 0.011, P  = 0.828), was observed. The results of the sensitivity analysis were robust, and no significant heterogeneity or horizontal pleiotropy was found. LIMITATIONS, REASONS FOR CAUTION This study is limited by the absence of female-specific GWAS data and the limited amount of GWAS data available for this study, as well as the need for caution in generalizing the findings to non-European ethnic groups. WIDER IMPLICATIONS OF THE FINDINGS These findings enhance the current understanding of the intricate association between vitamin D and pregnancy outcomes, challenging prevailing beliefs regarding the strong association with miscarriage. The results provide a special perspective that may prompt further exploration and potentially offer insights for guiding future research and informing clinical guidelines pertaining to the management of miscarriage. STUDY FUNDING/COMPETING INTEREST(S) This project was supported by the Hubei Provincial Natural Science Foundation Program General Surface Project (2022CFB200), the Key Research & Developmental Program of of Hubei Province (2022BCA042), the Fundamental Research Funds for the Central Universities (2042022gf0007, 2042022kf1210), and the Interdisciplinary Innovative Talents Foundation from Renmin Hospital of Wuhan University (JCRCWL-2022-001, JCRCYG-2022-009). All authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A. [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]

Context Recent studies have reported elevated urinary vitamin D binding protein (uVDBP) concentrations in patients with diabetic kidney disease, although the utility of uVDBP to predict deterioration of kidney function over time has not been examined. Objective Our objective was to assess the association of uVDBP with longitudinal changes in kidney function. Methods Adults at-risk for type 2 diabetes from the Prospective Metabolism and Islet Cell Evaluation (PROMISE) study had 3 assessments over 6 years (n = 727). Urinary albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were used as measures of kidney function. Measurements of uVDBP were performed with enzyme-linked immunosorbent assay and normalized to urine creatinine (uVDBP:cr). Generalized estimating equations (GEEs) evaluated longitudinal associations of uVDBP and uVDBP:cr with measures of kidney function, adjusting for covariates. Results Renal uVDBP loss increased with ACR severity at baseline. Individuals with normoalbuminuria, microalbuminuria, and macroalbuminuria had median log uVDBP:cr concentrations of 1.62 μg/mmol, 2.63 μg/mmol, and 2.48 μg/mmol, respectively, and ACR positively correlated with uVDBP concentrations (r = 0.37; P <.001). There was no significant association between uVDBP and eGFR at baseline. Adjusted longitudinal GEE models indicated that each SD increase both in baseline and longitudinal uVDBP:cr was significantly associated with higher ACR over 6 years (β = 30.67 and β = 32.91, respectively). Conversely, neither baseline nor longitudinal uVDBP:cr measures showed a significant association with changes in eGFR over time. These results suggest that loss of uVDBP:cr over time may be a useful marker for predicting renal tubular damage in individuals at risk for diabetes. [ABSTRACT FROM AUTHOR]

Context Vitamin D inadequacy is globally prevalent among pregnant women; however, its impact on pregnancy remains inconclusive. Objective This study aims to explore the associations of maternal and umbilical cord serum 25-hydroxyvitamin D (25(OH)D) levels with pregnancy and neonatal outcomes. Method We used archived serum samples from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study participants in the Hong Kong center and assayed maternal 25(OH)D levels at midgestation and umbilical cord 25(OH)D at birth using liquid chromatography–tandem mass spectroscopy. Data regarding pregnancy and perinatal outcomes were extracted from the HAPO study dataset and the hospital computerized medical system. Results Only 247 (16.4%) mothers and 66 (5.0%) neonates met the criteria for vitamin D sufficiency (ie, 25(OH)D ≥ 75 nmol/L). The ratio of umbilical cord to maternal vitamin D levels was positively associated with maternal age and ambient solar radiation at the month of delivery, while negatively associated with maternal serum total 25(OH)D at midgestation (all P <.001). Umbilical cord serum 25(OH)D was independently associated with a lower primary cesarean section rate (OR 0.990, 95% CI 0.982-0.999; P =.032). There were no associations of maternal and umbilical cord 25(OH)D levels with other adverse pregnancy and neonatal outcomes. Conclusion Placental vitamin D transfer was found to be higher with a lower maternal vitamin D level, older maternal age, and higher ambient solar radiation at the time of the delivery. The protective effect of sufficient vitamin D in a cesarean section will require further studies. [ABSTRACT FROM AUTHOR]

The diagnosis of hypocalcemia-induced tetany following a total thyroidectomy is not common. However, there is a higher risk in patients with a history of gastric bypass surgery due to their malabsorption condition. This case describes postoperative hungry bone syndrome resulting from chronic malabsorption in a patient with a history of bariatric surgery. It is important to consider alternative treatment options if the initial management proves ineffective. Typically, this is a temporary condition, but it's crucial to prioritize prevention in high-risk patients by providing perioperative calcium and vitamin D supplementation. [ABSTRACT FROM AUTHOR]

Context Gestational diabetes mellitus (GDM) is a common pregnancy complication, particularly in women undergoing assisted reproductive technology (ART). An association of GDM with vitamin D in women conceiving naturally has been described; however, studies have yielded heterogeneous results. Objective To analyze the association between prepregnancy total and free vitamin D and GDM incidence in women undergoing ART. Methods Post hoc analysis of a prospective study at the Reproductive and Genetic Hospital of CITIC-Xiangya in Changsha, China. Total and free vitamin D were measured 1 day before embryo transfer. The patients were screened for GDM using the oral glucose tolerance test. Results A total of 1593 women were included in the study, among whom 256 (16.1%) developed GDM. According to international guidelines for total 25-hydroxyvitamin D [25(OH)D], 47 (2.9%) patients had sufficient (≥30 ng/mL) levels, while 696 (43.7%) were insufficient (20 to <30 ng/mL) and 850 (54.4%) were deficient (<20 ng/mL). Comparing GDM and non-GDM patients, there was no significant difference in total nor free vitamin D levels (P =.340 and.849). Similarly, analysis of GDM rates by quintiles of total and free 25(OH)D showed no significant association in one-way ANOVA (P =.831 and.799). Multivariate logistic regression, considering age, BMI, and fasting glucose, also did not show a significant influence of the 2 vitamin D forms on GDM incidence (P =.266 and.123 respectively). Conclusion In this relatively vitamin D deficient/insufficient ART cohort, the degree of neither total nor free vitamin D deficiency before pregnancy was associated with the occurrence of GDM. [ABSTRACT FROM AUTHOR]

Hypoparathyroidism is one of the few remaining hormonal insufficiencies not treated with replacement of its missing hormone. Conventional therapy involves multiple daily oral doses of calcium, active vitamin D, and magnesium, which is not only cumbersome for patients, but carries risk of nephrocalcinosis and is inadequate in patients with enteral malabsorption. Subcutaneous parathyroid hormone 1-34 (PTH[1-34]) has been tested as a hormonal replacement therapy for treatment of hypoparathyroidism. PTH(1-34) delivered by continuous infusion via insulin pump decreases or eliminates the need for oral medications, stabilizes serum and urine calcium at normal levels with minimal fluctuation, and significantly reduces PTH doses. In this case report, we describe the clinical application of PTH(1-34) via insulin pump in an adolescent with autoimmune polyendocrinopathy syndrome type 1 (APS1). Transition to a PTH pump reduced hospital admissions for calcium abnormalities and allowed our patient to discontinue all scheduled daily conventional therapy. [ABSTRACT FROM AUTHOR]

