Vitamin D supplementation improves fasting insulin levels and HDL cholesterol in infertile men

2021 ◽  
Author(s):  
Rune Holt ◽  
Jørgen Holm Pedersen ◽  
Elsa Dinsdale ◽  
Filip Krag Knop ◽  
Anders Juul ◽  
...  
Keyword(s):  
Vitamin D ◽  
Placebo Group ◽  
Serum Insulin ◽  
Hdl Cholesterol ◽  
Vitamin D Supplementation ◽  
Vitamin D Status ◽  
Fasting Serum ◽  
Cholesterol Levels ◽  
Infertile Men ◽  
Fasting Plasma

Abstract Context Vitamin D has been linked with glucose and lipid metabolism. Men with impaired gonadal function have a higher risk of metabolic syndrome and mortality, and vitamin D status may be a reversible modulator. Objective Determine the effect of daily vitamin D and calcium supplementation for 150 days on glucose and lipid homeostasis in infertile men. Design A single-center, double-blinded, randomized clinical trial (NCT01304927), 307 infertile men were randomized (1:1) to a single dose of 300,000 IU cholecalciferol followed by 1,400 IU cholecalciferol + 500 mg of calcium daily (n=151) or placebo (n=156) for 150 days. Reported metabolic parameters including fasting plasma glucose, HbA1c, fasting serum insulin, homeostatic model assessment of insulin resistance (HOMA-IR), fasting plasma cholesterols and triglyceride were secondary endpoints. The primary endpoint semen quality has previously been reported. Results Men receiving vitamin D supplementation improved their vitamin D status, while vitamin D status was aggravated in the placebo group characterized by higher serum parathyroid hormone (PTH). At end of trial, men receiving vitamin D supplementation had 13% lower fasting serum insulin concentrations compared with the placebo-treated group (65 vs. 74 pmol/L, P = 0.018) and 19% lower HOMA-IR (2.2 vs. 2.7, P = 0.025). Moreover, men in the vitamin D group had higher high-density lipoprotein (HDL) cholesterol levels (1.38 vs. 1.32 mmol/L, P = 0.008) compared with the placebo group. Conclusion High-dose vitamin D supplementation had beneficial effects on glucose homeostasis and HDL cholesterol levels in infertile men.

scholarly journals Serum Testosterone Levels Are Not Modified by Vitamin D Supplementation in Dialysis Patients and Healthy Subjects

Nephron ◽  
2021 ◽  
pp. 1-5
Author(s):  
Christof Ulrich ◽  
Bogusz Trojanowicz ◽  
Roman Fiedler ◽  
Frank Bernhard Kraus ◽  
Gabriele I. Stangl ◽  
...  
Keyword(s):  
Vitamin D ◽  
Placebo Group ◽  
Healthy Subjects ◽  
Serum Testosterone ◽  
Hemodialysis Patients ◽  
Vitamin D Supplementation ◽  
Vitamin D Status ◽  
Healthy Individuals ◽  
Dialysis Patients ◽  
Testosterone Levels

