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.).

A phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy participants and patients with stable schizophrenia.

AIMS: TAK-041 (NBI-1065846), an orally available, investigational, small molecule agonist of GPR139, an orphan G-protein-coupled receptor, has shown promise in preclinical studies for the treatment of symptoms associated with schizophrenia. Here, we report the results from a phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy adults and exploratory efficacy assessment of TAK-041 as adjunctive therapy to antipsychotics in adults with stable schizophrenia (ClinicalTrials.gov: NCT02748694). METHODS: The study comprised 4 parts: parts 1-3 were undertaken in healthy adults and part 4 in patients with stable schizophrenia. Part 1 was a single-rising-dose study, part 2 was a multiple-rising-dose study that assessed plasma exposure and accumulation, part 3 evaluated the bioavailability of tablet formulation versus oral suspension, and part 4 was a repeat multiple-dose study in patients with stable schizophrenia. RESULTS: No serious adverse events were reported. TAK-041 had a nearly linear pharmacokinetics profile, with rapid absorption and long half-life of 170-302 hours across all doses tested. Bioavailability was similar between the tablet formulation and oral suspension, and no meaningful food effect was detected. Systemic exposure was 22-30% lower for patients with schizophrenia than for healthy volunteers. A potential signal of improvement was detected in the anxiety-depression scale of the Positive and Negative Syndrome Scale (P = .0002, not corrected for multiplicity) and the Temporal Experience of Pleasure Scale in patients with schizophrenia. CONCLUSION: TAK-041 was generally well tolerated in healthy volunteers and adults with schizophrenia. Further investigation of TAK-041 in individuals with schizophrenia is supported.

Safety, pharmacokinetics and quantitative EEG modulation of TAK-071, a novel muscarinic M1 receptor positive allosteric modulator, in healthy subjects.

AIMS: TAK-071 is a muscarinic M1 receptor positive allosteric modulator designed to have low cooperativity with acetylcholine. This was a first-in-human study to evaluate the safety, pharmacokinetics, and pharmacodynamics of TAK-071. METHODS: TAK-071 was administered as single and multiple doses in a randomized, double-blind, placebo-controlled, parallel-group design in healthy volunteers alone and in combination with donepezil. Laboratory, electrocardiogram (ECG) and electroencephalogram (EEG) evaluations were performed. Cerebrospinal fluid and blood samples were taken to evaluate the pharmacokinetics (PK), relative bioavailability and food effect. RESULTS: TAK-071 was safe and well tolerated, and no deaths or serious adverse events occurred. TAK-071 demonstrated a long mean (% coefficient of variation) half-life of 46.3 (25.2%) to 60.5 (51.5%) hours and excellent brain penetration following oral dosing. Coadministration with donepezil had no impact on the PK of either drug. There was no food effect on systemic exposure. Quantitative EEG analysis revealed that TAK-071 40-80 mg increased power in the 7-9 Hz range in the posterior electrode group with eyes open and 120-160 mg doses increased power in the 16-18 Hz range and reduced power in the 2-4 Hz range in central-posterior areas with eyes open and eyes closed. Functional connectivity was significantly reduced after TAK-071 at high doses and was enhanced with coadministration of donepezil under the eyes-closed condition. CONCLUSIONS: PK and safety profiles of TAK-071 were favorable, including those exceeding expected pharmacologically active doses based on preclinical data. When administered without donepezil TAK-071 was largely free of cholinergic adverse effects. Further clinical evaluation of TAK-071 is warranted.

Safety, pharmacokinetics and pharmacodynamics of TAK-418, a novel inhibitor of the epigenetic modulator lysine-specific demethylase 1A.