Magnesium and vitamin D play important roles in most cells of the body. These nutrients act in a coordinated fashion to maintain physiologic functions of various organs, and their abnormal balance could adversely affect these functions. Therefore, deficient states of both nutrients may lead to several chronic medical conditions and increased cardiovascular and all-cause mortality. Chronic kidney disease (CKD) patients have altered metabolism of both magnesium and vitamin D. Some studies indicate that magnesium could have a role in the synthesis and metabolism of vitamin D, and that magnesium supplementation substantially reversed the resistance to vitamin D treatment in some clinical situations. Recent observational studies also found that magnesium intake significantly interacted with vitamin D status and, particularly with the risk of cardiovascular mortality. It is therefore essential to ensure adequate levels of magnesium to obtain the optimal benefits of vitamin D supplementation in CKD patients. In this review, we discuss magnesium physiology, magnesium and vitamin D metabolism in CKD, potential metabolic interactions between magnesium and vitamin D and its clinical relevance, as well as the possible role of magnesium supplementation to assure adequate vitamin D levels. [ABSTRACT FROM AUTHOR]

Objective Optimization of maternal vitamin D (VD) status has beneficial effects on pregnancies, but little is known about it of twin pregnancies (TP). Our aim was to promote the current understanding of VD status and its associated factors in TP. Methods We performed liquid chromatography-tandem mass spectrometry to quantify 25-hydroxyvitamin D [25(OH)D] and used the enzyme-linked immunosorbent assay method to detect vitamin D binding protein (VDBP) in 218 singleton pregnancies (SP) and 236 TP. Results Levels of 25(OH)D and VDBP were higher in TP than SP. The 25(OH)D, free 25(OH)D, C-3 epimer of 25-hydroxyvitamin D [epi-25(OH)D], and VDBP all increased with gestational progress. Age, body 
mass index, and hemoglobin level were associated with VD deficiency (VDD). Analysis of covariance demonstrated that the 25(OH)D and VDBP of TP and SP still showed differences after adjusting for the above associated factors. Conclusion Differences in VD status were found in SP and TP, suggesting that the assessment of VD status in TP should be treated with caution. High VDD prevalence is observed among pregnant Chinese women, and it is recommended to promote evaluation for VDD. [ABSTRACT FROM AUTHOR]

Context: Primary hyperparathyroidism (PHPT) is associated with increased risk of morbidity and death, and vitamin D levels are a potentially confounding variable. Objective: The aim of this study was to assess morbidity and mortality associated with primary hyperparathyroidism (PHPT). Methods: In this population-based retrospective matched cohort study, data linkage of biochemistry, hospital admissions, prescribing, imaging, pathology, and deaths was used to identify patients across the region of Tayside, Scotland, who had PHPT from 1997 to 2019. Cox proportional hazards models and hazards ratios (HR) were used to explore the relationship between exposure to PHPT and several clinical outcomes. Comparisons were made with an age- and gender-matched cohort. Results: In 11 616 people with PHPT (66.8% female), with a mean follow-up period of 8.8 years, there was an adjusted HR of death of 2.05 (95% CI, 1.97-2.13) for those exposed to PHPT. There was also an increased risk of cardiovascular disease (HR = 1.34; 95% CI, 1.24-1.45), cerebrovascular disease (HR = 1.29; 95% CI, 1.15-1.45), diabetes (HR = 1.39; 95% CI, 1.26-1.54), renal stones (HR = 3.02; 95% CI, 2.19-4.17) and osteoporosis (HR = 1.31; 95% CI, 1.16-1.49). Following adjustment for serum vitamin D concentrations (n = 2748), increased risks for death, diabetes, renal stones, and osteoporosis persisted, but not for cardiovascular or cerebrovascular disease. Conclusion: In a large population-based study, PHPT was associated with death, diabetes, renal stones, and osteoporosis, independent of serum vitamin D concentration. [ABSTRACT FROM AUTHOR]

Multiple changes occur across various endocrine systems as an individual ages. The understanding of the factors that cause age-related changes and how they should be managed clinically is evolving. This statement reviews the current state of research in the growth hormone, adrenal, ovarian, testicular, and thyroid axes, as well as in osteoporosis, vitamin D deficiency, type 2 diabetes, and water metabolism, with a specific focus on older individuals. Each section describes the natural history and observational data in older individuals, available therapies, clinical trial data on efficacy and safety in older individuals, key points, and scientific gaps. The goal of this statement is to inform future research that refines prevention and treatment strategies in age-associated endocrine conditions, with the goal of improving the health of older individuals. [ABSTRACT FROM AUTHOR]

Vitamin D hydroxylation-deficient rickets type 1A is an autosomal recessive disorder caused by pathogenic variants in CYP27B1 gene, which encodes for 1α-hydroxylase, the enzyme responsible for the conversion of 25-OH vitamin D into its active form 1,25(OH)2 vitamin D. We report the case of a 3-year-old female Mexican patient with growth retardation and progressive bone deformity, whose laboratory studies showed 25-OH vitamin D deficiency, a normal serum calcium and an elevated intact parathyroid hormone level that remained high despite calcitriol, cholecalciferol, and calcium supplementation. 99mTc sestamibi gammagram showed findings suggestive of parathyroid hyperplasia. Bone histomorphometry showed an image consistent with hyperparathyroidism without findings of osteomalacia, so normocalcemic primary hyperparathyroidism was suspected and a subtotal parathyroidectomy was performed, with the patient developing postoperative hypoparathyroidism. When she arrived at our clinic at age 18 years, she showed calcium- and calcitriol-dependent hypocalcemia, with secondary hyperparathyroidism and low levels of 1,25(OH)2 vitamin D in the absence of a 25-OH vitamin D deficiency, reflecting a defect in 1α-hydroxylation. Molecular testing revealed compound heterozygous variants in CYP27B1 gene. This is the first reported case of an inherited disorder of vitamin D metabolism that was diagnosed and surgically treated as primary hyperparathyroidism. [ABSTRACT FROM AUTHOR]

Pathogenic variants of CYP24A1 are associated with hypercalcemia due to disruptions in the ability of 24-hydroxylase to break down 1,25-dihydroxyvitamin D (1,25-DHVD). A case involving a heterozygous pathogenic variant of CYP24A1 and primary hyperparathyroidism leading to severe hypercalcemia has not been previously reported. A 23-year-old woman presented with fatigue and was found to be hypercalcemic at 13.8 mg/dL [reference range, 8.4-10.2 pg/mL]. Her parathyroid hormone (PTH) was 62 pg/mL [reference range, 19-88 pg/mL] and 1,25-DHVD was elevated to 242.7 pg/mL [reference range, 18-72 pg/mL]. Other laboratory workup was unrevealing. She had a bone scan, whole body CT scan, and thyroid ultrasound that were normal. Her 25-hydroxy-vitamin D to 24,25-dihydroxy-vitamin D ratio was elevated at 25.18 (normal, < 25). Because of concern for primary hyperparathyroidism, she was referred to an endocrine surgeon and underwent a parathyroidectomy with the removal of a 3.5-gram adenoma. Pathology showed a parafibromin-deficient parathyroid neoplasm. Genetic testing demonstrated a heterozygous pathogenic variant in CYP24A1. Three weeks after surgery, PTH was 14 pg/mL (1.48 pmol/L), calcium and 1,25-DHVD normalized. In summary, we report a case where a patient with severe symptomatic hypercalcemia was found to have primary hyperparathyroidism exacerbated by an underlying heterozygous pathogenic variant in CYP24A1. [ABSTRACT FROM AUTHOR]

