Vitamin D Supplements for Prevention of Tuberculosis Infection and Disease.

BACKGROUND: Vitamin D metabolites support innate immune responses to Mycobacterium tuberculosis. Data from phase 3, randomized, controlled trials of vitamin D supplementation to prevent tuberculosis infection are lacking. METHODS: We randomly assigned children who had negative results for M. tuberculosis infection according to the QuantiFERON-TB Gold In-Tube assay (QFT) to receive a weekly oral dose of either 14,000 IU of vitamin D3 or placebo for 3 years. The primary outcome was a positive QFT result at the 3-year follow-up, expressed as a proportion of children. Secondary outcomes included the serum 25-hydroxyvitamin D (25[OH]D) level at the end of the trial and the incidence of tuberculosis disease, acute respiratory infection, and adverse events. RESULTS: A total of 8851 children underwent randomization: 4418 were assigned to the vitamin D group, and 4433 to the placebo group; 95.6% of children had a baseline serum 25(OH)D level of less than 20 ng per milliliter. Among children with a valid QFT result at the end of the trial, the percentage with a positive result was 3.6% (147 of 4074 children) in the vitamin D group and 3.3% (134 of 4043) in the placebo group (adjusted risk ratio, 1.10; 95% confidence interval [CI], 0.87 to 1.38; P = 0.42). The mean 25(OH)D level at the end of the trial was 31.0 ng per milliliter in the vitamin D group and 10.7 ng per milliliter in the placebo group (mean between-group difference, 20.3 ng per milliliter; 95% CI, 19.9 to 20.6). Tuberculosis disease was diagnosed in 21 children in the vitamin D group and in 25 children in the placebo group (adjusted risk ratio, 0.87; 95% CI, 0.49 to 1.55). A total of 29 children in the vitamin D group and 34 in the placebo group were hospitalized for treatment of acute respiratory infection (adjusted risk ratio, 0.86; 95% CI, 0.52 to 1.40). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS: Vitamin D supplementation did not result in a lower risk of tuberculosis infection, tuberculosis disease, or acute respiratory infection than placebo among vitamin D-deficient schoolchildren in Mongolia. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT02276755.).

Vitamin D, respiratory infections, and chronic disease: Review of meta-analyses and randomized clinical trials.

BACKGROUND: Observational studies have suggested associations of vitamin D deficiency (VDD) with respiratory tract infections, impaired bone health, and myriad chronic diseases. OBJECTIVE: To assess potential causal relationships between vitamin D supplementation and a reduced risk of these conditions, a review of the evidence across available meta-analyses of randomized control trials (RCTs) and RCTs was performed. METHOD: PubMed, Embase, Cochrane Library, and Web of Science were searched from their inception to March 2021. We included only RCTs and meta-analyses of RCTs focusing on the association between vitamin D and respiratory disease, bone health, cardiovascular disease (CVD), diabetes mellitus, and cancer. RESULTS: A total of 107 RCTs and 62 meta-analysis of RCTs were included. Although most RCTs did not support benefits of vitamin D supplementation, suggestive evidence for benefit was found in populations at greater risk of VDD and for acute respiratory infections, fractures in institutionalized older adults, type 2 diabetes among patients with prediabetes, and cancer mortality. In contrast, no compelling evidence for benefit was found for other respiratory conditions, fractures in community-dwelling adults, falls, cancer incidence, or CVD. CONCLUSIONS: Current evidence from RCTs and meta-analyses of RCTs is inconsistent regarding the effects of vitamin D supplementation on respiratory infections and chronic diseases. Individuals most likely to benefit are those with baseline VDD or with selected high-risk conditions. Public health initiatives are needed to eliminate VDD globally, and future research will be enhanced by a 'precision prevention' approach to identify those most likely to benefit from vitamin D supplementation.

Prevalence and Determinants of QuantiFERON-Diagnosed Tuberculosis Infection in 9810 Mongolian Schoolchildren.

BACKGROUND: There is controversy regarding the potential influence of vitamin D deficiency, exposure to environmental tobacco smoke, BCG vaccination, season, and body habitus on susceptibility to Mycobacterium tuberculosis (MTB) infection. METHODS: We conducted a cross-sectional analysis to identify determinants of a positive QuantiFERON-TB Gold (QFT) assay result in children aged 6-13 years attending 18 schools in Ulaanbaatar, Mongolia. Data relating to potential risk factors for MTB infection were collected by questionnaire, physical examination, and determination of serum 25-hydroxyvitamin D (25[OH]D) concentrations. Risk ratios (RRs) were calculated with adjustment for potential confounders, and population attributable fractions (PAFs) were calculated for modifiable risk factors identified. RESULTS: Nine hundred forty-six of 9810 (9.6%) participants had a positive QFT result. QFT positivity was independently associated with household exposure to pulmonary tuberculosis (adjusted RR [aRR], 4.75 [95% confidence interval {CI}, 4.13-5.46, P < .001]; PAF, 13.1% [95% CI, 11.1%-15.0%]), vitamin D deficiency (aRR, 1.23 [95% CI, 1.08-1.40], P = .002; PAF, 5.7% [95% CI, 1.9%-9.3%]), exposure to environmental tobacco smoke (1 indoor smoker, aRR, 1.19 [95% CI, 1.04-1.35]; ≥2 indoor smokers, aRR, 1.30 [95% CI, 1.02-1.64]; P for trend = .006; PAF, 7.2% [95% CI, 2.2%-12.0%]), and increasing age (aRR per additional year, 1.14 [95% CI, 1.10-1.19], P < .001). No statistically significant independent association was seen for presence of a BCG scar, season of sampling, or body mass index. CONCLUSIONS: Vitamin D deficiency and exposure to environmental tobacco smoke are potentially modifiable risk factors for MTB infection.

