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RationaleVitamin D deficiency has been implicated as a pathogenic factor in sepsis and intensive therapy unit mortality but has not been assessed as a risk factor for acute respiratory distress syndrome (ARDS). Causality of these associations has never been demonstrated.ObjectivesTo determine if ARDS is associated with vitamin D deficiency in a clinical setting and to determine if vitamin D deficiency in experimental models of ARDS influences its severity.MethodsHuman, murine and in vitro primary alveolar epithelial cell work were included in this study.FindingsVitamin D deficiency (plasma 25(OH)D levels <50 nmol/L) was ubiquitous in patients with ARDS and present in the vast majority of patients at risk of developing ARDS following oesophagectomy. In a murine model of intratracheal lipopolysaccharide challenge, dietary-induced vitamin D deficiency resulted in exaggerated alveolar inflammation, epithelial damage and hypoxia. In vitro, vitamin D has trophic effects on primary human alveolar epithelial cells affecting >600 genes. In a clinical setting, pharmacological repletion of vitamin D prior to oesophagectomy reduced the observed changes of in vivo measurements of alveolar capillary damage seen in deficient patients.ConclusionsVitamin D deficiency is common in people who develop ARDS. This deficiency of vitamin D appears to contribute to the development of the condition, and approaches to correct vitamin D deficiency in patients at risk of ARDS should be developed.Trial registrationUKCRN ID 11994.

Patients with chronic kidney disease (CKD) are often 25(OH)D 3 and 1,25(OH) 2 D 3 insufficient. We studied whether vitamin D repletion could correct aberrant adipose tissue and muscle metabolism in a mouse model of CKD-associated cachexia. Intraperitoneal administration of 25(OH)D 3 and 1,25(OH) 2 D 3 (75 μg/kg/day and 60 ng/kg/day respectively for 6 weeks) normalized serum concentrations of 25(OH)D 3 and 1,25(OH) 2 D 3 in CKD mice. Vitamin D repletion stimulated appetite, normalized weight gain, and improved fat and lean mass content in CKD mice. Vitamin D supplementation attenuated expression of key molecules involved in adipose tissue browning and ameliorated expression of thermogenic genes in adipose tissue and skeletal muscle in CKD mice. Furthermore, repletion of vitamin D improved skeletal muscle fiber size and in vivo muscle function, normalized muscle collagen content and attenuated muscle fat infiltration as well as pathogenetic molecular pathways related to muscle mass regulation in CKD mice. RNAseq analysis was performed on the gastrocnemius muscle. Ingenuity Pathway Analysis revealed that the top 12 differentially expressed genes in CKD were correlated with impaired muscle and neuron regeneration, enhanced muscle thermogenesis and fibrosis. Importantly, vitamin D repletion normalized the expression of those 12 genes in CKD mice. Vitamin D repletion may be an effective therapeutic strategy for adipose tissue browning and muscle wasting in CKD patients.

Objective To test the hypothesis that genetically low 25-hydroxyvitamin D concentrations are associated with increased mortality. Design Mendelian randomisation analysis. Setting Copenhagen City Heart Study, Copenhagen General Population Study, and Copenhagen Ischemic Heart Disease Study. Participants 95 766 white participants of Danish descent from three cohorts, with median follow-up times of 19.1, 5.8, and 7.9 years, genotyped for genetic variants in DHCR7 and CYP2R1 affecting plasma 25-hydroxyvitamin D concentrations; 35 334 also had plasma 25-hydroxyvitamin D measurements. Participants were followed from study entry through 2013, during which time 10 349 died. Main outcome measures All cause mortality and cause specific mortality, adjusted for common risk factors for all cause mortality based on the World Health Organization’s global health status. Results The multivariable adjusted hazard ratios for a 20 nmol/L lower plasma 25-hydroxyvitamin D concentration were 1.19 (95% confidence interval 1.14 to 1.25) for all cause mortality, 1.18 (1.09 to 1.28) for cardiovascular mortality, 1.12 (1.03 to 1.22) for cancer mortality, and 1.27 (1.15 to 1.40) for other mortality. Each increase in DHCR7/CYP2R1 allele score was associated with a 1.9 nmol/L lower plasma 25-hydroxyvitamin D concentration and with increased all cause, cancer, and other mortality but not with cardiovascular mortality. The odds ratio for a genetically determined 20 nmol/L lower plasma 25-hydroxyvitamin D concentration was 1.30 (1.05 to 1.61) for all cause mortality, with a corresponding observational multivariable adjusted odds ratio of 1.21 (1.11 to 1.31). Corresponding genetic and observational odds ratios were 0.77 (0.55 to 1.08) and 1.13 (1.03 to 1.24) for cardiovascular mortality, 1.43 (1.02 to 1.99) and 1.10 (1.02 to 1.19) for cancer mortality, and 1.44 (1.01 to 2.04) and 1.17 (1.06 to 1.29) for other mortality. The results were robust in sensitivity analyses. Conclusions Genetically low 25-hydroxyvitamin D concentrations were associated with increased all cause mortality, cancer mortality, and other mortality but not with increased cardiovascular mortality. These findings are compatible with the notion that genetically low 25-hydroxyvitamin D concentrations may be causally associated with cancer and other mortality but also suggest that the observational association with cardiovascular mortality could be the result of confounding.

