Managing children with frequent respiratory infections and associated wheezing: a preliminary randomized study with a new multicomponent nasal spray.

BACKGROUND: Preschoolers frequently have respiratory infections (RIs), which may cause wheezing in some subjects. Type 2 polarization may favor increased susceptibility to RIs and associated wheezing. Non-pharmacological remedies are garnering increasing interest as possible add-on therapies. The present preliminary study investigated the efficacy and safety of a new multi-component nasal spray in preschoolers with frequent RIs and associated wheezing. METHODS: Some preschoolers with these characteristics randomly took this product, containing lactoferrin, dipotassium glycyrrhizinate, carboxymethyl-beta-glucan, and vitamins C and D3 (Saflovir), two sprays per nostril twice daily for 3 months. Other children were randomly treated only with standard therapy. Outcomes included the number of RIs and wheezing episodes, use of medications, and severity of clinical manifestations. RESULTS: Preschoolers treated add-on with this multicomponent product experienced fewer RIs and used fewer beta-2 agonists than untreated children (P = 0.01 and 0.029, respectively). CONCLUSIONS: This preliminary study demonstrated that a multicomponent product, administered add-on as a nasal spray, could reduce the incidence of RIs and use of symptomatic drugs for relieving wheezing in children.

Two-Month Consumption of Orange Juice Enriched with Vitamin D3 and Probiotics Decreases Body Weight, Insulin Resistance, Blood Lipids, and Arterial Blood Pressure in High-Cardiometabolic-Risk Patients on a Westernized Type Diet: Results from a Randomized Clinical Trial.

This study examined the effects of orange juice (OJ) supplemented with vitamin D3 (2000 IU) and probiotics (Lacticaseibacillus casei Shirota and Lacticaseibacillus rhamnosus GG, 108 cfu/mL) on cardiometabolic risk factors in overweight and obese adults following a Westernized-type diet. Fifty-three high-risk individuals were randomly assigned to one of two groups. Over 8 weeks, one group consumed a vitamin D3 and probiotic-enriched OJ and the other regular OJ (control). Diets remained unchanged and were documented through food diaries. Measures of metabolic and inflammatory markers and blood pressure were measured at the start and end of the study. Post-intervention, the enriched OJ group showed the following significant metabolic improvements (without changes in triglycerides, inflammation, or central blood pressure): reduced fasting insulin, peripheral blood pressure, body weight (-1.4 kg 95% CI: -2.4, -0.4), energy (-270 kcal 95% CI: -553.2, -13.7), macronutrient (dietary fat -238 kcal 95% CI: -11.9, -1.0; carbohydrates -155 kcal 95% CI: -282.4, -27.3; sugars -16.1 g 95% CI: -11.9, -1.0) intake, and better lipid profiles (total cholesterol -10.3 mg/dL 95% CI: -21.4, 0.9; LDL-C -7 mg/dL 95% CI: -13.5, -0.5). The enriched OJ led to weight loss, less energy/macronutrient consumption, improved lipid profiles, and increased insulin sensitivity after 8 weeks in those following a Westernized diet, thus indicating potential benefits for cardiometabolic risk. This study was a part of FunJuice-T2EDK-01922, which was funded by the EU Regional Development Fund and Greek National Resources.

Alterations in regulators of the renal-bone axis, inflammation and iron status in older people with early renal impairment and the effect of vitamin D supplementation.

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

Effects of Vitamin D Supplementation on Central Hemodynamic Parameters and Autonomic Nervous System in Obese or Overweight Individuals. / Efeitos da Suplementação de Vitamina D sobre Parâmetros Hemodinâmicos Centrais e Sistema Nervoso Autônomo em Indivíduos com Obesidade ou Sobrepeso.

BACKGROUND: Previous studies have been inconsistent in demonstrating beneficial cardiovascular effects of vitamin D supplementation. OBJECTIVE: To evaluate the effects of vitamin D3 supplementation on central hemodynamic parameters and autonomic activity in obese/overweight individuals with low vitamin D levels (<30ng/dl). METHODS: Adults 40-65 years old with body mass index ≥25<40 kg/m2 were enrolled in this prospective, randomized, double-blind clinical trial (NCT05689632). Central hemodynamics was assessed using the oscillometric method (Mobil-O-Graph®), and heart rate variability using a Polar heart rate monitor (Kubios® software). Patients (n=53) received a placebo in the control group (CO, n=25) or vitamin D3 (VD, n=28) 7000 IU/day, and were evaluated before (W0) and after 8 weeks (W8) with a significance level of 0.05. RESULTS: The groups were homogeneous regarding age (51±6 vs 52±6 years, p=0.509) and vitamin D levels (22.8±4.9 vs 21.7±4.5ng/ml, p=0.590). At W8, the VD group had significantly higher levels of vitamin D (22.5 vs 35.6ng/ml, p<0.001). Only the VD group showed a significant reduction in systolic blood pressure (SBP; 123±15 vs 119±14mmHg, p=0.019) and alkaline phosphatase (213±55 vs 202±55mg/dl, p=0.012). The CO group showed an increase in augmentation pressure (AP: 9 vs 12 mmHg, p=0.028) and augmentation index (AIx: 26 vs 35%, p=0.020), which was not observed in the VD group (AP: 8 vs 8 mmHg, AIx: 26 vs 25%, p>0.05). VD group showed an increase in the parasympathetic nervous system index (PNSi) (-0.64±0.94 vs -0.16±1.10, p=0.028) and the R-R interval (866±138 vs 924±161 ms, p= 0.026). CONCLUSION: In this sample, eight weeks of daily vitamin D supplementation resulted in an improvement in blood pressure levels and autonomic balance.