Adjunctive vitamin D in tuberculosis treatment: meta-analysis of individual participant data.

BACKGROUND: Randomised controlled trials of adjunctive vitamin D in pulmonary tuberculosis (TB) treatment have yielded conflicting results. Individual participant data meta-analysis could identify factors explaining this variation. METHODS: We meta-analysed individual participant data from randomised controlled trials of vitamin D in patients receiving antimicrobial therapy for pulmonary TB. Primary outcome was time to sputum culture conversion. Secondary outcomes were time to sputum smear conversion, mean 8-week weight and incidence of adverse events. Pre-specified subgroup analyses were done according to baseline vitamin D status, age, sex, drug susceptibility, HIV status, extent of disease and vitamin D receptor genotype. RESULTS: Individual participant data were obtained for 1850 participants in eight studies. Vitamin D did not influence time to sputum culture conversion overall (adjusted HR 1.06, 95% CI 0.91-1.23), but it did accelerate sputum culture conversion in participants with multidrug-resistant pulmonary TB (adjusted HR 13.44, 95% CI 2.96-60.90); no such effect was seen in those whose isolate was sensitive to rifampicin and/or isoniazid (adjusted HR 1.02, 95% CI 0.88-1.19; p-value for interaction=0.02). Vitamin D accelerated sputum smear conversion overall (adjusted HR 1.15, 95% CI 1.01-1.31), but did not influence other secondary outcomes. CONCLUSIONS: Vitamin D did not influence time to sputum culture conversion overall, but it accelerated sputum culture conversion in patients with multidrug-resistant pulmonary TB.

Risk factors for active tuberculosis in 938 QuantiFERON-positive schoolchildren in Mongolia: a community-based cross-sectional study.

BACKGROUND: There is controversy regarding the relative influence of 'exogenous' versus 'endogenous' factors on the risk of progression from latent tuberculosis infection to active tuberculosis (TB) disease in children. METHODS: We conducted a cross-sectional analysis to identify risk factors for active tuberculosis in QuantiFERON®-TB Gold (QFT-G)-positive children aged 6-13 years attending 18 schools in Ulaanbaatar, Mongolia. Children underwent clinical and radiological screening for active tuberculosis, and data relating to potential risk factors for disease progression were collected by questionnaire and determination of serum 25-hydroxyvitamin D (25[OH]D) concentrations. Risk ratios were calculated using generalized estimating equations with adjustment for potential confounders. RESULTS: 129/938 (13.8%) QFT-positive children were diagnosed with active tuberculosis. Risk of active tuberculosis was independently associated with household exposure to pulmonary TB (adjusted risk ratio [aRR] 2.40, 95% CI 1.74 to 3.30, P < 0.001), month of sampling (adjusted risk ratio [aRR] for March-May vs. June-November 3.31, 95% CI 1.63 to 6.74, P < 0.001; aRR for December-February vs. June-November 2.53, 95% CI 1.23 to 5.19, P = 0.01) and active smoking by the child (aRR 5.23, 95% CI 2.70 to 10.12, P < 0.001). No statistically significant independent association was seen for age, sex, socio-economic factors, presence of a Bacillus Calmette-Guérin (BCG) scar, tobacco exposure or vitamin D status. CONCLUSIONS: Household exposure to active TB, winter or spring season and active smoking were independently associated with risk of active tuberculosis in QFT-positive children. Our findings highlight the potentially high yield of screening child household contacts of infectious index cases for active tuberculosis in low- and middle-income countries.

High-Dose Vitamin D3 during Tuberculosis Treatment in Mongolia. A Randomized Controlled Trial.