<b><i>Introduction:</i></b> Low serum testosterone is related to increased mortality in male dialysis patients. An association of vitamin D status with serum androgen levels with concordant seasonal variation has been described, but it is undecided whether vitamin D supplementation improves testosterone levels. <b><i>Methods:</i></b> In a randomized, placebo-controlled, and double-blind manner, we investigated the effects of an oral vitamin D supplementation in healthy subjects and hemodialysis patients on testosterone levels. One hundred three healthy individuals received cholecalciferol 800 IE/day (<i>n</i> = 52) or placebo (<i>n</i> = 51) for 12 weeks. Thirty-three hemodialysis patients received cholecalciferol adapted to their serum levels following current guidelines (<i>n</i> = 15) or placebo (<i>n</i> = 18) for 12 weeks. <b><i>Results:</i></b> In healthy individuals, 25(OH)D3 levels rose significantly in the verum group (38.1 ± 13.7 vs. 72.5 ± 15.4 nmol/L, <i>p</i> &#x3c; 0.001), whereas in the placebo group, levels dropped (37.7 ± 14.7 vs. 31.9 ± 13.1, <i>p</i> &#x3c; 0.001). Testosterone levels did not change significantly (verum, males: 20.9 ± 6.6 vs. 20.5 ± 7.9 nmol/L, <i>p</i> = 0.6; verum, females: 0.9 ± 0.5 vs. 0.92 ± 0.5, <i>p</i> = 0.4; placebo, males: 18.5 ± 10.2 vs. 21.8 ± 16.5, <i>p</i> = 0.07, placebo, females: 1.6 ± 4.2 vs. 1.6 ± 4.9, <i>p</i> = 0.6). In dialysis patients, the mean cholecalciferol level was only 32.3 ± 17.8 nmol/L, with only 2% of the values being within the normal range. Cholecalciferol levels normalized in the verum group (29.4 ± 11.2 vs. 87.8 ± 22.3, <i>p</i> &#x3c; 0.001), whereas levels dropped further in the placebo group (33.6 ± 16.6 vs. 24.6 ± 8.0 nmol/L, <i>p</i> &#x3c; 0.001). Testosterone levels did not change significantly (verum, males: 8.0 ± 3.7 vs. 7.8 ± 3.8, <i>p</i> = 0.8; verum, females: 1.3 ± 1.0 vs. 1.2 ± 1.0 nmol/L, <i>p</i> = 0.5; placebo, males: 11.9 ± 5.0 vs. 11.6 ± 4.0 nmol/L, <i>p</i> = 0.6; placebo, females: 0.8 ± 0.5 vs. 0.7 ± 0.4 nmol/L, <i>p</i> = 0.8). <b><i>Conclusion:</i></b> Serum testosterone levels in hemodialysis patients and healthy individuals are independent from vitamin D status and cannot be significantly increased by cholecalciferol supplementation.

scholarly journals Effects of vitamin D supplementation and seasonality on circulating cytokines in adolescents: analysis of data from a feasibility trial in Mongolia

2019 ◽  
Author(s):  
Sergey Yegorov ◽  
Sabri Bromage ◽  
Ninjin Boldbaatar ◽  
Davaasambuu Ganmaa
Keyword(s):  
Vitamin D ◽  
Placebo Group ◽  
Immune Dysfunction ◽  
Vitamin D Supplementation ◽  
Feasibility Trial ◽  
Human Populations ◽  
Vitamin D Status ◽  
Link Type ◽  
Cholecalciferol Supplementation ◽  
Circulating Cytokines

ABSTRACTVitamin D deficiency is prevalent in human populations and has been linked to immune dysfunction. Here we explored the effects of cholecalciferol supplementation on circulating cytokines in severely vitamin D deficient (blood 25(OH)D3 << 30 nmol/L) adolescents aged 12-15 from Mongolia. The study included 28 children receiving 800 IU daily cholecalciferol for 6 months spanning winter and spring, and 30 children receiving placebo during the same period. The levels of 25(OH)D3 were assessed at baseline, three and six months. Twenty-one cytokines were measured in serum at baseline and at six months. The median blood 25(OH)D3 concentration at baseline was 13.7 nmol/L (IQR=10.0-21.7). Supplementation tripled blood 25(OH)D3 levels (p<0.001) and reversed the direction of change for most cytokines (16/21, 86%). Supplementation was associated with elevated interleukin (IL)-6 (p=0.043). The placebo group had reduced MIP-1α (p=0.007) and IL-8 (p=0.034) at six months. These findings suggest that cholecalciferol supplementation and seasonality have a measurable impact on circulating cytokines in adolescents, identifying chemokines as potentially important biomarkers of vitamin D status in this population.ClinicalTrial.org ID:NCT01244204

The Effects of Vitamin D Supplementation on Glucose Metabolism and Lipid Profiles in Patients with Gestational Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

2017 ◽  
Vol 49 (09) ◽  
pp. 647-653 ◽  
Author(s):  
Maryam Akbari ◽  
Mahmood Mosazadeh ◽  
Kamran Lankarani ◽  
Reza Tabrizi ◽  
Mansooreh Samimi ◽  
...  
Keyword(s):  
Systematic Review ◽  
Vitamin D ◽  
Ldl Cholesterol ◽  
Meta Analysis ◽  
Hdl Cholesterol ◽  
Vitamin D Supplementation ◽  
Controlled Trials ◽  
Model Assessment ◽  
Randomized Controlled ◽  
Cholesterol Levels