FUNDAMENTO: Estudos prévios têm sido inconsistentes em demonstrar efeitos cardiovasculares benéficos da suplementação de vitamina D. OBJETIVO: Avaliar efeitos da suplementação de vitamina D3 sobre parâmetros hemodinâmicos centrais e atividade autonômica em indivíduos obesos/sobrepeso e baixos níveis de vitamina D (<30ng/dl). MÉTODOS: Ensaio clínico prospectivo, randomizado, duplo-cego (NCT05689632), adultos 40-65 anos com índice de massa corporal ≥25<40 kg/m2. Hemodinâmica central avaliada por método oscilométrico (Mobil-O-Graph®), variabilidade da frequência cardíaca utilizando frequencímetro Polar (software Kubios®). Os pacientes (n=53) receberam placebo no grupo controle (CO, n=25) ou vitamina D3 (VD, n=28) 7000 UI/dia, avaliados antes (S0) e após 8 semanas (S8) com nível de significância de 0,05. RESULTADOS: Os grupos foram homogêneos na idade (51±6 vs. 52±6 anos, p=0,509) e níveis de vitamina D (22,8±4,9 vs. 21,7±4,5ng/ml, p=0,590). Na S8, o grupo VD apresentou níveis significativamente maiores de vitamina D (22,5 vs. 35,6ng/ml, p<0,001). Apenas o grupo VD mostrou redução significativa da pressão arterial sistólica (PAS; 123±15 vs. 119±14mmHg, p=0,019) e fosfatase alcalina (213±55 vs. 202±55mg/dl, p=0,012). O grupo CO mostrou elevação da pressão de aumento (AP: 9 vs. 12mmHg, p=0,028) e do índice de incremento (Aix: 26 vs. 35%, p=0,020), o que não foi observado no grupo VD (AP: 8 vs. 8mmHg, Aix: 26 vs. 25%, p>0,05). Grupo VD apresentou aumento no índice do sistema nervoso (iSN) parassimpático (-0,64±0,94 vs. -0,16±1,10, p=0,028) e no intervalo R-R (866±138 vs. 924±161ms, p=0,026). CONCLUSÃO: Nesta amostra, a suplementação diária de vitamina D durante oito semanas resultou em melhora dos níveis pressóricos, parâmetros hemodinâmicos centrais e do equilíbrio autonômico.

Monitoring the utilization and effectiveness of Iron and Vitamin D supplementations program and its predictive factors in high schools' girls in Qom, Iran.

Background: Iron and Vitamin D3 deficiency is one of the major global health problems in teenagers and adolescent population. This study was aimed to monitor the utilization and predictive factors of Iron and Vitamin D Supplementations Program (IVDSP) in high schools' girls. Methods: In a cross sectional study, the pattern of Iron and D3 consumption based on IVDSP on 400 high schools' girl in Qom, Iran assesses. Data collection was used by a reliable and standard researcher based questionnaire and daily, weekly, monthly and seasonally consumption of complementary minerals in schools were gathered. Data analysis conducted using SPSS version 20 (SPSS Inc., Chicago, IL, USA) by chi square, independent t-test and multivariate logistic regression. Results: The mean age of subjects was 15.14 ± 1.52 years and ranged from 12 to 18 years old. The total weekly prevalence of D3 and Iron consumption in high schools' girls was calculated 36.73% and the weekly prevalence of Iron and monthly prevalence of Vitamin D3 consumption was 33.75% and 40.5%, respectively. The most common causes of non-consumption were bad taste 49.31%, Iranian made drug 20.27%, drug sensitivity 19.82% and drug interaction 10.60%, respectively. Conclusions: The inadequate and incomplete rate of IVDSP in Qom was high and more than 60% of distributed supplementations have been wasted. Results showed that students who were participated in educational orientation classes were more successful and eager in Iron and Vitamin D3 consumption. Therefore, more educational explanatory interventions for both students and her parents recommended to increase the efficiency of the program.

Effect of Calcium and Vitamin D Supplementation (Dairy vs. Pharmacological) on Bone Health of Underprivileged Indian Children and Youth with Type-1 Diabetes: A Randomized Controlled Trial.