RATIONALE: Existing trials of adjunctive vitamin D in the treatment of pulmonary tuberculosis (PTB) are variously limited by small sample sizes, inadequate dosing regimens, and high baseline vitamin D status among participants. Comprehensive analyses of the effects of genetic variation in the vitamin D pathway on response to vitamin D supplementation are lacking. OBJECTIVES: To determine the effect of high-dose vitamin D3 on response to antimicrobial therapy for PTB and to evaluate the influence of single-nucleotide polymorphisms (SNPs) in vitamin D pathway genes on response to adjunctive vitamin D3. METHODS: We conducted a clinical trial in 390 adults with PTB in Ulaanbaatar, Mongolia, who were randomized to receive four biweekly doses of 3.5 mg (140,000 IU) vitamin D3 (n = 190) or placebo (n = 200) during intensive-phase antituberculosis treatment. MEASUREMENTS AND MAIN RESULTS: The intervention elevated 8-week serum 25-hydroxyvitamin D concentrations (154.5 nmol/L vs. 15.2 nmol/L in active vs. placebo arms, respectively; 95% confidence interval for difference, 125.9-154.7 nmol/L; P < 0.001) but did not influence time to sputum culture conversion overall (adjusted hazard ratio, 1.09; 95% confidence interval, 0.86-1.36; P = 0.48). Adjunctive vitamin D3 accelerated sputum culture conversion in patients with one or more minor alleles for SNPs in genes encoding the vitamin D receptor (rs4334089, rs11568820) and 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1: rs4646536) (adjusted hazard ratio ≥ 1.47; P for interaction ≤ 0.02). CONCLUSIONS: Vitamin D3 did not influence time to sputum culture conversion in the study population overall. Effects of the intervention were modified by SNPs in VDR and CYP27B1. Clinical trial registered with www.clinicaltrials.gov (NCT01657656).

Vitamin D supplements for fracture prevention in schoolchildren in Mongolia: analysis of secondary outcomes from a multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Vitamin D supplementation has been shown to increase total hip areal bone mineral density in healthy children and adolescents. We aimed to investigate whether supplementing schoolchildren living in Mongolia with weekly vitamin D3 for 3 years affected fracture risk. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled trial across 18 public schools in Ulaanbaatar, Mongolia. Schoolchildren were eligible if they were aged 6-13 years at screening, had a negative QuantiFERON-TB Gold In-tube assay (QFT) result, were not hypersensitive to vitamin D or immunocompromised, did not use vitamin D supplements, did not have clinical signs of rickets, and had no intention of leaving Ulaanbaatar within 3 years. Participants were randomly assigned (1:1) to receive either vitamin D (oral dose of 14 000 international units [IU] vitamin D3, once per week) or placebo for 3 years using permuted block randomisation stratified by school of attendance. Participants, care providers, and all trial staff were masked to group assignment during the intervention. Prespecified secondary outcomes were incidence of fractures and adverse events, ascertained using questionnaires. The fracture and safety analyses included participants who completed at least one follow-up fracture questionnaire. We estimated adjusted risk ratios (RRs) and 95% CIs using generalised linear models with binomial distribution and a log link function with adjustment for school of attendance. The trial is registered with ClinicalTrials.gov, NCT02276755, and the intervention ended in May, 2019. FINDINGS: Between Sept 2, 2015, and March 20, 2017, 11 475 children were invited to participate in the study and 8851 were recruited and randomly assigned to receive either vitamin D (n=4418) or placebo (n=4433). 8348 participants were included in the fracture and safety analyses (4176 [94·5%] in the vitamin D group and 4172 [94·1%] in the placebo group). Of these, 4125 (49·4%) were female, 4223 (50·6%) were male, and 7701 (92·2%) were of Khalkh ancestry. Median age was 9·2 years (IQR 8·0-10·7) and 7975 (95·5%) participants had baseline serum 25-hydroxyvitamin D concentrations less than 50 nmol/L. During a median follow-up of 3·0 years (IQR 2·9-3·1), 268 (6·4%) participants in the vitamin D group and 253 (6·1%) in the placebo group reported one or more fractures (adjusted RR 1·10, 95% CI 0·93-1·29; p=0·27). Incidence of adverse events did not differ between study groups. INTERPRETATION: Oral vitamin D supplementation at a dose of 14 000 IU/week for 3 years was safe, but did not influence fracture risk in schoolchildren living in Mongolia who had a high baseline prevalence of vitamin D deficiency. FUNDING: US National Institutes of Health.

Influence of vitamin D supplementation on muscle strength and exercise capacity in Mongolian schoolchildren: a randomised controlled trial.

Objective: To determine whether weekly oral vitamin D supplementation influences grip strength, explosive leg power, cardiorespiratory fitness or spirometric lung volumes in Mongolian schoolchildren. Methods: Multicentre, randomised, double-blind, placebo-controlled clinical trial conducted in children aged 6-13 years at baseline attending 18 schools in Ulaanbaatar. The intervention was weekly oral doses of 14,000 IU vitamin D3 (n=4418) or placebo (n=4433) for 3 years. Outcome measures were grip strength, standing long jump distance and serum 25-hydroxyvitamin D (25[OH]D) concentrations (determined in all participants), peak oxygen uptake (VO2peak, determined in a subset of 632 participants using 20-metre multi-stage shuttle run tests) and spirometric outcomes (determined in a subset of 1,343 participants). Results: 99.8% of participants had serum 25(OH)D concentrations <75 nmol/L at baseline, and mean end-study 25(OH)D concentrations in children randomised to vitamin D vs. placebo were 77.4 vs. 26.7 nmol/L (mean difference 50.7 nmol/L, 95% CI, 49.7 to 51.4). However, vitamin D supplementation did not influence mean grip strength, standing long jump distance, VO2peak, spirometric lung volumes or peak expiratory flow rate, either overall or within sub-groups defined by sex, baseline 25(OH)D concentration <25 vs. ≥25 nmol/L or calcium intake <500 vs. ≥500 mg/day. Conclusion: A 3-year course of weekly oral supplementation with 14,000 IU vitamin D3 elevated serum 25(OH)D concentrations in Mongolian schoolchildren with a high baseline prevalence of vitamin D deficiency. However, this intervention did not influence grip strength, explosive leg power, peak oxygen uptake or spirometric lung volumes, either overall or in sub-group analyses.