Vitamin D treatment has been found to decrease the incidence of viral respiratory tract infection, especially in patients with vitamin D deficiency. Whether vitamin D is associated with coronavirus disease 2019 (COVID-19) incidence is unknown. To examine whether the last vitamin D status before COVID-19 testing is associated with COVID-19 test results. This retrospective cohort study at an urban academic medical center included patients with a 25-hydroxycholecalciferol or 1,25-dihydroxycholecalciferol level measured within 1 year before being tested for COVID-19 from March 3 to April 10, 2020. Vitamin D deficiency was defined by the last measurement of 25-hydroxycholecalciferol less than 20 ng/mL or 1,25-dihydroxycholecalciferol less than 18 pg/mL before COVID-19 testing. Treatment changes were defined by changes in vitamin D type and dose between the date of the last vitamin D level measurement and the date of COVID-19 testing. Vitamin D deficiency and treatment changes were combined to categorize the most recent vitamin D status before COVID-19 testing as likely deficient (last level deficient and treatment not increased), likely sufficient (last level not deficient and treatment not decreased), and 2 groups with uncertain deficiency (last level deficient and treatment increased, and last level not deficient and treatment decreased). The outcome was a positive COVID-19 polymerase chain reaction test result. Multivariable analysis tested whether vitamin D status before COVID-19 testing was associated with testing positive for COVID-19, controlling for demographic and comorbidity indicators. A total of 489 patients (mean [SD] age, 49.2 [18.4] years; 366 [75%] women; and 331 [68%] race other than White) had a vitamin D level measured in the year before COVID-19 testing. Vitamin D status before COVID-19 testing was categorized as likely deficient for 124 participants (25%), likely sufficient for 287 (59%), and uncertain for 78 (16%). Overall, 71 participants (15%) tested positive for COVID-19. In multivariate analysis, testing positive for COVID-19 was associated with increasing age up to age 50 years (relative risk, 1.06; 95% CI, 1.01-1.09; P = .02); non-White race (relative risk, 2.54; 95% CI, 1.26-5.12; P = .009), and likely deficient vitamin D status (relative risk, 1.77; 95% CI, 1.12-2.81; P = .02) compared with likely sufficient vitamin D status. Predicted COVID-19 rates in the deficient group were 21.6% (95% CI, 14.0%-29.2%) vs 12.2%(95% CI, 8.9%-15.4%) in the sufficient group. In this single-center, retrospective cohort study, likely deficient vitamin D status was associated with increased COVID-19 risk, a finding that suggests that randomized trials may be needed to determine whether vitamin D affects COVID-19 risk.