BACKGROUND: Bone health is affected by chronic childhood disorders including type-1 diabetes mellitus (T1DM). We conducted this randomized controlled trial with the objective of investigating the effect of 1-year supplementation of vitamin-D with milk or with pharmacological calcium on bone mass accrual in underprivileged Indian children and youth with T1DM. METHODS: 5 to 23year old (n = 203) underprivileged children and youth with T1DM were allocated to one of three groups: Milk (group A-received 200 ml milk + 1000 international unit (IU) vitamin-D3/day), Calcium supplement (group B-received 500 mg of calcium carbonate + 1000 IU of vitamin-D3/day) or standard of care/control (group C). Anthropometry, clinical details, biochemistry, diet (3-day 24-h recall), physical activity (questionnaires adapted for Indian children) and bone health parameters (using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography- DXA and pQCT respectively) were evaluated at enrolment and end of 12 month intervention. RESULTS: Total body less head(TBLH) bone mineral content (BMC(g)) and bone mineral density (BMD(gm/cm2)) were significantly higher at end of study in girls in both supplemented groups (TBLHBMC-A-1011.8 ±â€¯307.8, B-983.2 ±â€¯352.9, C-792.8 ±â€¯346.8. TBLHBMD-A-± 0.2, B-0.8 ±â€¯0.2, C-0.6 ±â€¯0.2, p < 0.05). Z score of lumbar spine bone mineral apparent density of supplemented participants of both sexes was significantly higher than controls (Boys- A-0.7 ±â€¯1.1, B-0.6 ±â€¯1.4, C- -0.7 ±â€¯1.1; Girls- A-1.1 ±â€¯1.1, B-0.9 ±â€¯3.4, C- -1.7 ±â€¯1.3, p < 0.05). A significantly higher percentage increase was found in cortical thickness in girls in both supplemented groups (A-17.9 ±â€¯28.6, B-15.3 ±â€¯16.5, C-7.6 ±â€¯26.2); the differences remained after adjusting for confounders. CONCLUSION: Supplementation with milk or pharmacological calcium (+vitaminD3) improved bone outcomes-particularly geometry in children with T1DM with more pronounced effect in girls. Pharmacological calcium may be more cost effective in optimising bone health in T1DM in resource limited settings.

High-dose vitamin D3 supplementation in pregnancy and risk of neurodevelopmental disorders in the children at age 10: A randomized clinical trial.

BACKGROUND: Vitamin D deficiency in pregnancy may increase the risk of autism and attention deficit hyperactivity disorder (ADHD). OBJECTIVE: The objective of this study was to estimate the effect of vitamin D3 supplementation in pregnancy on risk of autism and ADHD. DESIGN: This randomized clinical trial was part of the COpenhagen Prospective Study on Neuro-PSYCHiatric Development (COPYCH) project nested within the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) cohort comprising a population-based sample of 700 healthy mother-child pairs enrolled at week 24 of pregnancy. Maternal 25-hydroxy-vitamin D (25(OH)D) was measured at inclusion and 623 mothers were randomized 1:1 to either high-dose (2800 IU/d) or standard dose (400 IU/d) vitamin D3 until 1 wk postpartum (315 received high-dose, 308 standard dose). At age 10, diagnoses and symptom load of autism and ADHD, respectively, were established using the Kiddie-Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. RESULTS: The psychopathologic evaluation was completed by 591 children aged 10 y, and 16 children (2.7%) were diagnosed with autism and 65 (11.0%) with ADHD. Hereof, 496 children participated in the vitamin D3 trial (246 received high-dose, 250 standard dose). Of these, 12 children (2.4%) were diagnosed with autism and 58 (11.7%) with ADHD. Higher maternal preintervention 25(OH)D levels were associated with a decreased risk of autism [odd ratio (OR) per 10 nmol/L: 0.76 (0.59,0.97); P = 0.034], lower autistic symptom load [ß per 10 nmol/L: -0.03 (-0.05,0.00); P = 0.024), and decreased risk of ADHD diagnosis (OR per 10 nmol/L: 0.88 (0.78,0.99); P = 0.033]. High-dose vitamin D3 supplementation was not associated with risk of autism or ADHD. CONCLUSIONS: Higher maternal preintervention 25(OH)D was associated with a decreased risk of autism, lower autistic symptom load, and decreased risk of ADHD diagnosis, but high-dose vitamin D3 supplementation in pregnancy had no effect on risk of autism and ADHD. This trial was registered at clinicaltrials.gov as NCT00856947.

Comparison of the Effect of Daily Vitamin D2 and Vitamin D3 Supplementation on Serum 25-Hydroxyvitamin D Concentration (Total 25(OH)D, 25(OH)D2, and 25(OH)D3) and Importance of Body Mass Index: A Systematic Review and Meta-Analysis.