Maternal vitamin D intakes during pregnancy and child health outcome.

We conducted a follow up of the children in Mongolia whose mothers received one of the three doses of vitamin D (600, 2000, or 4000 IU daily) during pregnancy as part of the randomized, double-blind, clinical trial of vitamin D supplementation to determine their impact on child health to two years. In the parental trial, 119 pregnant women were assigned to 600 IU/day, 121 were assigned 2000 IU/day, and 120 were assigned 4000 IU/day starting at 12-16 weeks' gestation and continuing throughout pregnancy. At baseline, maternal serum 25(OH)D concentrations were similar across arms; 91 % were 50 nmol/l. As expected, there was a dose-response association between the amount of vitamin D consumed (600, 2000, or 4000 IU daily) and maternal 25(OH)D levels at the end of the intervention. Total 311 children of 311 mothers were followed for 2 years to evaluate health outcomes. We determined the child's health outcomes (rickets, respiratory disease [pneumonia, asthma], and diarrhea/vomiting) using a questionnaire and physical examination (3, 6, and 24 months of age). Low levels of mothers' serum 25(OH)D during pregnancy increased the risk of developing rickets, respiratory illness, and other diseases in children during the early childhood period. Rickets was diagnosed in 15.6 % of children of women who received 600 IU of vitamin D during pregnancy, which was higher than in other vitamin D groups. Children in the group whose mothers received low doses of vitamin D (600 IU/day) had a greater probability of developing respiratory diseases compared to the other groups: pneumonia was diagnosed in n = 36 (35.0 %) which was significantly higher than the group receiving vitamin D 4000 IU/day (n = 34 (31.5 %) p = 0.048). In the group whose pregnant mother consumed 600 IU/day of vitamin D, the risk of child pneumonia was ∼ 2 times higher than in the group who consumed 4000 IU/day (OR=1.99, 95 % CI: 1.01-3.90). The incidence of diarrhea and vomiting in children was 12.1 % lower in the 2000 IU/day group and 13.1 % lower in the 4000 IU/day group compared with the 600 IU/day group (p = 0.051). The offspring of pregnant women who regularly used vitamin D at doses above 600 IU/day had lower respiratory disease, rickets, and diarrheal risks at 2 years.

Influence of Vitamin D Supplementation on Growth, Body Composition, and Pubertal Development Among School-aged Children in an Area With a High Prevalence of Vitamin D Deficiency: A Randomized Clinical Trial.

Importance: Vitamin D deficiency (defined as 25-hydroxyvitamin D [25(OH)D] <20 ng/mL) is prevalent among children living in temperate climates and has been reported to associate independently with stunting, obesity, and early activation of the hypothalamic-pituitary-gonadal axis. Phase 3 randomized clinical trials to investigate the influence of long-term vitamin D replacement on growth, body composition, and pubertal development of school-aged children with vitamin D deficiency are lacking. Objective: To determine whether weekly oral vitamin D supplementation influences linear growth, body composition, or pubertal development in school-aged children living in a setting where vitamin D deficiency is highly prevalent. Design, Setting, and Participants: This secondary analysis of a double-blind, placebo-controlled randomized clinical trial was conducted from June 2016 to June 2019 at 18 grade schools in Ulaanbaatar, Mongolia. School-aged children (6 to 13 years at baseline) attending participating schools were included. Exclusion criteria included a positive QuantiFERON-TB Gold in-tube assay result, conditions or medications associated with altered vitamin D metabolism, use of vitamin D supplements, signs of rickets, or intention to move from Ulaanbaatar within 4 years. Of 11 475 children invited to participate in the study, 9814 underwent QFT testing, and 8851 with negative results were included in the study. All but 1 participant in the placebo group completed follow-up and were included in the present analysis. Data were analyzed from November 2021 to February 2022. Interventions: Weekly oral doses of vitamin D3, 14 000 IU, (n = 4418), or placebo (n = 4433) for 3 years. Main Outcomes and Measures: Mean z scores for height for age, body mass index for age, and waist-to-height ratio; mean percentage body fat, fat mass, and fat-free mass; and mean Tanner scores for pubertal development. Results: Of 8851 participants, 4366 (49.3%) were female, and 8165 (92.2%) were of Khalkh ethnicity; the mean (SD) age was 9.4 (1.6) years. A total of 8453 participants (95.5%) were vitamin D deficient at baseline, and mean end-of-study 25(OH)D concentrations among participants randomized to vitamin D vs placebo were 31.0 vs 10.7 ng/mL (mean difference, 20.3; 95% CI; 19.9-20.6). However, vitamin D supplementation did not influence mean height for age, body mass index for age, waist-to-height ratio, percentage body fat, fat mass, fat-free mass, or Tanner scores, either overall or within subgroups defined by baseline 25(OH)D concentration less than 10 ng/mL vs 10 ng/mL or greater, estimated calcium intake less than 500 mg/d vs 500 mg/d or greater, or male vs female sex. Conclusions and Relevance: In school-aged children in this study with low baseline vitamin D status, oral vitamin D3 supplementation at a dose of 14 000 IU per week for 3 years was effective in elevating 25(OH)D concentrations but did not influence growth, body composition, or pubertal development. Trial Registration: ClinicalTrials.gov Identifier: NCT02276755.