A high prevalence of vitamin D (calcidiol) serum deficiency has been described in several autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (AR), and systemic lupus erythematosus (SLE). Vitamin D is a potent immunonutrient that through its main metabolite calcitriol, regulates the immunomodulation of macrophages, dendritic cells, T and B lymphocytes, which express the vitamin D receptor (VDR), and they produce and respond to calcitriol. Genetic association studies have shown that up to 65% of vitamin D serum variance may be explained due to genetic background. The 90% of genetic variability takes place in the form of single nucleotide polymorphisms (SNPs), and SNPs in genes related to vitamin D metabolism have been linked to influence the calcidiol serum levels, such as in the vitamin D binding protein (VDBP; rs2282679 GC), 25-hydroxylase (rs10751657 CYP2R1), 1α-hydroxylase (rs10877012, CYP27B1) and the vitamin D receptor (FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) VDR). Therefore, the aim of this comprehensive literature review was to discuss the current findings of functional SNPs in GC, CYP2R1, CYP27B1, and VDR associated to genetic risk, and the most common clinical features of MS, RA, and SLE.

Recent evidence revealed extra skeleton activity of vitamin D, including prevention from cardiometabolic diseases and cancer development as well as anti-inflammatory properties. It is worth noting that vitamin D deficiency is very common and may be associated with the pathogenesis of insulin-resistance-related diseases, including obesity and diabetes. This review aims to provide molecular mechanisms showing how vitamin D deficiency may be involved in the insulin resistance formation. The PUBMED database and published reference lists were searched to find studies published between 1980 and 2019. It was identified that molecular action of vitamin D is involved in maintaining the normal resting levels of ROS and Ca2+, not only in pancreatic β-cells, but also in insulin responsive tissues. Both genomic and non-genomic action of vitamin D is directed towards insulin signaling. Thereby, vitamin D reduces the extent of pathologies associated with insulin resistance such as oxidative stress and inflammation. More recently, it was also shown that vitamin D prevents epigenetic alterations associated with insulin resistance and diabetes. In conclusion, vitamin D deficiency is one of the factors accelerating insulin resistance formation. The results of basic and clinical research support beneficial action of vitamin D in the reduction of insulin resistance and related pathologies.

For maintaining the healthy metabolic status, vitamin D is a beneficial metabolite stored majorly in its pre-activated form, 25-hydroxyvitamin D (25(OH)D ). Due to its important role in bone strengthening, the study was planned to quantify 25(OH)D levels in our blood. Quantification techniques for 25(OH)D are costly thus requiring a need for a low cost, and sensitive detection methods. In this work, an economic, and sensitive sensor for the detection of 25(OH)D was developed using aptamer and graphene oxide (GO). Aptamer is an oligonucleotide, sensitive towards its target, whereas, GO with 2D nanosheets provides excellent quenching surface. Aptamer labeled with fluorescein (5', 6-FAM) is adsorbed by π-π interaction on the GO sheets leading to quenching of the fluorescence due to Förster resonance energy transfer (FRET). However, in the presence of 25(OH)D , a major portion of aptamer fluorescence remains unaltered, due to its association with 25(OH)D . However, in the absence, aptamer fluorescence gets fully quenched. Fluorescence intensity quenching was monitored using fluorescence spectrophotometer and agarose gel based system. The limit of detection of 25(OH)D by this method was found to be 0.15 µg/mL whereas when GO-COOH was used, limit of detection was improved to 0.075 µg/mL. Therefore, this method could come up as a new sensing method in the field of vitamin D detection.

Vitamin D2 and vitamin D3 have been hypothesized to exert differential effects on vitamin D metabolism. To compare the influence of administering vitamin D2 vs vitamin D3 on metabolism of vitamin D3. We measured baseline and 4-month serum concentrations of vitamin D3, 25-hydroxyvitamin D3 [25(OH)D3], 25-hydroxyvitamin D2, 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3], 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], and 4β,25-dihydroxyvitamin D3 [4β,25(OH)2D3] in 52 adults randomized to receive a total of four oral bolus doses of 2.5 mg vitamin D2 (n = 28) or vitamin D3 (n = 24) over four months. Metabolite-to-parent compound ratios were calculated to estimate hydroxylase activity. Pairwise before vs after comparisons were made to evaluate effects of vitamin D2 and vitamin D3 on metabolism of vitamin D. Mean postsupplementation metabolite-to-parent ratios were then compared between groups. Vitamin D2 was less effective than vitamin D3 in elevating total serum 25(OH)D concentration. Vitamin D2 suppressed mean four-month serum concentrations of 25(OH)D3, 24R,25(OH)2D3, 1α,25(OH)2D3, and 4β,25(OH)2D3 and mean ratios of 25(OH)D3 to D3 and 1α,25(OH)2D3 to 25(OH)D3, while increasing the mean ratio of 24R,25(OH)2D3 to 25(OH)D3. Vitamin D3 increased mean four-month serum concentrations of 25(OH)D3, 24R,25(OH)2D3, 1α,25(OH)2D3, and 4β,25(OH)2D3 and the mean ratio of 24R,25(OH)2D3 to 25(OH)D3. Participants receiving vitamin D2 had lower mean postsupplementation ratios of 25(OH)D3 to vitamin D3 and 1α,25(OH)2D3 to 25(OH)D3 than those receiving vitamin D3. Mean postsupplementation ratios of 24R,25(OH)2D3 to 25(OH)D3 and 4β,25(OH)2D3 to 25(OH)D3 did not differ between groups. Bolus-dose vitamin D2 is less effective than bolus-dose vitamin D3 in elevating total serum 25(OH)D concentration. Administration of vitamin D2 reduces 25-hydroxylation of vitamin D3 and 1-α hydroxylation of 25(OH)D3, while increasing 24R-hydroxylation of 25(OH)D3.