BACKGROUND: Two previous meta-analyses showed smaller differences between vitamin D3 and vitamin D2 in raising serum 25-hydroxyvitamin D [25(OH)D] and a consistently high heterogeneity when only including daily dosing studies. OBJECTIVE: This study aimed to compare more frequently dosed vitamin D2 and vitamin D3 in improving total 25(OH)D and determine the concomitant effect of response modifiers on heterogeneity, and secondly, to compare the vitamin D2-associated change in 25(OH)D2 with the vitamin D3-associated change in 25(OH)D3. METHODS: PubMed, EMBASE, Cochrane, and the Web of Science Core collection were searched for randomized controlled trials of vitamin D2 compared with vitamin D3, daily or once/twice weekly dosed. After screening for eligibility, relevant data were extracted for meta-analyses to determine the standardized mean difference when different methods of 25(OH)D analyses were used. Otherwise, the weighted mean difference (WMD) was determined. RESULTS: Overall, the results based on 20 comparative studies showed vitamin D3 to be superior to vitamin D2 in raising total 25(OH)D concentrations, but vitamin D2 and vitamin D3 had a similar positive impact on their corresponding 25(OH)D hydroxylated forms. The WMD in change in total 25(OH)D based on 12 daily dosed vitamin D2-vitamin D3 comparisons, analyzed using liquid chromatography-tandem mass spectrometry, was 10.39 nmol/L (40%) lower for the vitamin D2 group compared with the vitamin D3 group (95% confidence interval: -14.62, -6.16; I2 = 64%; P < 00001). Body mass index (BMI) appeared to be the strongest response modifier, reducing heterogeneity to 0% in both subgroups. The vitamin D2- and vitamin D3-induced change in total 25(OH)D lost significance predominantly in subjects with a BMI >25 kg/m2 (P = 0.99). However, information on BMI was only available in 13/17 daily dosed comparisons. CONCLUSIONS: Vitamin D3 leads to a greater increase of 25(OH)D than vitamin D2, even if limited to daily dose studies, but vitamin D2 and vitamin D3 had similar positive impacts on their corresponding 25(OH)D hydroxylated forms. Next to baseline 25(OH)D concentration, BMI should be considered when comparing the effect of daily vitamin D2 and vitamin D3 supplementation on total 25(OH)D concentration. This study was registered in PROSPERO as CRD42021272674.

Combined microneedling with topical vitamin D3 or bimatoprost versus microneedling alone in the treatment of alopecia areata: A comparative randomized trial.

INTRODUCTION: Alopecia areata (AA) is a challenging disease with variable treatment outcomes. Hair follicles express vitamin D receptors. Therefore, vitamin D3 may be promising for AA treatment through immunomodulatory mechanisms. The efficacy of bimatoprost in scalp AA treatment was reported by few studies. OBJECTIVE: To evaluate the efficacy and safety of microneedling (MN) with topical vitamin D3 versus MN with bimatoprost in comparison with MN alone in the treatment of localized AA. PATIENTS AND METHODS: Seventy-five patients with localized AA were divided into three groups. The first group: 25 patients were treated with MN alone. The second group: 25 patients treated with MN combined with topical vitamin D3. The third group: 25 patients treated with MN combined with bimatoprost solution. The response was evaluated clinically and dermoscopically. RESULTS: At the end of the study, all groups showed a statistically significant decrease in the SALT score compared to the baseline. The clinical response (regrowth scale): vitamin D and bimatoprost groups showed a statistically significant higher regrowth scale compared to MN alone group (p-value = 0.000). After treatment, hair regrowth was significantly higher in MN combined with bimatoprost than in MN combined with topical vitamin D3. However, after 3 months of follow-up, there was no statistically significant difference between both groups. Side effects were mild and transient in all groups. CONCLUSION: Topical vitamin D3 and bimatoprost combined with MN are safe and effective therapeutic options for localized AA.

Effect of Vitamin D Supplementation on Bone Mass in Infants With 25-Hydroxyvitamin D Concentrations Less Than 50 nmol/L: A Prespecified Secondary Analysis of a Randomized Clinical Trial.

Importance: The dose of supplemental vitamin D needed in infants born with serum 25-hydroxyvitamin D (25[OH]D) concentrations less than 50 nmol/L (ie, 20 ng/mL) is unclear. Objective: To determine whether a higher dose (1000 IU vs 400 IU per day) is required in infants born with 25(OH)D concentrations less than 50 nmol/L for bone mineral accretion across infancy. Design, Setting, and Participants: In this prespecified secondary analysis of a double-blinded randomized clinical trial, conducted from March 2016 to March 2019 in a single center in Greater Montreal, Quebec, Canada, a consecutive sample of 139 healthy term singletons were recruited from 866 infants screened for vitamin D status at birth. Data were analyzed from June 2021 to November 2022. Interventions: Capillary blood was collected 24 to 36 hours after birth to measure serum total 25(OH)D concentrations. Infants with 25(OH)D concentrations less than 50 nmol/L were randomized to receive either 1000 IU or 400 IU per day of oral vitamin D3 supplementation from age 1 to 12 months. Infants with 25(OH)D concentrations of 50 nmol/L or greater formed a reference group. Main Outcomes and Measures: Measures at age 1, 3, 6, and 12 months were preplanned and included whole-body bone mineral content, lumbar spine bone mineral content, and bone mineral density using dual-energy x-ray absorptiometry, and serum 25(OH)D3 using liquid chromatography tandem mass spectrometry. Results: Of 139 included infants, 81 (58.3%) were male, and the median (IQR) gestational age at birth was 39.6 (38.9-40.6) weeks. A total of 49 infants were included in the 1000 IU per day group, 49 infants in the 400 IU per day group, and 41 in the reference group. Mean (SD) whole-body bone mineral content was not different between trial groups over time (1000 IU per day, 173.09 [2.36] g; 400 IU per day, 165.94 [66.08] g). Similarly, no differences were observed in lumbar spine bone mineral content or density. Mean (SD) serum 25(OH)D3 concentrations were significantly higher in the 1000 IU per day group from age 3 to 12 months (3 months, 115.2 [35.3] nmol/L; 6 months, 121.6 [34.4] nmol/L; 12 months, 99.6 [28.8] nmol/L) compared with the 400 IU per day trial group (3 months, 77.4 [23.3] nmol/L; 6 months, 85.1 [18.6] nmol/L; 12 months, 82.3 [14.3] nmol/L). Conclusions and Relevance: In this study, a higher dose of vitamin D supplementation in infants born with 25(OH)D concentrations less than 50 nmol/L did not present advantages to bone mass in infancy. This study supports a standard dose of 400 IU per day of vitamin D supplementation for breastfed infants in Montreal. Trial Registration: ClinicalTrials.gov Identifier: NCT02563015.