AbstractThis systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to summarize the effect of vitamin D supplementation on glucose homeostasis parameters and lipid profiles in gestational diabetes (GDM) patients. We conducted an electronic systematic search of MEDLINE, and 4 other research databases from inception to August 2016, in addition to performing hand searches and consulting with experts in the field. The index of heterogeneity between studies was determined using Cochran (Q) and I-squared tests. Given the existing heterogeneity between studies, a fix or random effect model was performed to estimate the standardized mean difference (SMD) for each variable by using inverse variance method and Cohen statistics. Six randomized clinical trials (187 subjects and 184 controls) were included. The results showed that vitamin D supplementation significantly reduced the homeostasis model assessment of insulin resistance (HOMA-IR) [SMD −0.66; 95% confidence interval (CI), −1.14 to −0.18], homeostatic model assessment-B cell function (HOMA-B) (SMD −0.52; 95% CI, −0.79 to −0.25), LDL-cholesterol levels (SMD −0.33; 95% CI, −0.58 to −0.07), and significantly increased quantitative insulin sensitivity check index (QUICKI) (SMD 0.73; 95% CI, 0.26 to 1.20). We found no beneficial effect of vitamin D supplementation on fasting plasma glucose (FPG), insulin, HbA1c, total-, HDL-cholesterol, and triglycerides concentrations. In conclusion, this meta-analysis demonstrated that vitamin D supplementation may lead to an improvement in HOMA-IR, QUICKI, and LDL-cholesterol levels, but did not affect FPG, insulin, HbA1c, triglycerides, total- and HDL-cholesterol levels; however, vitamin D supplementation increased HOMA-B.

Vitamin D Deficiency/Insufficiency and Challenges in Developing Global Vitamin D Fortification and Supplementation Policy in Adults

2012 ◽  
Vol 82 (4) ◽  
pp. 237-259 ◽  
Author(s):  
Moshe Ben-Shoshan
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Search Strategy ◽  
Epidemiologic Studies ◽  
Vitamin D Supplementation ◽  
Vitamin D Status ◽  
Societal Burden ◽  
Time Period ◽  
New Guidelines ◽  
In Cis

This review summarizes studies discussing vitamin D status in adults and reveals that vitamin D deficiency/insufficiency is highly prevalent in adults and that current fortification and supplementation policies are inadequate. Background and aims: Studies suggest a crucial role for adequate vitamin D status in various health conditions including bone metabolism, cancer, cardiovascular diseases, and allergies. However, relatively little is known about poor vitamin D status and unmet needs in adults. This report aims to highlight the contribution of epidemiologic studies (through the identification of health effects and societal burden) to the development of vitamin D fortification and supplementation policies and reveal unmet global challenges in adults. Methods: In order to assess worldwide vitamin D status in adults, the search strategy combined the medical literature database MEDLINE (using PubMed) for the time period between January 1, 1980 and February 28, 2011, using the key words “vitamin D” “deficiency” and “insufficiency”, and included articles in which access to full text was possible and in which healthy adults were assessed according to one of four commonly used vitamin D threshold classifications. Results: This report reveals that vitamin D deficiency occurs in 4.10 % [95 % CI (confidence interval), 3.93 %, 4.27 %] to 55.05 % (54.07 %, 56.03 %) of adults, while insufficiency occurs in 26.07 % (24.82 %, 27.33 %) to 78.50 % (77.85 %, 79.16 %), depending on the classification used. However, lack of overlap in CIs and high value of I2 statistics indicate considerable heterogeneity between studies. Further, certain populations (i. e. dark-skinned individuals, immigrants, and pregnant women) may be at higher risk for poor vitamin D status. Conclusion: Current policies for vitamin D supplementation and fortification are inadequate and new guidelines are required to improve vitamin D status in adults.

scholarly journals Does vitamin D supplementation prevent SARS-CoV-2 infection in military personnel? Review of the evidence