Latent TB Infection, Vitamin D Status and COVID-19 Severity in Mongolian Patients.

We aimed to determine potential risk factors for COVID-19 severity including serum vitamin D levels and latent TB infection among Mongolian inpatients diagnosed with COVID-19, and to study the effects of disease complications and treatment outcomes. This study included patients admitted to the Mongolian National Center for Communicable Disease, a main referral center for infectious disease in Mongolia, with COVID-19 ascertained by a positive PCR test. Patients' demographic, clinical, and laboratory data were analyzed. Of the 270 patients enrolled, 125 (46%) had mild-to-moderate illness, 86 (32%) had severe illness, and 59 (22%) had critical illness. Ten (91%) of the 11 patients who had active TB were hospitalized with severe or critical COVID-19, suggesting that they had a higher risk of falling into the severe category (OR = 10.6 [1.2; 92.0] 95% CI). Severe vitamin D deficiency (25(OH)D < 10 ng/mL) was present in 32% of the patients, but was not significantly associated with the severity of illness (p = 0.65). Older age, being male, having active TB and/or COPD were associated with greater COVID-19 severity, whereas a history of COVID-19 vaccination and the presence of a BCG vaccination scar were protective in terms of disease severity.

Influence of vitamin D supplementation on fracture risk, bone mineral density and bone biochemistry in Mongolian schoolchildren: multicenter double-blind randomized placebo-controlled trial.

Background: Randomized controlled trials (RCT) of vitamin D supplementation to reduce fracture risk in children are lacking. Methods: We conducted a Phase 3 RCT of weekly oral supplementation with 14,000 IU vitamin D3 for 3 years in Mongolian schoolchildren aged 6-13 years. Serum 25-hydroxyvitamin D (25[OH]D) concentrations and the proportion of participants reporting ≥1 fracture were secondary outcomes for the main trial. Radial bone mineral density (BMD) was assessed in a nested sub-study, with serum concentrations of parathyroid hormone (PTH) and bone-specific alkaline phosphatase (BALP) determined in a subset of participants. Findings: 8851 children were enrolled in the main trial, of whom 1465 also participated in the sub-study. Vitamin D deficiency was prevalent at baseline (25[OH]D <20 ng/mL in 90.1%). The intervention elevated 25(OH)D concentrations (adjusted inter-arm mean difference [aMD] 20.3 ng/mL, 95% CI 19.9 to 20.6) and suppressed PTH concentrations (aMD -13.6 pmol/L, 95% CI -23.5 to -3.7), but it did not influence fracture risk (adjusted risk ratio 1.10, 95% CI 0.93 to 1.29, P=0.27) or radial BMD z-score (aMD -0.06, 95% CI -0.18 to 0.07, P=0.36). Vitamin D suppressed serum BALP concentrations more among participants with baseline 25(OH)D concentrations <10 vs. ≥10 ng/mL (Pinteraction=0.04). However, effects of the intervention on fracture risk and radial BMD were not modified by baseline vitamin D status (Pinteraction≥0.67). Interpretation: Weekly oral vitamin D supplementation elevated serum 25(OH)D concentrations and suppressed PTH concentrations in vitamin D-deficient schoolchildren in Mongolia. However, this was not associated with reduced fracture risk or increased radial BMD. Funding: National Institutes of Health.

Milk, dairy intake and risk of endometrial cancer: a 26-year follow-up.

Estrogens have a central role in the etiology of endometrial cancer. Milk and dairy products are a source of steroid hormones and growth factors that might have physiological effects in humans. We hypothesized that high intakes of milk and dairy products are associated with an increased risk of endometrial cancer, particularly among postmenopausal women not using hormone therapy. This was a prospective cohort study with 68,019 female participants in the Nurses' Health Study aged 34-59 in 1980. Milk and dairy consumption were assessed in 1980, 1984, 1986, 1990, 1994, 1998 and 2002 as servings per day and the follow-up continued through 2006. The multivariate relative risks (RRs) of adenocarcinoma of the endometrium across categories of cumulatively averaged total dairy consumption compared with < 1 svg/day were: 0.94 (95% CI = 0.71-1.25) for 1-1.4 svg/day, 1.14 (0.87-1.49) for 1.5-1.9 svg/day, 1.10 (0.84-1.44) for 2-2.9 svg/day, 1.26 (0.94-1.70) for ≥ 3 svg/day (p for trend = 0.06). The association between total dairy intake and endometrial cancer was significant only among the postmenopausal women (for ≥ 3 svg/day RR = 1.41, 95% CI = 1.01-1.98, p for trend = 0.02) and was evident only among those who were not currently using hormone therapy (RR = 1.58, 95% CI = 1.05-2.36, p for trend = 0.003). Total dairy intake was not significantly associated with risk of preinvasive endometrial cancer. In conclusion, we observed a marginally significant overall association between dairy intake and endometrial cancer and a stronger association among postmenopausal women who were not using estrogen-containing hormones.