Vitamin D3 Supplementation Promotes Regulatory T-Cells to Maintain Immune Homeostasis After Surgery for Early Stages of Colorectal Cancer.

BACKGROUND/AIM: Vitamin D3 (VD3) affects the regulation of the immune system, including the differentiation and function of regulatory T-cells (Tregs). Tregs play an important role in maintaining immune homeostasis in patients with colorectal cancer (CRC). The effects of VD3 on Treg-associated immune function were investigated in Thai patients in the early stages of CRC. MATERIALS AND METHODS: Twenty-eight patients were randomized to one of two groups: Untreated or treatment with VD3 for 3 months. Whole blood samples were collected at baseline, and at 1 and 3 months. Peripheral blood mononuclear cells were isolated and the populations of forkhead box P3-positive Treg cells was analyzed by flow cytometry. The levels of Treg-associated cytokines, interleukin 10 (IL-10) and transforming growth factor beta 1 (TGF-ß1), were measured by enzyme-linked immunosorbent assays. RESULTS: Serum VD3 levels of the VD3-treated group were significantly increased at 1 (p=0.017) and 3 months (p<0.001) compared to the untreated control group. The mean percentage of Tregs was maintained between 1 and 3 months in the VD3-treated group. At 3 months, the untreated group had significantly lower Treg levels than the VD3-treated group (p=0.043). Serum IL-10 levels of the VD3-treated group were statistically increased at 1 month compared to the control group (p=0.032). No significant difference in serum TGF-ß1 levels was observed between the two groups. However, the TGF-ß1 level in the VD3-treated group at 1 month was lower than that of the control. CONCLUSION: Our findings suggest that VD3 supplementation can maintain immune responses in the early stages of CRC, helping to control Treg function. Therefore, VD3 should be supplemented to maintain immune homeostasis, especially in patients with vitamin D deficiency.

Changes in bone biomarkers in response to different dosing regimens of cholecalciferol supplementation in children with chronic kidney disease.

BACKGROUND: The effect of different dosing regimens of cholecalciferol supplementation on bone biomarkers has not been studied in children with chronic kidney disease (CKD). METHODS: This is a post hoc analysis of a multi-center randomized controlled trial which included children with CKD stages 2-4 with vitamin D deficiency (25-hydroxy vitamin D (25OHD) < 30 ng/ml) randomized 1:1:1 to receive an equivalent dose of oral cholecalciferol as daily, weekly or monthly treatment. Markers of bone formation (bone alkaline phosphatase (BAP), procollagen I N terminal peptide (PINP)), bone resorption (tartarate-resistant acid phosphatase 5b (TRAP), C terminal telopeptide (CTX)), and osteocyte markers (intact fibroblast growth factor 23 (iFGF23), sclerostin) and soluble klotho were measured at baseline and after 3 months of intensive replacement therapy. The change in biomarkers and ratio of markers of bone formation to resorption were compared between treatment arms. BAP and TRAP were expressed as age- and sex-specific z-scores. RESULTS: 25OHD levels increased with cholecalciferol supplementation, with 85% achieving normal levels. There was a significant increase in the BAP/TRAP ratio (p = 0.04), iFGF23 (p = 0.004), and klotho (p = 0.002) with cholecalciferol therapy, but this was comparable across all three therapy arms. The BAPz was significantly higher in the weekly arm (p = 0.01). The change in 25OHD (Δ25OHD) inversely correlated with ΔPTH (r = - 0.4, p < 0.001). CONCLUSIONS: Although cholecalciferol supplementation was associated with a significant increase in bone formation, the three dosing regimens of cholecalciferol supplementation have a comparable effect on the bone biomarker profile, suggesting that they can be used interchangeably to suit the patient's needs and optimize adherence to therapy. A higher resolution version of the Graphical abstract is available as Supplementary information.