2021 ◽  
pp. bmjmilitary-2020-001686
Author(s):  
Iain T Parsons ◽  
R M Gifford ◽  
M J Stacey ◽  
L E Lamb ◽  
M K O'Shea ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Supplementation ◽  
Vitamin D Status ◽  
Military Studies ◽  
Vitamin D Receptors ◽  
Area Of Interest ◽  
Military Populations ◽  
Tract Infections ◽  
Recruit Training

For most individuals residing in Northwestern Europe, maintaining replete vitamin D status throughout the year is unlikely without vitamin D supplementation and deficiency remains common. Military studies have investigated the association with vitamin D status, and subsequent supplementation, with the risk of stress fractures particularly during recruit training. The expression of nuclear vitamin D receptors and vitamin D metabolic enzymes in immune cells additionally provides a rationale for the potential role of vitamin D in maintaining immune homeostasis. One particular area of interest has been in the prevention of acute respiratory tract infections (ARTIs). The aims of this review were to consider the evidence of vitamin D supplementation in military populations in the prevention of ARTIs, including SARS-CoV-2 infection and consequent COVID-19 illness. The occupational/organisational importance of reducing transmission of SARS-CoV-2, especially where infected young adults may be asymptomatic, presymptomatic or paucisymptomatic, is also discussed.

scholarly journals Bone mineral density at age 7 years does not associate with adherence to vitamin D supplementation guidelines in infancy or vitamin D status in pregnancy and childhood: An Odense Child Cohort study

2021 ◽  
pp. 1-33
Author(s):  
Signe Monrad Nørgaard ◽  
Christine Dalgård ◽  
Malene Søborg Heidemann ◽  
Anders Jørgen Schou ◽  
Henrik Thybo Christesen
Keyword(s):  
Bone Mineral Density ◽  
Vitamin D ◽  
Bone Mineral ◽  
Vitamin D Supplementation ◽  
Vitamin D Status ◽  
Mineral Density ◽  
Mineral Concentration ◽  
High Adherence ◽  
Bone Mineralisation ◽  
In Pregnancy

Abstract Vitamin D supplementation in infancy is recommended to prevent rickets. At the population level, its effects on bone mineralisation are largely unknown. We aimed to explore whether adherence to national vitamin D supplementation guidelines (10 µg/day up to age 2 years), supplementation at ages 5 and 7 years, and serum 25-hydroxyvitamin D (s-25(OH)D) at various time points associated with bone mineral density (BMD) at age 7 years in the Odense Child Cohort, Denmark (n=1,194). High adherence was defined as supplementation with 10 µg vitamin D 6-7 times per week during ≥ 80 % of the observation time. S-25(OH)D was analysed using liquid chromatography-tandem mass spectrometry. Total-body-less-head (TBLH) BMD was measured by dual-energy X-ray absorptiometry. At median age 18.1 months, 53.9 % (n=475/881) reported high adherence. The median s-25(OH)D was 64.7, 78.8, 46.0, and 71.8 nmol/l in early pregnancy, late pregnancy, cord blood, and at 5 years, respectively. The mean (SD) TBLH BMD at median age 7.1 years was 0.613 (0.049) g/cm2 (z-score +0.363 (0.824)). In adjusted analyses, vitamin D supplementation up to 18 months, and at 5 and 7 years, was not associated with TBLH BMD. Similarly, no robust associations were found between TBLH BMD and s-25(OH)D at any time point. No associations were found for TBLH bone mineral concentration or bone area. In this population with relatively high s-25(OH)D concentrations, no consistent associations were found between adherence to vitamin D supplementation recommendations or vitamin D status in pregnancy or childhood, and bone mineralisation at age 7 years.

scholarly journals The Clinical Effect of Oral Vitamin D2 Supplementation on Psoriasis: A Double-Blind, Randomized, Placebo-Controlled Study

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Wareeporn Disphanurat ◽  
Wongsiya Viarasilpa ◽  
Panlop Chakkavittumrong ◽  
Padcha Pongcharoen
Keyword(s):  
Vitamin D ◽  
Placebo Group ◽  
Adverse Events ◽  
Clinical Effect ◽  
Vitamin D Supplementation ◽  
P Value ◽  
Vitamin D2 ◽  
Oral Vitamin ◽  
Pasi Score ◽  
The Mean