Changes in Vascular Function from Preconception to Postpartum Among Mongolian Women.

Background: Pregnancy is associated with physiological changes to meet the metabolic demands of the growing fetus. To understand adverse pregnancy outcomes it is important to establish vascular changes throughout pregnancy. We examined longitudinal changes in vascular measurements from prepregnancy through postpartum. Materials and Methods: Seventy women planning to conceive in Ulaanbaatar, Mongolia enrolled in this prospective study. Within 6 months, 44 (63%) had conceived; of which 36 (82%) delivered. Ten (28%) developed complex pregnancies and were analyzed separately. Vascular measures included central systolic blood pressure (cSBP), central diastolic blood pressure (cDBP), augmentation index corrected for heart rate of 75 beats/minute (AIx-75), and pulse wave velocity (PWV). Measurements were performed at prepregnancy, second trimester (22-24 weeks), third trimester (34-36 weeks), and 2 months postpartum. Missing values (n = 0-6 per time period) were replaced by multiple imputation. A repeated measures analysis of variance analyzed changes within individual women over the four time points adjusted for age, parity, and body mass index. Results: We observed significant reductions from prepregnancy to second trimester for mean Alx-75 (17.1%-12.6%; p = 0.006) and cSBP (91.7-86.8 mmHg; p = 0.03) but not for cDBP or PWV. Both mean AIx-75 and cSBP increased in third trimester. In the postpartum, cSBP returned to prepregnancy levels, whereas AIx-75 exceeded prepregnancy levels, although this fell short of significance (p = 0.09). Similar vascular patterns were observed in women with complex pregnancies for AIx-75; however, PWV increased from the second trimester and remained higher through postpartum, although not significant. Conclusion: In Mongolian women, we observed a decrease in AIx-75 and cSBP from prepregnancy through second trimester, which resolved postpartum. These results provide an understanding of changes across pregnancies in an Asian country. Future studies should assess vascular changes across pregnancies to determine if it can predict conditions such as pre-eclampsia.

Assessing the quality of tuberculosis care using routine surveillance data: a process evaluation employing the Zero TB Indicator Framework in Mongolia.

OBJECTIVES: To evaluate the feasibility of the Zero TB Indicator Framework as a tool for assessing the quality of tuberculosis (TB) case-finding, treatment and prevention services in Mongolia. SETTING: Primary health centres, TB dispensaries, and surrounding communities in four districts of Mongolia. DESIGN: Three retrospective cross-sectional cohort studies, and two longitudinal studies each individually nested in one of the cohort studies. PARTICIPANTS: 15 947 community members from high TB-risk populations; 8518 patients screened for TB in primary health centres and referred to dispensaries; 857 patients with index TB and 2352 household contacts. PRIMARY AND SECONDARY OUTCOME MEASURES: 14 indicators of the quality of TB care defined by the Zero TB Indicator Framework and organised into three care cascades, evaluating community-based active case-finding, passive case-finding in health facilities and TB screening and prevention among close contacts; individual and health-system predictors of these indicators. RESULTS: The cumulative proportions of participants receiving guideline-adherent care varied widely, from 96% for community-based active case-finding, to 79% for TB preventive therapy among household contacts, to only 67% for passive case-finding in primary health centres and TB dispensaries (range: 29%-80% across districts). The odds of patients completing active TB treatment decreased substantially with increasing age (aOR: 0.76 per decade, 95% CI: 0.71 to 0.83, p<0.001) and among men (aOR: 0.56, 95% CI: 0.36 to 0.88, p=0.013). Contacts of older index patients also had lower odds of initiating and completing of TB preventive therapy (aOR: 0.60 per decade, 95% CI: 0.38 to 0.93, p=0.022). CONCLUSIONS: The Zero TB Framework provided a feasible and adaptable approach for using routine surveillance data to evaluate the quality of TB care and identify associated individual and health system factors. Future research should evaluate strategies for collecting process indicators more efficiently; gather qualitative data on explanations for low-quality care; and deploy quality improvement interventions.

Prevalence and Determinants of Vitamin D Deficiency in 9595 Mongolian Schoolchildren: A Cross-Sectional Study.