Both experimental and clinical findings linking vitamin D to cardiovascular (CV) risk have prompted consideration of its supplementation to improve overall health. Yet several meta-analyses do not provide support for the clinical effectiveness of this strategy. Meanwhile, the understanding of the roles of vitamin D in the pathophysiology of CV diseases has evolved. Specifically, recent work has revealed some non-classical pleiotropic effects of vitamin D, increasing the complexity of vitamin D signalling. Within particular microenvironments (e.g. dysfunctional adipose tissue and atherosclerotic plaque), vitamin D can act locally at cellular level through intracrine/autocrine/paracrine feedforward and feedback circuits. Within atherosclerotic tissues, 'local' vitamin D levels may influence relevant systemic consequences independently of its circulating pool. Moreover, vitamin D links closely to other signalling pathways of CV relevance including those driving cellular senescence, ageing, and age-related diseases—among them CV conditions. This review updates knowledge on vitamin D biology aiming to clarify the widening gap between experimental and clinical evidence. It highlights the potential reverse causation confounding correlation between vitamin D status and CV health, and the need to consider novel pathophysiological concepts in the design of future clinical trials that explore the effects of vitamin D on atherosclerosis and risk of CV events. [ABSTRACT FROM AUTHOR]

The situation of secondary hyperparathyroidism (SHPT) in chronic kidney disease patients not on dialysis (ND-CKD) is probably best characterised by the Kidney Disease: Improving Global Outcomes Chronic Kidney Disease–Mineral and Bone Disorder Update 2017 guideline 4.2.1 stating that the optimal parathyroid hormone levels are not known in these stages. Furthermore, new caution became recommended with regard to the routine use of active vitamin D analogues in early CKD stages and moderate SHPT phenotypes, due to their potential risks for hypercalcaemia and hyperphosphataemia aggravation. Nevertheless, there is still a substantial clinical need to prevent the development of parathyroid gland autonomy, with its associated consequences of bone and vascular damage, including fracture risks and cardiovascular events. Therefore we now attempt to review the current guideline-based and clinical practice management of SHPT in ND-CKD, including their strengths and weaknesses, favouring individualised approaches respecting calcium and phosphate homeostasis. We further comment on extended-release calcifediol (ERC) as a new differential therapeutic option now also available in Europe and on a potentially novel understanding of a required vitamin D saturation in more advanced CKD stages. There is no doubt, however, that knowledge gaps will remain unless powerful randomised controlled trials with hard and meaningful endpoints are performed. [ABSTRACT FROM AUTHOR]

Context: Lower 25-hydroxyvitamin D (25(OH)D) levels have consistently been associated with higher mortality among participants with colorectal cancer (CRC). Objective: To investigate whether the association between 25(OH)D and CRC mortality differs according to vitamin D binding protein (also known as Gc) isoforms. Methods: We examined the association between prediagnostic 25(OH)D levels and overall and CRC-specific mortality among participants with CRC within 2 prospective US cohorts. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs. Results: 588 participants with CRC were observed until the date of death or last follow-up (2018), whichever came first. Deficient vs sufficient 25(OH)D concentrations (<30 vs ≥50 nmol/L) were associated with higher overall mortality (HR 2.06; 95% CI 1.34-3.18) but not with CRC-specific mortality (HR 1.51; 95% CI 0.75-3.07). The HRs for overall mortality comparing deficient vs sufficient concentrations were 2.43 (95% CI 1.26- 4.70) for those with the Gc1-1 isoform (rs4588 CC) and 1.63 (95% CI 0.88-3.02) for those with the Gc1-2 or Gc2-2 (rs4588 CA or AA) isoform (P for interaction=.54). The HRs for CRC-specific mortality were 1.18 (95% CI 0.27-5.14) for those with the Gc1-1 isoform and 1.41 (95% CI 0.62-3.24) for those with the Gc1-2 or Gc2-2 isoform (P for interaction=.94). Conclusion: In these 2 US cohorts, we found that lower 25(OH)D levels were associated with higher overall mortality, but this association did not differ by Gc isoforms. [ABSTRACT FROM AUTHOR]

Taking care of patients with parathyroid disorders during pregnancy requires consideration of the physiological fundamental changes in bone and mineral metabolism occurring in these women. Diagnostic and therapeutic procedures regarding primary hyperparathyroidism (PHPT) and hypoparathyroidism significantly differ from the nonpregnant population. PHPT should preferably be cured by parathyroidectomy before pregnancy since in women with hypercalcemic PHPT, maternal and fetal pregnancy complications seem to increase according to the degree of hypercalcemia. Parathyroidectomy, if needed during pregnancy, is preferentially performed in the second trimester. Conservative treatment is recommended for milder cases and is mainly restricted to hydration, with only limited evidence regarding drug treatment. Women with hypoparathyroidism can be informed that there are no major concerns regarding disease-associated infertility and that the risk of pregnancy complications is low if the disease is properly managed. Regular active surveillance is recommended, as requirements for calcium and active vitamin D may change during the course of pregnancy in either direction, with an overall trend for rather reduced doses. Any woman suffering from parathyroid disorders during pregnancy requires further surveillance in the postpartum period and during lactation, as there is an increased risk of hypercalcemia after delivery. Newborns of mothers with parathyroid diseases should, depending on disease severity, be carefully monitored for calcium levels in the first days (to weeks) after delivery since intrauterine exposure to hyper- or hypocalcemia may impact their postnatal regulation of calcium metabolism. [ABSTRACT FROM AUTHOR]

Context: Observational studies investigating the role of vitamin D in renal function have yielded inconsistent results. Objective: We tested whether 25-hydroxyvitamin D (25[OH]D) serum levels are associated with renal function, and inversely, whether altered renal function causes changes in 25(OH)D, using Mendelian randomization (MR). Methods: In this two-sample MR study, we used single nucleotide polymorphisms (SNP) associated with 25(OH)D in 443 734 Europeans and evaluated their effects on estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), chronic kidney disease (CKD) risk and progression in genome-wide association studies totaling over 1 million Europeans. To control for pleiotropy, we also used SNPs solely in DHCR7, CYP2R1, and GC, all genes with known roles in vitamin D metabolism. We performed a reverse MR, using SNPs for the above indices of renal function to study causal effects on 25(OH)D levels. Results: We did not find robust evidence supporting effects of 25(OH)D on eGFR, BUN, and CKD or its progression. Our inverse variance weighted MR demonstrated a 0.56 decrease in standardized log-transformed 25(OH)D (95% CI-0.73, -0.41; P=2.89 x 10-12) per unit increase in log-transformed eGFR. Increased BUN was associated with increased 25(OH)D (β=0.25, 95% CI 0.15, 0.36; P=4.12 x 10-6 per unit increase in log-transformed BUN). Finally, genetically predicted CKD conferred a 0.05 increase in standardized log-transformed 25(OH)D level (95% CI 0.04, 0.06; P=1.06 x 10-13). Other MR methods confirmed the findings of the main analyses. Conclusion: Genetically predicted CKD, increased BUN, and decreased eGFR are associated with increased 25(OH)D levels, but we found no causal effect of 25(OH)D on renal function in Europeans. [ABSTRACT FROM AUTHOR]