Background. There are limited randomized controlled trials of oral vitamin D supplementation in psoriasis, especially in Asia, and the results are inconclusive. Objective. To investigate the clinical effect of oral vitamin D supplementation on psoriasis. Methods. Patients with psoriasis were randomized to receive vitamin D2 60,000 IU or similar-looking placebo pills once every 2 weeks for 6 months. The primary outcome was improvement of the Psoriasis Area and Severity Index (PASI) score at 3 and 6 months after treatment. Serum levels of 25(OH)D, calcium, phosphate, parathyroid hormone, and C-reactive protein and adverse events were monitored. The chi-square test, Fisher’s exact test, Student’s t-test, and Spearman’s correlation analysis were used in statistical analysis. Results. Of 50 subjects screened, 45 were eligible and randomized to the oral vitamin D2 group (n=23) or placebo group (n=22). At enrollment, the mean PASI score was 4.45, and 26.7% of patients had vitamin D deficiency. At 3 months, the oral vitamin D2 group had significantly higher PASI improvement than the placebo group (mean PASI improvement: 1.43 versus [vs.] -0.33, p-value=0.034; mean %PASI improvement: 34.21% vs. -1.85%, p-value=0.039). The mean serum 25(OH)D level was significantly higher in the oral vitamin D group than in the placebo group (27.4 vs. 22.4 ng/mL, p-value=0.029). Serum 25(OH)D concentrations were significantly inversely correlated with PASI scores at the 6-month follow-up. No major adverse event was observed overall. Conclusion. Oral vitamin D2 supplementation in patients with psoriasis increased the serum vitamin D level and significantly improved the treatment outcome without increasing adverse events. Trial Registration. This trial is registered with Thai Clinical Trials Registry TCTR20180613001.

scholarly journals Modifiable factors of vitamin D status among a Brazilian osteoporotic population attended a public outpatient clinic

2014 ◽  
Vol 58 (5) ◽  
pp. 572-582 ◽  
Author(s):  
Marília Brasilio Rodrigues Camargo ◽  
llda Sizue Kunii ◽  
Lilian Fukusima Hayashi ◽  
Patrícia Muszkat ◽  
Catherine Gusman Anelli ◽  
...  
Keyword(s):  
Physical Activity ◽  
Vitamin D ◽  
Dietary Habits ◽  
Vitamin D Supplementation ◽  
Community Dwelling ◽  
Vitamin D Status ◽  
Mineral Density ◽  
Cross Sectional ◽  
Modifiable Factors ◽  
The Mean

Objectives To evaluate the serum 25-hydroxyvitamin D [25(OH)D] concentration in Brazilian osteoporotic patients and the modifiable factors of vitamin D status in this population. Subjects and methods In a cross-sectional study, 363 community-dwelling patients who sought specialized medical care were evaluated between autumn and spring in São Paulo, Brazil. Serum levels of 25(OH)D and parathormone (PTH), biochemical and anthropometric measurements, and bone density scans were obtained. The group was assessed using two questionnaires: one questionnaire covered lifestyle and dietary habits, skin phototype, sun exposure, medical conditions, and levels of vitamin D supplementation (cholecalciferol); the other questionnaire assessed health-related quality-of-life. Logistic regression and a decision tree were used to assess the association between the variables and the adequacy of vitamin D status. Results The mean age of the overall sample was 67.9 ± 8.6 years, and the mean 25(OH)D concentration was 24.8 ng/mL. The prevalence of inadequate vitamin D status was high (73.3%), although 81.5% of the subjects were receiving cholecalciferol (mean dose of 8,169 IU/week). 25(OH)D was positively correlated with femoral neck bone mineral density and negatively correlated with PTH. In the multivariate analysis, the dose of cholecalciferol, engagement in physical activity and the month of the year (September) were associated with improvement in vitamin D status. Conclusions In this osteoporotic population, vitamin D supplementation of 7,000 IU/week is not enough to reach the desired 25(OH)D concentration (≥ 30 ng/mL). Engagement in physical activity and the month of the year are modifiable factors of the vitamin D status in this population.

scholarly journals Effect of vitamin D supplementation on disease activity (SLEDAI) and fatigue in Systemic Lupus Erythematosus patients with hipovitamin D: An Open Clinical Trial