Recommendations for vitamin D supplementation for preterm infants span a wide range of doses. Response to vitamin D supplementation and impact on outcomes in preterm infants is not well understood. Evaluate serum 25(OH)D3 concentration changes after 4 weeks in response to two different doses of vitamin D3 supplementation in a population of premature infants and quantify the impact on NICU outcomes. 32 infants born at 24-32 weeks gestation were prospectively randomized to receive 400 or 800 IU/day vitamin D3 supplementation. Serum 25(OH)D3 levels were measured every 4 weeks. The Wilcoxon signed rank test was used to compare serum levels of 25(OH)D3 at 4 weeks and each subsequent time point. A p-value of <0.05 was considered statistically significant. Serum 25(OH)D3 levels at birth were 41.9 and 42.9 nmol/l for infants in the 400 IU group and 800 IU group, respectively (p = 0.86). Cord 25(OH)D3 concentrations significantly correlated with gestational age (r = 0.40, p = 0.04). After 4 weeks of D3 supplementation, median 25(OH)D3 levels increased in both groups (84.6vs. 105.3 nmol/l for 400 vs. 800 IU/day respectively, with significantly more improvement in the higher dose (p = 0.048). Infants in the 400 IU group were significantly more likely to have dual energy x-ray absorptiometry (DEXA) bone density measurements <10 percentile (56% vs 16%, p = 0.04). Improvement in 25(OH)D3 levels at 4 weeks, bone density, and trends towards improvement in linear growth support consideration of a daily dose of 800 IU of vitamin D for infants <32 weeks cared for in the NICU.

Vitamin D and calcium in follicular fluid play an important role in modulating steroidogenesis, folliculogenesis, and oocyte quality determination. Both collaborate to produce top-quality embryos (TQE) during in vitro fertilization (IVF). In this study, we compared free 25(OH)D3 and calcium levels in follicular fluid between TQE and non-TQE groups. This cross-sectional study included women who underwent IVF procedures at tertiary hospitals in Bandung, Indonesia. Ovarian follicular fluid was collected during the ovum pick-up procedure. The examination of 25(OH)D3 levels, vitamin d -binding protein, and calcium in the follicles was done using an enzyme-linked immunosorbent assay (ELISA). Free 25(OH)D3 levels were calculated using the Vermeulen formula. A total of 173 samples met the study criteria, including 86 subjects in the TQE group and 87 subjects in the non-TQE group. There was a significant difference in free 25(OH)D3 follicular fluid levels between the TQE and non-TQE groups (p = 0.017); however, there was no significant difference in calcium levels between the two groups (p = 0.805). We also found that there was a significant association between free 25(OH)D3 follicular fluid levels and embryo quality (OR 3.05, 95% CI 1.46–6.38; p-value = 0.002); however, there was no significant association between follicular fluid calcium and embryo quality [p = 0.144 and OR, 1.74 (95% CI 0.82–3.68)]. The results suggest that free 25(OH)D3 and calcium in the follicular fluid act independently during steroidogenesis, folliculogenesis, and fertilization.