Vitamin D is one of the most commonly recommended dietary supplements and is often the first medication ever prescribed in infancy. However, with the variety of concentrations available, including many over-the-counter formulations, dosing errors can easily occur. We present a case of a breastfed infant with a calcium level greater than 23 mg/dL (5.75 mmol/L), whose severe hypercalcemia was due to hypervitaminosis D from accidentally overdosed vitamin D supplementation. We consider the differential diagnosis for her presentation and review the interventions required for treatment of her hypercalcemia. Notably, we reinforce the importance of carefully reviewing dosing of vitamin D supplementation with families. We also discuss the management of hypercalcemia, including the role of fluids, diuretics, and glucocorticoids, as well as the long-term sequalae of severe hypercalcemia. [ABSTRACT FROM AUTHOR]

Objective: This work aims to review and discuss controversial topics in the field of vitamin D, SARS-CoV-2 infection, and COVID-19. Methods: The International Conferences “Controversies in Vitamin D” are a series of workshops that started in 2017 featuring international experts and leaders in vitamin D research and clinical practice. The fifth annual conference was held in Stresa, Italy, September 15 to 18, 2021. Evidence: Before the event, participants reviewed available studies on their assigned topic, drafted a related abstract, and presented their findings at the time of the conference. Relevant literature that became available since was also discussed within the panel and updated accordingly. Consensus: Before the event, the drafted abstracts had been merged to prepare a preliminary document. After the conference presentations, in-depth discussions in open sessions led to consensus. The document was subsequently modified according to discussions and up-to-date literature inclusion. Conclusions: There is quite consistent evidence for an association between low 25 OH vitamin D (25(OH)D) levels and poor COVID-19 outcomes, despite heterogeneous publications of variable quality. However, the low vitamin D status in COVID-19 patients might also reflect reverse causality. Vitamin D supplementation might have a positive role in COVID-19 prevention. The evidence supporting a beneficial effect of vitamin D treatment in decreasing the risk of COVID-19 complications is conflicting. Conclusive statements regarding the beneficial effect of vitamin D in this context await high-quality, randomized controlled trials. [ABSTRACT FROM AUTHOR]

Background Idiopathic calcium nephrolithiasis (ICN) is a common condition with a complex phenotype influenced by both environmental and genetic factors. In our study we investigated the association of allelic variants with the history of nephrolithiasis. Methods We genotyped and selected 10 candidate genes potentially related to ICN from 3046 subjects participating in the INCIPE survey cohort (Initiative on Nephropathy, of relevance to public health, which is Chronic, possibly in its Initial stages, and carries a Potential risk of major clinical End-points), a study enrolling subjects from the general population in the Veneto region in Italy. Results Overall, 66 224 variants mapping on the 10 candidate genes were studied. A total of 69 and 18 variants in INCIPE-1 and INCIPE-2, respectively, were significantly associated with stone history (SH). Only two variants, rs36106327 (chr20:54 171 755, intron variant) and rs35792925 (chr20:54 173 157, intron variant) of the CYP24A1 gene were observed to be consistently associated with ICN. Neither variant has been previously reported in association with renal stones or other conditions. Carriers of CYP24A1 variants showed a significant increase in the ratio of 1,25 (OH)2 vitamin D to 25 (OH) vitamin D compared with controls (P  = .043). Although not associated with ICN in this study, the rs4811494 CYP24A1 variant that was reported to be causative of nephrolithiasis was very prevalent in heterozygosity (20%). Conclusion Our data suggest a possible role for CYP24A1 variants in the risk of nephrolithiasis. Genetic validation studies in larger sample sets will be necessary to confirm our findings. [ABSTRACT FROM AUTHOR]

However, vitamin D supplementation for individuals within a normal range of circulating vitamin D would have very little, if any, benefits regarding the risk of CVD. Google Scholar Crossref Search ADS PubMed WorldCat 16 Zhou A, Selvanayagam JB, Hyppönen E. Non-linear Mendelian randomization analyses support a role for vitamin D deficiency in cardiovascular disease risk. The authors pointed out that whereas severe vitamin D deficiency is relatively rare, low concentrations are globally rather common; in the UK Biobank, 55% of participants had circulating vitamin D concentrations < 50 nmol/L, the threshold concentration indicated by the non-linear Mendelian randomization analyses. [Extracted from the article]

Background Low vitamin D status is often associated with systemic low-grade inflammation as reflected by elevated C-reactive protein (CRP) levels. We investigated the causality and direction of the association between vitamin D status and CRP using linear and non-linear Mendelian randomization (MR) analyses. Methods MR analyses were conducted using data from 294 970 unrelated participants of White-British ancestry from the UK Biobank. Serum 25-hydroxyvitamin D [25(OH)D] and CRP concentrations were instrumented using 35 and 46 genome-wide significant variants, respectively. Results In non-linear MR analysis, genetically predicted serum 25(OH)D had an L-shaped association with serum CRP, where CRP levels decreased sharply with increasing 25(OH)D concentration for participants within the deficiency range (<25 nmol/L) and levelled off at ∼50 nmol/L of 25(OH)D (Pnon-linear  = 1.49E-4). Analyses using several pleiotropy-robust methods provided consistent results in stratified MR analyses, confirming the inverse association between 25(OH)D and CRP in the deficiency range (P  = 1.10E-05) but not with higher concentrations. Neither linear or non-linear MR analysis supported a causal effect of serum CRP level on 25(OH)D concentration (Plinear  = 0.32 and Pnon-linear  = 0.76). Conclusion The observed association between 25(OH)D and CRP is likely to be caused by vitamin D deficiency. Correction of low vitamin D status may reduce chronic inflammation. [ABSTRACT FROM AUTHOR]

Context: Laparoscopic sleeve gastrectomy (LSG), now the most commonly performed bariatric operation, is a highly effective treatment for obesity. While Roux-en-Y gastric bypass is known to impair intestinal fractional calcium absorption (FCA) and negatively affect bone metabolism, LSG’s effects on calcium homeostasis and bone health have not been well characterized. Objective: We determined the effect of LSG on FCA, while maintaining robust 25-hydroxyvitamin D (25OHD) levels and recommended calcium intake. Design, setting, participants: Prospective pre-post observational cohort study of 35 women and men with severe obesity undergoing LSG. Main outcomes: FCA was measured preoperatively and 6 months postoperatively with a gold-standard dual stable isotope method. Other measures included calciotropic hormones, bone turnover markers, and bone mineral density (BMD) by dual-energy X-ray absorptiometry and quantitative computed tomography. Results: Mean±SD FCA decreased from 31.4±15.4% preoperatively to 16.1±12.3% postoperatively (P<0.01), while median (interquartile range) 25OHD levels were 39 (32-46) ng/mL and 36 (30-46) ng/mL, respectively. Concurrently, median 1,25-dihydroxyvitamin D level increased from 60 (50-82) pg/mL to 86 (72-107) pg/mL (P<0.01), without significant changes in parathyroid hormone or 24-hour urinary calcium levels. Bone turnover marker levels increased substantially, and areal BMD decreased at the proximal femur. Those with lower postoperative FCA had greater areal BMD loss at the total hip (ρ=0.45, P<0.01). Conclusions: FCA decreases after LSG, with a concurrent rise in bone turnover marker levels and decline in BMD, despite robust 25OHD levels and with recommended calcium intake. Decline in FCA could contribute to negative skeletal effects following LSG. [ABSTRACT FROM AUTHOR]