2018 ◽  
Vol 8 (2) ◽  
Author(s):  
Achmad Rifa’i ◽  
Handono Kalim ◽  
Kusworini Kusworini ◽  
Cesarius Singgih Wahono
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Clinical Trial ◽  
Vitamin D ◽  
Placebo Group ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Vitamin D Supplementation ◽  
Control Group ◽  
Systemic Lupus ◽  
Significant Difference

Background : Low level of vitamin D impact the disease activity and the degree of fatigue in SLE patients. This study aims to determine the effect of vitamin D supplementation on disease activity and fatigue condition in Systemic Lupus Erythematosus (SLE) patients with hipovitamin D.Methods: We performed an open clinical trial. Subjects were randomized into two different groups (supplementation or placebo) using simple random sampling. The treatment group got vitamin D3 softgel/ cholecalciferol 1200 IU/day or 30 mg/day, while the control group gotplacebo for 3 months. SLEDAI scores and FSS scores were calculated at pre and posttreatment.Results: There were 20 subjectsfor supplementation group and 19 subjects in the placebo group. From this study, before and after treatment, we found a significant difference of mean level of vitamin D in supplementation group (p=0.000), and no significant difference inpatients with placebo (p=0.427). Moreover, from the SLEDAI score analysis, observed a significant difference bothin the supplemented group (p=0.000) and the placebo group (p=0.006). FSS scores significantly different in the supplemented group (p=0.000). Incorrelation test,there was a negative correlation (r=-0763) between vitamin D level and disease activity (SLEDAI), and both showing stastistical significance between thepre supplementation (p=0.000) and post supplementation (r=-0846; p=0.000). Similarly to theFSS scores, there was a meaningfulnegative correlation (r=-0.931, p=0.000) between the level of vitamin D with FSS scores pre and post supplementation (r=-0.911; p= 0.000). Furthermore, there was a significant correlation between disease activity (SLEDAI) pre supplementation with fatigue condition pre supplementation (r=0.846; p = 0.000) and postsupplementation (r=0.913; p= 0.000).Conclusion: The supplementation of vitamin D 1200 IU per day in patients with SLE improve disease activity and degree of fatigue. Keywords: vitamin D, disease activity, fatigue, SLE

scholarly journals Vitamin D Status and Severe COVID-19 Disease Outcomes in Hospitalized Patients

2021 ◽  
Vol 12 ◽  
pp. 215013272110412
Author(s):  
Jennifer L. Pecina ◽  
Stephen P. Merry ◽  
John G. Park ◽  
Tom D. Thacher
Keyword(s):  
Vitamin D ◽  
Assisted Ventilation ◽  
Vitamin D Supplementation ◽  
Hospitalized Patients ◽  
Vitamin D Status ◽  
Icu Admission ◽  
Hydroxyvitamin D ◽  
Duration Of Hospitalization ◽  
D Values ◽  
Relationship Of

Background: Vitamin D deficiency may increase the risk of severe COVID-19 disease. Objectives: To determine if 25-hydroxyvitamin D [25(OH)D] levels in patients hospitalized for COVID-19 were associated with the clinical outcomes of days on oxygen, duration of hospitalization, ICU admission, need for assisted ventilation, or mortality. Methods: We conducted a retrospective study of 92 patients admitted to the hospital with SARS-CoV-2 infection between April 16, 2020 and October 17, 2020. Multivariable regression was performed to assess the independent relationship of 25(OH)D values on outcomes, adjusting for significant covariates and the hospitalization day the level was tested. Results: About 15 patients (16.3%) had 25(OH)D levels <20 ng/mL. Only 1 patient (3.4%) who had documented vitamin D supplementation prior to admission had 25(OH)D <20 ng/mL. Serum 25(OH)D concentrations were not significantly associated with any of our primary outcomes of days on oxygen, duration of hospitalization, intensive care unit (ICU) admission, need for mechanical ventilation, or mortality in any of the adjusted multivariable models. Adjusting for the hospital day of 25(OH)D sampling did not alter the relationship of 25(OH)D with any outcomes. Conclusion: Vitamin D status was not related to any of the primary outcomes reflecting severity of COVID-19 in hospitalized patients. However, our sample size may have lacked sufficient power to demonstrate a small effect of vitamin D status on these outcomes.

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