Critique of Public Health Guidance for Vitamin D and Sun Exposure in the Context of Cancer and COVID-19.

Official public health pronouncements about sun exposure and vitamin D can be summarized as follows: First, there is no such thing as a safe tan. Therefore, avoid exposing the skin to sunshine. Second, in the absence of sunshine, a daily intake of 800 IU/day (20 mcg/d) vitamin D or less is sufficient for the health needs of almost all members of the population. However, exposure of the skin to sunlight induces multiple mechanisms that lower blood pressure, while also initiating production of vitamin D, which is needed to produce a hormone that regulates multiple systems including the cellular biology that affects cancer mortality. Disease-prevention relationships point to a beneficial threshold for serum 25-hydroxyvitamin D [25(OH)D; the index of vitamin D nutrition] that is at least 75 nmol/l (30 ng/ml). To ensure the threshold for all adults, an average per-day minimum total input of vitamin D3 from sunshine/UVB exposure, and/or from food (natural food like fish or fortified food like milk), and/or vitamin supplementation of at least 4,000 IU/d (100 mcg/d) is required. Strong, although not Level-1, evidence indicates that the maintenance of that threshold will lower mortality overall, lower mortality from cancer, and lower the risk of certain other diseases such as respiratory infection and COVID-19.

Modulation of cardiometabolic risk and CardioRenal syndrome by oral vitamin D3 supplementation in Black and White Southern Sahara residents with chronic kidney disease Stage 3: focus on racial and ethnic disparities.

OBJECTIVES: Several studies have shown that cholecalciferol supplementation (25OHD-S) in chronic kidney disease (CKD) improves kidney injury by reducing fibrosis-related vascular calcification and declining apoptosis-linked nephron damage. METHODS: The oral 25OHD-S was evaluated in 60,000 IU/month/36 weeks versus in 2000 IU/d/24 weeks in CKD Stage 3 with serum 25OHD level < 20 ng/mL. The study was undertaken on 156 black subjects and 150 white subjects Southern Sahara (SS). All biomarkers of cardiometabolic (CMet) and cardiorenal (CRenal) syndrome, Renin-angiotensin-aldosterone system (RAAS) profile, secondary hyperparathyroidism (SHPT), N-terminal pro B-type natriuretic peptide (NT-proBNP), Troponin T (cTnT) and atherogenicity risk were assessed by biochemical methods. Estimate glomerular filtration rate (eGFR) by chronic CKD-EPI equation formula. Total serum vitamin D by liquid chromatography-tandem mass spectrometry (MS). RESULTS: Vitamin D deficiency alters in the same manner CMet, CRenal, and others biomarkers in both groups SS; however, these disorders are more acute in blacks compared to whites SS. Oral 25OHD-S a highlighted improvement of eGFR drop, SHPT decrease, decline proteinuria, and cardiac failure risk (NT-proBNP and cTnT) attenuation. Concomitantly, 25OHD-S normalizes Renin, Aldosterone, and Angiotensin System (RAAS) activity. Nevertheless, homocysteine and Lp (a) do not modulate by 25OHD-S. CONCLUSIONS: The oral vitamin D3 supplementation, according the dose, and the treatment duration does not like in black-skinned people versus to white-skinned inhabitants, while the 02 groups are native to the same Saharan environment. It emerge that a high intermittent dose through an extensive supplementation (60,000 IU/36 weeks) was more effective in black subjects. At opposite, a lower dose during a short period supplementation is sufficient (2000 IU/24 weeks) in white subjects.

Vitamin D supplementation and increased dairy protein intake do not affect muscle strength or physical function in healthy 6-8-year-old children: the D-pro randomized trial.

PURPOSE: To investigate separate and combined effects of vitamin D supplementation during the extended winter and increased dairy protein intake on muscle strength and physical function in children, and furthermore to explore potential sex differences. METHODS: In a 2 × 2-factorial, randomized winter trial, 183 healthy, 6-8-year-old children received blinded tablets with 20 µg/day vitamin D3 or placebo, and substituted 260 g/day dairy with yogurts with high (HP, 10 g protein/100 g) or normal protein content (NP, 3.5 g protein/100 g) for 24 weeks during winter at 55° N. We measured maximal isometric handgrip and leg press strength, and physical function by jump tests and a 30 s sit-to-stand test. Physical activity was measured by 7-day accelerometry. RESULTS: Baseline (mean ± SD) serum 25-hydroxyvitamin D was 80.8 ± 17.2 nmol/L, which increased to 88.7 ± 17.6 nmol/L with vitamin D supplementation and decreased to 48.4 ± 19.2 nmol/L with placebo. Baseline protein intake was 15.5 ± 2.4 E%, which increased to 18.4 ± 3.4 E% with HP and was unchanged with NP. We found no separate or combined effects of vitamin D supplementation and/or increased dairy protein intake on muscle strength or physical function (all P > 0.20). There was an interaction on the sit-to-stand test (Pvitamin×yogurt = 0.02), which however disappeared after adjusting for physical activity (P = 0.16). Further, vitamin D supplementation increased leg press strength relatively more in girls compared to boys (mean [95% CI] 158 [17, 299] N; Pvitamin×sex = 0.047). CONCLUSION: Overall, vitamin D and dairy protein supplementation during the extended winter did not affect muscle strength or physical function in healthy children. Potential sex differences of vitamin D supplementation should be investigated further. REGISTERED AT CLINICALTRIALS.GOV: NCT0395673.