Context The skeletal effects of vitamin D remain controversial and it is uncertain whether variation in serum 25-hydroxyvitamin D (25OHD) levels over time influences bone mineral density (BMD). Objective We evaluated longitudinal stability of serum 25OHD and associations with changes in BMD in participants aged 46-70 years at baseline. Methods We studied 3698 Busselton Healthy Ageing Study participants (2040 female) with serum 25OHD and dual-energy x-ray absorptiometry (DXA) BMD assessments at baseline and at ∼6 years follow-up. Restricted cubic splines were used to evaluate associations between changes in 25OHD and BMD. Results Mean season-corrected serum 25OHD was 81.3 ± 22.7 and 78.8 ± 23.1 nmol/L at baseline and 6 years, respectively, and showed moderate correlation (intraclass correlation coefficient: 0.724). Significant predictors of change in 25OHD concentration (Δ25OHD) included baseline 25OHD, change in body mass index and vitamin D supplementation at follow-up. Greater decline in serum 25OHD over time was associated with significantly greater reduction in BMD at total hip and femoral neck, but the magnitude of the differences was small (estimated differences 0.004 g/cm2 and 0.005-0.007 g/cm2, respectively, for lowest quartile of Δ25OHD compared with higher quartiles, adjusted for sex, baseline BMD, 25OHD, and demographics). No significant associations between Δ25OHD and lumbar spine BMD were observed. Increase in 25OHD levels was not associated with change in BMD. Conclusions In this predominantly vitamin D–replete middle-aged cohort, serum 25OHD showed moderate longitudinal stability. Declining serum 25OHD over time was associated with greater reduction in BMD at the total hip and femoral neck. [ABSTRACT FROM AUTHOR]

Rickets is a disorder of impaired bone mineralization that can arise from nutritional deficiencies and inherited conditions. We describe a 10-yearold girl presenting with genu valgum and a history of renal stones due to hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a rare inherited form of rickets characterized by high 1,25 vitamin D levels, hypophosphatemia with inappropriate renal phosphate wasting, and hypercalciuria. After the diagnosis was confirmed, she began treatment with phosphorus supplementation and stopped taking vitamin D, leading to improved bone mineral density and reduction in renal symptoms. Patients with HHRH can be distinguished from those with other forms of hypophosphatemic rickets by their high 1,25 vitamin D levels in conjunction with low to normal parathyroid hormone and fibroblast growth factor 23 (FGF23) levels. Genetic testing for SLC34A3 variants provides a definitive diagnosis. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to examine serum leukocyte cell-derived chemotaxin 2 (LECT2) levels in osteoporosis subjects to confirm its association with osteoporosis. Methods A total of 204 adult subjects were recruited. Bone mineral densities (BMD) were assessed and blood samples were collected for measurements of biomedical parameters and the bone turnover markers. Serum LECT2 levels were measured by enzyme-linked immunosorbent assay. The relationships between serum LECT2 levels and other parameters were analyzed using the Spearman correlation coefficient. Results Serum LECT2 levels were significantly increased in osteoporosis subjects over controls. We found a significantly negative correlation of serum LECT2 with BMD, 25-hydroxy-vitamin D, and creatinine and a significantly positive correlation with C-terminal telopeptide of type 1 collagen and total cholesterol. Conclusion Serum LECT2 levels were significantly upregulated in osteoporosis subjects and correlated with the severity of bone loss. Serum LECT2 could be a potential biomarker to assess the risk of bone loss. [ABSTRACT FROM AUTHOR]

Objective Vitamin D might participate in the pathogenesis of several immune-mediated diseases, but few related data are available for ANCA-associated vasculitis (AAV). In this study, we analysed the association between vitamin D status and disease in patients with AAV. Methods Serum levels of 25(OH)D2/3 were measured in 125 randomly selected patients with AAV [granulomatosis with polyangiitis (n  = 50), eosinophilic granulomatosis with polyangiitis (n  = 50) or microscopic polyangiitis (n  = 25)] enrolled in the Vasculitis Clinical Research Consortium Longitudinal Studies at the time of enrolment and a subsequent relapse visit. Sufficient, insufficient and deficient vitamin D status were defined as 25(OH)D3 levels >30, 20–30 and ˂20 ng/ml, respectively. Results Seventy of 125 patients (56%) were female, with a mean age of 51.5 (16) years at diagnosis; 84 (67%) were ANCA positive. Mean 25(OH)D was 37.6 (16) ng/ml, with vitamin D deficiency in 13 (10.4%) and insufficiency in 26 (20.8%). In univariate analysis, lower vitamin D status was associated with male sex (P  = 0.027) and disease activity (P  = 0.047). In univariate and multivariate analyses, deficient vitamin D status was associated with disease activity (P  = 0.015). Mean 25(OH)D status in the 21 patients with a subsequent relapse did not differ between baseline and relapse visit [37.8 (16) vs 38.0 (10) ng/ml, respectively; P  = 0.92]. Conclusion Most patients with AAV have sufficient 25(OH)D levels, although those with lower vitamin D status were more likely to be male and to have active disease. Whether optimization of vitamin D status alters disease manifestations or activity in AAV remains to be determined. Trial Registration Vasculitis Clinical Research Consortium (VCRC) Longitudinal Study (LS), NCT00315380, https://clinicaltrials.gov/ct2/show/NCT00315380 [ABSTRACT FROM AUTHOR]

Context There are few studies of 25-hydroxyvitamin D (25(OH)D) concentrations in healthy adults in Brazil. Objective This work aimed to estimate the prevalence of vitamin D status and its association with lifestyle, sociodemographic, and anthropometric data in 3 regions of Brazil. Methods A cross-sectional study was conducted among blood donors of both sexes, living in the cities of Salvador, São Paulo, and Curitiba during summer. Blood samples were collected during the procedure. Serum 25(OH)D and parathyroid hormone (PTH) were measured in the same laboratory using chemiluminescence immunoassays. Lifestyle, sociodemographic, and anthropometric data were gathered by an interview with a standardized questionnaire. Vitamin D deficiency and insufficiency was defined as 25(OH)D levels below 20 ng/mL and below 30 ng/mL, respectively. Results A total of 1004 healthy adults were evaluated with mean levels of 25(OH)D (28.7 ± 9.27 ng/mL) and PTH (34.4 ± 15.1 pg/mL). The standardized prevalence of vitamin D deficiency and insufficiency was in the study population 15.3% and 50.9%: in Salvador 12.1% and 47.6%, in São Paulo 20.5%, and 52.4% and in Curitiba 12.7% and 52.1%, (P =.0004). PTH levels were negatively correlated with 25(OH)D levels. Greater body mass index (BMI) and higher latitude were significant predictors of vitamin D deficiency, whereas skin color (White), longer duration of sun exposure, and current use of dietary supplement were protective. Conclusion This study confirmed the high prevalence of vitamin D deficiency and insufficiency even in the midsummer in a healthy population of Brazil. Vitamin D levels are associated with sun exposure, latitude, BMI, skin color, and use of supplements. [ABSTRACT FROM AUTHOR]