Population-based data relating to vitamin D status of children in Northeast Asia are lacking. We conducted a cross-sectional study to determine the prevalence and determinants of vitamin D deficiency in 9595 schoolchildren aged 6-13 years in Ulaanbaatar (UB), the capital city of Mongolia. Risk factors for vitamin D deficiency were collected by questionnaire, and serum 25-hydroxyvitamin D (25[OH]D) concentrations were measured using an enzyme-linked fluorescent assay, standardized and categorized as deficient (25[OH]D <10 ng/mL) or not. Odds ratios for associations between independent variables and risk of vitamin D deficiency were calculated using multivariate analysis with adjustment for potential confounders. The prevalence of vitamins D deficiency was 40.6% (95% CI 39.7% to 41.6%). It was independently associated with female gender (adjusted odds ratio [aOR] for girls vs. boys 1.23, 95% CI 1.11-1.35), month of sampling (aORs for December-February vs. June-November 5.28 [4.53-6.15], March-May vs. June-November 14.85 [12.46-17.74]), lower levels of parental education (P for trend <0.001), lower frequency of egg consumption (P for trend <0.001), active tuberculosis (aOR 1.40 [1.03-1.94]), household smoking (aOR 1.13 [1.02 to1.25]), and shorter time outdoors (P for trend <0.001). We report a very high prevalence of vitamin D deficiency among Mongolian schoolchildren, which requires addressing as a public health priority.

The vitamin D for COVID-19 (VIVID) trial: A pragmatic cluster-randomized design.

OBJECTIVES: To determine the effect of vitamin D supplementation on disease progression and post-exposure prophylaxis for COVID-19 infection. We hypothesize that high-dose vitamin D3 supplementation will reduce risk of hospitalization/death among those with recently diagnosed COVID-19 infection and will reduce risk of COVID-19 infection among their close household contacts. METHODS: We report the rationale and design of a planned pragmatic, cluster randomized, double-blinded trial (N = 2700 in total nationwide), with 1500 newly diagnosed individuals with COVID-19 infection, together with up to one close household contact each (~1200 contacts), randomized to either vitamin D3 (loading dose, then 3200 IU/day) or placebo in a 1:1 ratio and a household cluster design. The study duration is 4 weeks. The primary outcome for newly diagnosed individuals is the occurrence of hospitalization and/or mortality. Key secondary outcomes include symptom severity scores among cases and changes in the infection (seroconversion) status for their close household contacts. Changes in vitamin D 25(OH)D levels will be assessed and their relation to study outcomes will be explored. CONCLUSIONS: The proposed pragmatic trial will allow parallel testing of vitamin D3 supplementation for early treatment and post-exposure prophylaxis of COVID-19. The household cluster design provides a cost-efficient approach to testing an intervention for reducing rates of hospitalization and/or mortality in newly diagnosed cases and preventing infection among their close household contacts.

Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials.

BACKGROUND: A 2017 meta-analysis of data from 25 randomised controlled trials (RCTs) of vitamin D supplementation for the prevention of acute respiratory infections (ARIs) revealed a protective effect of this intervention. We aimed to examine the link between vitamin D supplementation and prevention of ARIs in an updated meta-analysis. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov registry for studies listed from database inception to May 1, 2020. Double-blind RCTs of vitamin D3, vitamin D2, or 25-hydroxyvitamin D (25[OH]D) supplementation for any duration, with a placebo or low-dose vitamin D control, were eligible if they had been approved by a research ethics committee, and if ARI incidence was collected prospectively and prespecified as an efficacy outcome. Studies reporting results of long-term follow-up of primary RCTs were excluded. Aggregated study-level data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. Using the proportion of participants in each trial who had one or more ARIs, we did a random-effects meta-analysis to obtain pooled odds ratios (ORs) and 95% CIs to estimate the effect of vitamin D supplementation on the risk of having one or more ARIs (primary outcome) compared with placebo. Subgroup analyses were done to estimate whether the effects of vitamin D supplementation on the risk of ARI varied according to baseline 25(OH)D concentration (<25 nmol/L vs 25·0-49·9 nmol/L vs 50·0-74·9 nmol/L vs >75·0 nmol/L), vitamin D dose (daily equivalent of <400 international units [IU] vs 400-1000 IU vs 1001-2000 IU vs >2000 IU), dosing frequency (daily vs weekly vs once per month to once every 3 months), trial duration (≤12 months vs >12 months), age at enrolment (<1·00 years vs 1·00-15·99 years vs 16·00-64·99 years vs ≥65·00 years), and presence versus absence of airway disease (ie, asthma only, COPD only, or unrestricted). Risk of bias was assessed with the Cochrane Collaboration Risk of Bias Tool. The study was registered with PROSPERO, CRD42020190633. FINDINGS: We identified 1528 articles, of which 46 RCTs (75 541 participants) were eligible. Data for the primary outcome were obtained for 48 488 (98·1%) of 49 419 participants (aged 0-95 years) in 43 studies. A significantly lower proportion of participants in the vitamin D supplementation group had one or more ARIs (14 332 [61·3%] of 23 364 participants) than in the placebo group (14 217 [62·3%] of 22 802 participants), with an OR of 0·92 (95% CI 0·86-0·99; 37 studies; I2=35·6%, pheterogeneity=0·018). No significant effect of vitamin D supplementation on the risk of having one or more ARIs was observed for any of the subgroups defined by baseline 25(OH)D concentration. However, protective effects of supplementation were observed in trials in which vitamin D was given in a daily dosing regimen (OR 0·78 [95% CI 0·65-0·94]; 19 studies; I2=53·5%, pheterogeneity=0·003), at daily dose equivalents of 400-1000 IU (0·70 [0·55-0·89]; ten studies; I2=31·2%, pheterogeneity=0·16), for a duration of 12 months or less (0·82 [0·72-0·93]; 29 studies; I2=38·1%, pheterogeneity=0·021), and to participants aged 1·00-15·99 years at enrolment (0·71 [0·57-0·90]; 15 studies; I2=46·0%, pheterogeneity=0·027). No significant interaction between allocation to the vitamin D supplementation group versus the placebo group and dose, dose frequency, study duration, or age was observed. In addition, no significant difference in the proportion of participants who had at least one serious adverse event in the vitamin supplementation group compared with the placebo group was observed (0·97 [0·86-1·07]; 36 studies; I2=0·0%, pheterogeneity=0·99). Risk of bias within individual studies was assessed as being low for all but three trials. INTERPRETATION: Despite evidence of significant heterogeneity across trials, vitamin D supplementation was safe and overall reduced the risk of ARI compared with placebo, although the risk reduction was small. Protection was associated with administration of daily doses of 400-1000 IU for up to 12 months, and age at enrolment of 1·00-15·99 years. The relevance of these findings to COVID-19 is not known and requires further investigation. FUNDING: None.