Enhanced in vitro tumoricidal effects of 5-Fluorouracil, thymoquinone, and active vitamin D3 triple therapy against colon cancer cells by attenuating the PI3K/AKT/mTOR pathway.

AIMS: This study measured the effects of 5-Fluorouracil (5-FU), calcitriol (VD3), and/or thymoquinone (TQ) single/dual/triple therapies on cell cycle progression, apoptosis, inhibition of the PI3K/AKT/mTOR pathway, and oxidative stress against colorectal cancer (CRC). MAIN METHODS: The HT29, SW480 and SW620 cell lines were treated with 5-FU (50 µM), VD3 (25 µM), and TQ (75 µM), alone or combined for 12 h, prior to cell cycle/apoptosis analyses. KEY FINDINGS: TQ monotherapy had greater anticancer effects to active VD3 or 5-FU, revealing higher expression of p21/p27/PTEN/BAX/Cyto-C/Casp-3 and increased levels of total glutathione, with inhibitions in CCND1/CCND3/BCL-2 and PI3K/AKT/mTOR molecules, alongside higher rates of apoptosis in HT29, SW480 and SW620 cells (P < 0.005 for all markers). Additionally, all combination protocols revealed enhanced modulations of the PI3K/PTEN/Akt/mTOR pathway, higher expression of p21/p27/PTEN/BAX/Cyto-C/Casp-3, and better anti-oxidant effects, than the monotherapies. Although TQ/5-FU and TQ/VD3 co-therapies were better relative to the VD3/5-FU regimen, the best tumoricidal effects were observed with triple therapy in the HT29 and SW480 cell lines, possibly by boosted attenuations of the PI3K/AKT/mTOR oncogenic pathway. In contrast, TQ single treatment was more effective than the triple therapy regimen in metastatic SW620 cells, suggesting that this protocol would be more useful therapeutically in late-stage CRC. SIGNIFICANCE: In conclusion, this study is the first to demonstrated enhanced anti-tumorigenic effects for VD3, TQ, and 5-FU triple therapy against CRC cells and could represent the best strategy for treating early stages of malignancy, whereas TQ monotherapy could be a better approach for treating metastatic forms of the disease.

Monthly Increase in Vitamin D Levels upon Supplementation with 2000 IU/Day in Healthy Volunteers: Result from "Integriamoci", a Pilot Pharmacokinetic Study.

Vitamin D (VD) is a calcium- and phosphate-controlling hormone used to treat bone disorders; yet, several other effects are progressively emerging. VD deficiency is highly prevalent worldwide, with suboptimal exposure to sunlight listed among the leading causes: oral supplementation with either cholecalciferol or calcitriol is used. However, there is a scarcity of clinical studies investigating how quickly VD concentrations can increase after supplementation. In this pilot study, the commercial supplement ImmuD3 (by Erboristeria Magentina®) was chosen as the source of VD and 2000 IU/day was administered for one month to 21 healthy volunteers that had not taken any other VD supplements in the previous 30 days. Plasma VD levels were measured through liquid chromatography coupled to tandem mass spectrometry after 7, 14, and 28 days of supplementation. We found that 95% of the participants had insufficient VD levels at baseline (<30 ng/mL; median 23.72 ng/mL; IQR 18.10-26.15), but after 28 days of supplementation, this percentage dropped to 62% (median 28.35 ng/mL; IQR 25.78-35.20). The median increase in VD level was 3.09 ng/mL (IQR 1.60-5.68) after 7 days and 8.85 ng/mL (IQR 2.85-13.97F) after 28 days. This study suggests the need for continuing VD supplementation and for measuring target level attainment.

Efficacy and Safety of High-dose Cholecalciferol in Patients With Inflammatory Bowel Disease Receiving Infliximab.