Background While the risk of exceeding the standard range of phosphorus levels has been investigated, the impact of the degree of fluctuations has not been investigated. Methods Data were derived from the Japan Dialysis Active Vitamin D trial, a 4-year prospective, randomized study involving 976 patients without secondary hyperparathyroidism undergoing hemodialysis in Japan. Laboratory data were collected every 6 months and the primary outcome was the time to the occurrence of cardiovascular events. The effect of time-dependent changes in phosphorus levels was assessed using a time-varying Cox proportional hazards regression model. Results The median serum phosphorus levels at baseline and at the final observation were 4.70 mg/dl [interquartile range (IQR) 3.90–5.30] and 5.00 mg/dl (IQR 4.20–5.80), respectively. Over each 6-month period, phosphorus changes ranged from −7.1 to +6.7 mg/dl, with a median value of −0.1 to +0.3 mg/dl. During follow-up, composite cardiovascular events occurred in 103 of 964 patients. Although the P -value for the interaction between serum phosphorus level fluctuations and baseline phosphorus levels was insignificant, the following trends were observed. First, patients with relatively high initial phosphorus levels over a 6-month period showed a trend towards a higher hazard, with greater changes in the phosphorus level over the 6-month period. Second, it was suggested that oral vitamin D receptor activators could contribute to the relationship between fluctuating phosphorus levels and cardiovascular events. Conclusions Our results suggest the importance of maintaining stable phosphorus levels, not only in the normal range, but also without fluctuations, in the risk of cardiovascular events among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis. [ABSTRACT FROM AUTHOR]

Context: X-linked hypophosphatemia (XLH) is a rare genetic disease caused by a primary excess of fibroblast growth factor 23 (FGF23). FGF23 has been associated with inflammation and impaired osteoclastogenesis, but these pathways have not been investigated in XLH. Objective: This work aimed to evaluate whether XLH patients display peculiar inflammatory profile and increased osteoclastic activity. Methods: We performed a prospective, multicenter, cross-sectional study analyzing transcript expression of 8 inflammatory markers (Il6, Il8, Il1ß, CXCL1, CCL2, CXCR3, Il1R, Il6R) by real-time quantitative polymerase chain reaction on peripheral blood mononuclear cells (PBMCs) purified from total blood samples extracted from patients and healthy control individuals. The effect of native/active vitamin D on osteoclast formation was also assessed in vitro from XLH patients' PBMCs. Results: In total, 28 XLH patients (17 children, among them 6 undergoing standard of care [SOC] and 11 burosumab therapy) and 19 controls were enrolled. Expression of most inflammatory markers was significantly increased in PBMCs from XLH patients compared to controls. No differences were observed between the burosumab and SOC subgroups. Osteoclast formation was significantly impaired in XLH patients. XLH mature osteoclasts displayed higher levels of inflammatory markers, being however lower in cells derived from the burosumab subgroup (as opposed to SOC). Conclusion: We describe for the first time a peculiar inflammatory profile in XLH. Since XLH patients have a propensity to develop arterial hypertension, obesity, and enthesopathies, and because inflammation can worsen these clinical outcomes, we hypothesize that inflammation may play a critical role in these extraskeletal complications of XLH. [ABSTRACT FROM AUTHOR]

Background The evidence regarding the efficacy of vitamin D supplementation in reducing severity of COVID-19 is still insufficient. This is partially due to the lack of primary robust trial-based data and heterogeneous study designs. Aim This evidence summary, aims to study the effect of vitamin D supplementation on morbidity and mortality in hospitalized COVID-19 patients. Design: Evidence summary of systematic reviews Methods For this study, systematic reviews and meta-analysis published from December 2019 to January 2022 presenting the impact of vitamin D supplementation on COVID-19 severity were screened and selected from PubMed and Google scholar. After initial screening, 10 eligible reviews were identified and quality of included reviews were assessed using AMSTAR and GRADE tools and overlapping among the primary studies used were also assessed. Results The number of primary studies included in the systematic reviews ranged from 3 to 13. Meta-analysis of seven systematic reviews showed strong evidence that vitamin D supplementation reduces the risk of mortality (Odds ratio: 0.48, 95% CI: 0.346–0.664; P  < 0.001) in COVID patients. It was also observed that supplementation reduces the need for intensive care (Odds ratio: 0.35; 95%CI: 0.28–0.44; P  < 0.001) and mechanical ventilation (Odds ratio: 0.54; 95% CI: 0.411–0.708; P  < 0.001) requirement. The findings were robust and reliable as level of heterogeneity was considerably low. However the included studies were of varied quality. Qualitative analysis showed that supplements (oral and IV) are well tolerated, safe and effective in COVID patients. Conclusion The findings of this study show that vitamin D supplementation is effective in reducing the COVID-19 severity. Hence, vitamin D should be recommended as an adjuvant therapy for COVID-19.However, more robust and larger trials are required to substantiate it further. [ABSTRACT FROM AUTHOR]

Context: Conventional prediction models for vitamin D deficiency have limited accuracy. Background: Using cross-sectional data, we developed models based on machine learning (ML) and compared their performance with those based on a conventional approach. Methods: Participants were 5106 community-resident adults (50-84 years; 58% male). In the randomly sampled training set (65%), we constructed 5 ML models: lasso regression, elastic net regression, random forest, gradient boosted decision tree, and dense neural network. The reference model was a logistic regression model. Outcomes were deseasonalized serum 25-hydroxyvitamin D (25(OH)D) <50 nmol/L (yes/no) and <25 nmol/L (yes/no). In the test set (the remaining 35%), we evaluated predictive performance of each model, including area under the receiver operating characteristic curve (AUC) and net benefit (decision curves). Results: Overall, 1270 (25%) and 91 (2%) had 25(OH)D <50 and <25 nmol/L, respectively. Compared with the reference model, the ML models predicted 25(OH)D <50 nmol/L with similar accuracy. However, for prediction of 25(OH)D <25 nmol/L, all ML models had higher AUC point estimates than the reference model by up to 0.14. AUC was highest for elastic net regression (0.93; 95% CI 0.90-0.96), compared with 0.81 (95% CI 0.71-0.91) for the reference model. In the decision curve analysis, ML models mostly achieved a greater net benefit across a range of thresholds. Conclusion: Compared with conventional models, ML models predicted 25(OH)D <50 nmol/L with similar accuracy but they predicted 25(OH) D <25 nmol/L with greater accuracy. The latter finding suggests a role for ML models in participant selection for vitamin D supplement trials. [ABSTRACT FROM AUTHOR]