Diet and Nutrition Status of Mongolian Adults.

(1) Background: Aspects of the Mongolian food supply, including high availability of animal-source foods and few plant foods, are plausibly associated with disease in the population. Data on Mongolian diets are lacking, and these risks are poorly quantified. The purpose of this study was to provide a multifaceted nutritional analysis of the modern Mongolian diet. (2) Methods: The study population consisted of 167 male and 167 female healthy non-pregnant urban and nomadic adults (22-55 years) randomly selected from lists of residents in 8 regions. From 2011-2016, 3-day weighed diet records and serum were collected twice from each participant in summer and winter; anthropometry was collected once from each participant. Serum was analyzed for biomarkers, and nutrient intake computed using purpose-built food composition data and adjusted for within-person variation. Exploratory dietary patterns were derived and analyzed for associations with diet and nutrition measurements. (3) Results: We collected 1838 of an expected 1986 diet records (92.5%), 610/658 serum samples (92.7%), and 315/334 height and weight measurements (94.3%). Sixty-one percent of men and 51% of women were overweight or obese. Consumption of red meat, refined grains, and whole-fat dairy was high, while that of fruits, non-tuberous vegetables, eggs, nuts and seeds, fish and poultry, and whole grains was low. Dairy and red meat were more consumed in summer and winter, respectively. Dietary inadequacy of 10 of 21 assessed nutrients, including fiber, folate, and vitamin D were >50% prevalent, while protein, zinc, and vitamin B12 inadequacy were low. Biochemical evidence of iron and vitamin A deficiency was also low. Three dietary patterns (Urban, Transitional, Nomadic) explained 41% of variation in food consumption. The Urban pattern was positively associated with BMI in multivariate analysis. (4) Conclusions: Results indicate a high prevalence of key dietary inadequacies and overweight among Mongolian adults. Prior studies by our group have suggested that expanded supplementation and food fortification would be effective in addressing micronutrient inadequacies; these strategies should be coupled with measures to mitigate the growing burden of chronic disease.

Maternal Pregnancy Hormone Concentrations in Countries with Very Low and High Breast Cancer Risk.

BACKGROUND: Breast cancer rates in Asia are much lower than in Europe and North America. Within Asia, rates are lower in Mongolia than in neighboring countries. Variation in pregnancy exposure to endogenous hormone concentrations may explain the differences, but data are lacking. METHODS: We measured maternal serum progesterone, prolactin, estradiol and estrone concentrations in the second half of pregnancy in a cross-sectional study of urban (n = 143-194 depending on the analyte) and rural (n = 150-193) Mongolian women, and U.S. women from Boston (n = 66-204). Medical records provided information on maternal and perinatal factors. Geometric mean hormones were estimated from standard linear models with the log-hormone as the dependent variable and country as the independent variable adjusted for maternal and gestational age at blood draw. RESULTS: Mean concentrations of prolactin (5722 vs. 4648 uIU/mL; p < 0.0001) and estradiol (17.7 vs. 13.6 ng/mL; p < 0.0001) were greater in Mongolian than U.S. women, while progesterone (147 vs. 201 ng/mL; p < 0.0001) was lower. Mean hormone concentrations were similar in rural and urban Mongolian women. Results were generally similar, with additional adjustment for gravidity, parity, height, body mass index at blood draw, education and alcohol use during pregnancy, and when stratified by offspring sex or parity. CONCLUSIONS: Mongolian women had greater concentrations of prolactin and estrogen and lower concentrations of progesterone than U.S. women, while hormone concentrations were similar in rural and urban Mongolian pregnancies. IMPACT: These data do not support the hypothesis that estrogen concentrations in pregnant women are lower in Mongolian compared with Caucasian women.