OBJECTIVE: Vitamin D deficiency is prevalent in patients with inflammatory bowel disease (IBD). The goal of this study was to assess the efficacy and safety of high-dose, interval cholecalciferol administration in patients with IBD receiving infliximab. METHODS: This prospective, longitudinal, open-label study enrolled pediatric and young adult patients with IBD and vitamin D deficiency. Subjects received 50,000 IU every 4 to 5 weeks (n = 11) or 100,000 IU every 6 to 8 weeks (n = 32) of oral cholecalciferol for 1 year. Dosing was directly observed and administered in conjunction with infliximab infusions. The primary endpoint was vitamin D sufficiency, defined as a 25-hydroxy-vitamin D (25-OHD) level ≥30 ng/mL. RESULTS: Forty-three participants constituted the primary analysis population. 25-OHD levels reached steady-state after the third dose, and mean increases in 25-OHD levels were 8 vs. 4.5 ng/mL in the 100,000 IU vs. 50,000 IU treatment groups, respectively. Only 43.8% of patients receiving 100,000 IU and 18.2% of patients receiving 50,000 IU achieved sufficiency. There was no difference in the 25-OHD level responsiveness in patients with Crohn disease versus those with ulcerative colitis (P = 0.72). There was no correlation between 25-OHD levels and clinical disease activity in patients with Crohn disease (P = 0.85) or ulcerative colitis (P = 0.24). CONCLUSIONS: Supplementation with cholecalciferol was well-tolerated and direct observation is a promising paradigm for ensuring compliance with therapy. Patients with IBD, however, appear to require high doses of cholecalciferol, with less than half of patients (37% overall) achieving vitamin D sufficiency. Additional studies are necessary to determine the optimal treatment regimens.

Effect of a single high dose of vitamin D3 on cytokines, chemokines, and growth factor in patients with moderate to severe COVID-19.

BACKGROUND: The modulating effect of vitamin D on cytokine concentrations in severe coronavirus disease 2019 (COVID-19) remains unknown. OBJECTIVES: We aimed to investigate the effect of a single high dose of vitamin D3 on cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19. METHODS: This is a post hoc, ancillary, and exploratory analysis from a multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients with moderate to severe COVID-19 were recruited from 2 hospitals in São Paulo, Brazil. Of 240 randomly assigned patients, 200 were assessed in this study and randomly assigned to receive a single oral dose of 200,000 IU vitamin D3 (n = 101) or placebo (n = 99). The primary outcome was hospital length of stay, which has been published in our previous study. The prespecified secondary outcomes were serum concentrations of IL-1ß, IL-6, IL-10, TNF-α, and 25-hydroxyvitamin D. The post hoc exploratory secondary outcomes were IL-4, IL-12p70, IL-17A, IFN-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8, IFN-inducible protein-10 (IP-10), macrophage inflammatory protein-1ß (MIP-1ß), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and leukocyte count. Generalized estimating equations for repeated measures, with Bonferroni's adjustment, were used for testing all outcomes. RESULTS: The study included 200 patients with a mean ± SD age of 55.5 ± 14.3 y and BMI of 32.2 ± 7.1 kg/m2, of which 109 (54.5%) were male. GM-CSF concentrations showed a significant group-by-time interaction effect (P = 0.04), although the between-group difference at postintervention after Bonferroni's adjustment was not significant. No significant effects were observed for the other outcomes. CONCLUSIONS: The findings do not support the use of a single dose of 200,000 IU vitamin D3, compared with placebo, for the improvement of cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19.This trial was registered at clinicaltrials.gov as NCT04449718.

The effects of fish oil plus vitamin D3 intervention on non-alcoholic fatty liver disease: a randomized controlled trial.

PURPOSE: The present study aimed to investigate fish oil plus vitamin D3 (FO + D) supplementation on biomarkers of non-alcoholic fatty liver disease (NAFLD). METHODS: In a 3-month randomized controlled trial, 111 subjects with NAFLD, aged 56.0 ± 15.9 y, were randomized into FO + D group (n = 37), fish oil group (FO, n = 37) or corn oil group (CO, n = 37). The subjects consumed the following capsules (3 g/day), which provided 2.34 g/day of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) + 1680 IU vitamin D3 (FO + D group), or 2.34 g/day of EPA + DHA (FO group), or 1.70 g/d linoleic acid (CO group). RESULTS: Using multivariable-adjusted general linear model, there were significant net reductions in serum alanine aminotransferase (ALT), and triacylglycerol (TAG) and TNF-α levels in the FO + D and FO groups, compared with the control group (P < 0.05). The supplemental FO + D also showed significant reductions in insulin (- 1.58 ± 2.00 mU/L vs. - 0.63 ± 1.55 mU/L, P = 0.050) and IL-1ß (- 6.92 ± 7.29 ng/L vs. 1.06 ± 5.83 ng/L, P < 0.001) in comparison with control group. Although there were no significant differences between FO + D and FO groups regarding biochemical parameters, supplemental FO + D showed decreases in ALT (from 26.2 ± 13.5 U/L to 21.4 ± 9.6 U/L, P = 0.007), aspartate aminotransferase (AST, from 22.5 ± 7.0 U/L to 20.2 ± 4.0 U/L, P = 0.029), HOMA-IR (from 3.69 ± 1.22 to 3.38 ± 1.10, P = 0.047), and TNF-α (from 0.43 ± 0.38 ng/L to 0.25 ± 0.42 ng/L, P < 0.001) levels following the intervention. CONCLUSION: The present study demonstrated that groups supplemented with FO + D and FO had similar beneficial effects on biomarkers of hepatocellular damage and plasma TAG levels in subjects with NAFLD, while in the FO + D group, there were some suggestive additional benefits compared with FO group on insulin levels and inflammation. TRIAL REGISTRATION: ChiCTR1900024866.