Aims: Residual beta cell function in type 1 diabetes (T1D) is associated with lower risk of complications. Autoantigen therapy with GAD-alum (Diamyd) given in 3 intralymphatic injections with oral vitamin D has shown promising results in persons with T1D carrying the human leukocyte antigen (HLA) DR3-DQ2 haplotype in the phase 2b trial DIAGNODE-2. We aimed to explore the efficacy of intralymphatic GAD-alum on blood glucose recorded by continuous glucose monitoring (CGM). Methods: DIAGNODE-2 (NCT03345004) was a multicenter, randomized, placebo-controlled, double-blind trial of 109 recent-onset T1D patients aged 12 to 24 years with GAD65 antibodies and fasting C-peptide > 0.12 nmol/L, which randomized patients to 3 intralymphatic injections of 4 μg GAD-alum and oral vitamin D, or placebo. We report results for exploratory endpoints assessed by 14-day CGM at months 0, 6, and 15. Treatment arms were compared by mixed-effects models for repeated measures adjusting for baseline values. Results: We included 98 patients with CGM recordings of sufficient quality (DR3-DQ2-positive patients: 27 GAD-alum-treated and 15 placebotreated). In DR3-DQ2-positive patients, percent of time in range (TIR, 3.9-10 mmol/L) declined less between baseline and month 15 in GAD-alumtreated compared with placebo-treated patients (-5.1% and -16.7%, respectively; P = 0.0075), with reduced time > 13.9 mmol/L (P = 0.0036), and significant benefits on the glucose management indicator (P = 0.0025). No differences were detected for hypoglycemia. GAD-alum compared to placebo lowered the increase in glycemic variability (standard deviation) observed in both groups (P = 0.0219). Change in C-peptide was correlated with the change in TIR. Conclusions: Intralymphatic GAD-alum improves glycemic control in recently diagnosed T1D patients carrying HLA DR3-DQ2. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether 25-hydroxyvitamin D (25-OH D) levels are associated with bone outcomes in a multiracial cohort of young adults. Methods: This cross-sectional study included 165 participants (83 men, 82 women, 18-30 years of age) who self-identified as Asian, Black, or White. We measured bone microarchitecture and strength of the distal radius and tibia using high-resolution peripheral quantitative computed tomography. We used linear regression to estimate the association between 25-OH D (ng/mL) and bone measurements, adjusting for race, sex, age, weight, height, calcium intake, physical activity, and season. Results: A total of 43.6% of participants were 25-OH D deficient (<20 ng/mL) with greater prevalence in Asian (38.9%) and Black (43.1%) compared with White (18.0%) participants (P < 0.001). At the distal radius, 25-OH D was positively associated with cortical area, trabecular density, cortical thickness, cortical porosity, and failure load (P < 0.05 for all). At the distal tibia, higher 25-OH D was associated with higher cortical area, trabecular density, trabecular number, failure load, and lower trabecular separation and cortical density (P < 0.05 for all). After multivariable adjustment, those with 25-OH D deficiency had generally worse bone microarchitecture than those with 25-OH D sufficiency. Black individuals had largely more favorable bone outcomes than Asian and White individuals, despite higher prevalence of 25-OH D deficiency. Conclusions: We found a high prevalence of 25-OH D deficiency in a multiracial cohort of young adults. Lower 25-OH D was associated with worse bone outcomes at the distal radius and tibia at the time of peak bone mass, warranting further attention to vitamin D status in young adults. [ABSTRACT FROM AUTHOR]

Context: Leukocyte telomere length (LTL) is a biomarker of biological aging and is associated with metabolic diseases such as type 2 diabetes. Insufficient maternal vitamin D was associated with increased risk for many diseases and adverse later life outcomes. Objective: This study investigates the relationship between vitamin D levels and offspring LTL at early life. Methods: This observational, longitudinal, hospital-based cohort study included eligible mother-child pairs from the HAPO Hong Kong Field Centre, with 853 offspring at age 6.96 ± 0.44 (mean ± SD) years. LTL was measured using real-time polymerase chain reaction while serum vitamin D metabolites 25(OH)D2, 25(OH)D3, and 3-epi-25(OH)D3 were measured in maternal blood (at gestation 24-32 weeks) and cord blood by liquid chromatography–mass spectrometry. Results: LTL at follow-up was significantly shorter in boys compared with girls (P < 0.001) at age 7. Childhood LTL was negatively associated with childhood BMI (β ± SE = -0.016 ± 0.007)(P = 0.02) and HOMA-IR (β ± SE = −0.065 ± 0.021)(P = 0.002). Multiple linear regression was used to evaluate the relationship between 25(OH)D and LTL, with covariate adjustments. Childhood LTL was positively correlated with total maternal 25(OH)D (0.048 ± 0.017) (P = 0.004) and maternal 3-epi-25(OH)D3 (0.05 ± 0.017) (P = 0.003), even after adjustment for covariates. A similar association was also noted for cord 3-epi-25(OH)D3 (0.037 ± 0.018) (P = 0.035) after adjustment for offspring sex and age. Conclusion: Our findings suggest 25(OH)D3 and 3-epi-25(OH)D3 in utero may impact on childhood LTLs, highlighting a potential link between maternal vitamin D and biological aging. [ABSTRACT FROM AUTHOR]

Aim: To evaluate early, before the onset of cardiovascular events and of chronic renal insufficiency, the association between chronic kidney disease (CKD)-mineral bone disorder (MBD) biomarkers and vascular stiffness [Cardio Ankle Vascular Index (CAVI)] in the course of type 2 diabetes (T2DM). Method: We evaluated 174 T2DM patients [median age 56 years; male/female (M/F) 100/74] with diabetes duration < 10 years and without decreased estimated glomerular filtration rate (eGFR; ≥60 mL/min/1.73 m2) or macrovascular complications. Thirty-four age-matched healthy subjects [M/F 13/21; age 53.5 (50.0-57.7) years; eGFR 107.5 (97.0-119.7) mL/ min1.73 m2] served as local reference control for CAVI (pathological: ≥8) and the novel CKD-MBD biomarkers. Results: Albumin-to-creatinine ratio (ACR) averaged 8.5 mg/g (5.6-17.2) with 12.6% of the patients showing pathologic values, indicative of incipient diabetic nephropathy. Serum parathyroid hormone, fibroblast growth factor 23, and sclerostin were higher while 1,25-dihydroxyvitamin D and Klotho were lower than a control group. CAVI was normal (<8) in only 54% and correlated positively with age (P < 0.001), hemoglobin 1A1c (P = 0.036), and systolic (P = 0.021) and diastolic blood pressure (DBP) (P = 0.001) and negatively correlated with 25-hydroxyvitamin D (P = 0.046). In multivariate analysis, age, DBP, ACR, and serum Klotho were independent positive predictors of CAVI. Conclusion: In the absence of overt cardiovascular disease and of chronic renal insufficiency, CAVI is frequently pathologic in T2DM. DBP and ACR are modifiable risk factors of vascular stiffness in T2DM, thus warranting optimal assessment. [ABSTRACT FROM AUTHOR]

Background: The prevalence of vitamin D deficiency varies across countries and few data exist in the adult population in Greece.Objectives: To assess vitamin D levels in unselected patients from primary care and to investigate possible correlations with clinical, seasonal, and quality-of-life parameters.Methods: In this cross-sectional study, 389 consecutive patients were included. They were grouped according to vitamin D status as vitamin D deficient (<20 ng/mL) and vitamin D sufficient groups (≥20 ng/mL). Demographic, Epworth Sleepiness Scale (ESS), Athens Insomnia Scale (AIS), Beck Depression Inventory (BDI), and Fatigue Severity Scale (FSS) scores were measured and compared between groups.Results: Vitamin D deficiency (<20 ng/mL) was observed in 50.4% of the cohort. Female gender (76% vs 66%, P = 0.026), obesity (42% vs 26%, P = 0.005), and hypertension (55% vs 43%, P = 0.023) were higher in the vitamin D deficiency group compared with the group without deficiency. After multiparametric adjustments (for age, gender, obesity, comorbidities, and seasonality), hypertension (odds ratio [OR] = 2.338, 95% confidence interval [CI] = 1.257-4.349, P = 0.007), excessive daytime sleepiness (ESS >10; OR = 3.345, 95% CI = 1.124-9.948, P = 0.029), depressive symptoms (BDI >10; OR = 3.769, 95% CI = 0.984-14.443, P = 0.04), and fatigue (FSS >36; OR = 7.157, 95% CI = 0.855-59.877, P = 0.04) showed significant independent associations with vitamin D deficiency in specific subgroups of patients.Conclusion: A large proportion of patients in primary care had vitamin D deficiency, independently associated with hypertension, sleepiness, depressive symptoms, and fatigue. Further research is needed in order to determine the role of vitamin D in these patients. [ABSTRACT FROM AUTHOR]

Background: Pharmacological therapy may be useful in the treatment of moderate to severe hypercalcemia in patients with infantile hypercalcemia-1 (HCINF1) due to pathogenic variants in the cytochrome P450 24 subfamily A member 1 (CYP24A1). Rifampin is an antituberculosis drug that is a potent inducer of cytochrome P450 3 subfamily A member 4, which is involved in an alternative catabolic pathway of vitamin D. The efficacy of rifampin in improving hypercalcemia was previously reported, but many questions remain on the long-term efficacy and safety. The aim of the study is to test the long-term efficacy and safety of rifampin in a patient with HCINF1. Methods: We report clinical, biochemical, and imaging features of a 23-year-old man affected by HCINF1 with moderate hypercalcemia (12.9 mg/dL), symptomatic nephrolithiasis, nephrocalcinosis, and impaired kidney function [estimated glomerular filtration rate (eGFR) 60 mL/min/1.73 m² ] treated with rifampin for an overall period of 24 months. Kidney, liver, and adrenal function were evaluated at every follow-up visit. Results: In 2 months, rifampin induced a normalization of serum calcium (9.6 mg/dL) associated with an improvement of kidney function (eGFR 92 mL/min/1.73 m² ) stable during the treatment. After 15 months, rifampin was temporally withdrawn because of asthenia, unrelated to impairment of adrenal function. After 3 months, the timing of drug administration was shifted from the morning to the evening, obtaining the remission of asthenia. At the end of follow-up, the nephrolithiasis disappeared and the nephrocalcinosis was stable. Conclusions: Rifampin could represent an effective choice to induce a stable reduction of calcium levels in patients with HCINF1, with a good safety profile [ABSTRACT FROM AUTHOR]

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

Context: A protective or causative role of vitamin D status on the risk of nonalcoholic fatty liver disease (NAFLD) remains inconclusive. Objective: To evaluate the association between changes in serum 25-hydroxyvitamin D [25(OH)D] status during follow-up and the risk of incident NAFLD and resolution of preexisting NAFLD. Design: A retrospective cohort study. Setting: Kangbuk Samsung Health Study based on routine health screening examinations. Participants: Korean adults (mean age, 36.8 years; range, 18-96 years) who underwent comprehensive health examinations including assessment of serum 25(OH)D levels Main Outcome Measures: The main outcomes were (1) incidence and (2) resolution of NAFLD assessed by liver ultrasound. Cox proportional hazard models were used to estimate hazard ratios (HRs) with 95% CIs for outcomes according to serum 25(OH)D levels. Results: Among 139 599 participants without NAFLD at baseline, 27 531 developed NAFLD during follow-up. Serum 25(OH)D levels were significantly and inversely associated with NAFLD development. Among 48 702 participants with NAFLD at baseline, 13 449 showed NAFLD resolution. Multivariable-adjusted HR (95% CI) for NAFLD resolution comparing 25(OH)D 10 to <20, 20 to <30, and ≥30 ng/mL to <10 ng/mL were 1.09 (1.03-1.15), 1.13 (1.06-1.21), and 1.21 (1.09-1.35), respectively. Additionally, an increase in 25(OH)D levels between baseline and the subsequent visit (median, 1.8 years) was associated with decreased NAFLD incidence, while persistently adequate 25(OH)D levels over time was associated with decreased incidence and increased resolution of NAFLD. Conclusions: Maintaining adequate serum 25(OH)D concentrations may be beneficial for both prevention as well as resolution of NAFLD. [ABSTRACT FROM AUTHOR]

Recently, interest in supplementing vitamin D (Vit D) to improve aspects of health, mainly in human fertility, has emerged. Still, supplementation of Vit D above the minimum required levels has yet to be explored in cattle despite evidence for Vit D receptors in reproductive tissues. The objective of this study was to establish if a dose–response relationship exists between Vit D exposure and success of in vitro production (IVP) of embryos and, if acute supplementation of Vit D improves pregnancy rates during timed artificial insemination (TAI) of dairy cows. Cumulus-oocyte complexes (COCs) were obtained from ovaries acquired from a local abattoir and cultured in five different IVP treatments from three separate collections (Control, 50, 100, 150, and 200 ng/mL of 1,25(OH)2D3; n = 20–30 COCs/group). In Experiment 2, dairy breed cows (n = 100) were synchronized for TAI with the PresynchOvsynch protocol. Cows received 150,000 IU of Vit D (n = 48) or castor oil as control (n = 53) along with gonadotropin-releasing hormone (GnRH) 24 h before TAI. Serum samples were collected before and 24 h after treatment. A small cohort of cows (n = 4) received the same treatments in two separate cycles and follicular fluid (FF) was collected after 24 h for calcidiol (25OHD) analyses. Increased concentrations of Vit D resulted in decreased rates of maturation of COC (150 and 200 ng/mL vs. control and 50 ng/mL; P = 0.01). Supplementation with 50 ng/mL resulted in greater numbers of early blastocyst and blastocyst stage embryos (P < 0.009). Pregnancy at first breeding did not differ (P = 0.13) between groups, but serum 25OHD increased in treated females after 24 h (P = 0.002). The FF 25OHD levels were reflective of serum levels, however, the observed increase in the treatment cycle (P = 0.04) was parallel to an overall increase in serum 25OHD during the entire second cycle, likely due to increased environmental sunlight exposure (March, control vs. May, treatment). A similar increase in the serum 25OHD in the lactating commercial herd maintained in covered housing was not observed, although experiments were conducted during a similar timeframe. This herd had levels of 25OHD near the low end of sufficiency according to National Research Council (NRC) guidelines. We conclude mild Vitamin D supplementation with concentrations at the higher end of NRC guidelines can improve maturation rates of recovered COCs. However, longer term supplementation may be needed to appreciate any benefits on fertility. [ABSTRACT FROM AUTHOR]