AIMS: Dysregulation of histone methylation epigenetic marks may result in intellectual and developmental disability, as seen in Kabuki syndrome. Animal data suggest that increasing histone methylation by inhibiting lysine-specific demethylase 1A (LSD1) may improve cognitive outcomes in a model of Kabuki syndrome. TAK-418 is a novel LSD1 inhibitor, developed as a potential therapeutic agent for central nervous system disorders such as Kabuki syndrome. Here, we report safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single and multiple doses of TAK-418 (ClinicalTrials.gov: NCT03228433, NCT03501069). METHODS: Two randomized, double-blind, placebo-controlled, phase 1 studies of oral TAK-418 were performed, a first-in-human single-rising-dose (SRD) study (5-60 mg) in healthy adult male and female volunteers (placebo, n = 10; TAK-418, n = 30), and an SRD (120-160 mg) and multiple-rising-dose (MRD) study (20-160 mg once daily for 10 days) in healthy female volunteers (placebo, n = 2 [SRD] and n = 6 [MRD]; TAK-418, n = 6 [SRD] and n = 18 [MRD]). RESULTS: TAK-418 was well tolerated. No clinically significant changes in laboratory test results or vital signs were observed and no serious adverse events were reported. TAK-418 had a nearly linear pharmacokinetic profile, with rapid absorption and short terminal half-life across the evaluated dose range. No obvious accumulation was observed after daily administration for 10 days. Administration with food delayed peak plasma concentrations but overall exposure was unaffected. TAK-418 rapidly crossed the blood-brain barrier and generally showed a dose-dependent response in the peripheral pharmacodynamic biomarker formyl-flavin adenine dinucleotide. CONCLUSION: The brain-penetrant LSD1 inhibitor TAK-418 was well tolerated, with pharmacokinetic and pharmacodynamic effects that support further investigation.

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.

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.

Nepal Pioneer Worksite Intervention Study to lower cardio-metabolic risk factors: design and protocol.

BACKGROUND: To increase cardiovascular disease prevention efforts, worksite interventions can promote healthy food choices, facilitate health education, increase physical activity and provide social support. This pioneer study will measure the effectiveness of a cafeteria and a behavioral intervention on cardio-metabolic risk in a worksite in Nepal. METHODS: The Nepal Pioneer Worksite Intervention Study is a two-step intervention study conducted in Dhulikhel Hospital in eastern Nepal. In the first step, we will assess the effectiveness of a 6-month cafeteria intervention on cardio-metabolic risk using a pre-post design. In the second step, we will conduct a 6-month, open-masked, two-arm randomized trial by allocating half of the participants to an individual behavioral intervention based on the 'diabetes prevention program' for the prevention of cardio-metabolic risk. We will recruit 366 full time employees with elevated blood pressure, fasting blood sugar, or glycosylated haemoglobin (HbA1c). At baseline, we will measure their demographic variables, lifestyle factors, anthropometry, fasting blood sugar, HbA1c,and lipid profiles. We will measure cardio-metabolic outcomes at 6 months, 12 months, and 18 months. At 12 months, we will compare the proportion of participants who have attained two or more cardio-metabolic risk factor reduction goals (HbA1c decrease ≥0.5%; systolic blood pressure decrease ≥5 mmHg; or triglycerides decrease ≥10 mg/dL) during the cafeteria intervention period and the control period using generalized estimating equations. At 18 months, we will compare the proportion from the 'cafeteria only arm' to the 'cafeteria and behavior arm' for the same outcome using a chi-square test. DISCUSSION: This pioneer study will estimate the effect of environmental-level changes on lowering cardio-metabolic risks; and added benefit of an individual-level dietary intervention. If the study demonstrates a significant effect, a scaled up approach could produce an important reduction in cardiovascular disease burden through environmental and individual level prevention programs in Nepal and similar worksites worldwide. TRIAL REGISTRATION: The trial was retrospectively registered on clincaltrials.gov (Identification Member: NCT03447340 ; Date of Registration: February 27, 2018).

Evaluating Public Health Interventions: 7. Let the Subject Matter Choose the Effect Measure: Ratio, Difference, or Something Else Entirely.

We define measures of effect used in public health evaluations, which include the risk difference and the risk ratio, the population-attributable risk, years of life lost or gained, disability-adjusted life years, quality-adjusted life years, and the incremental cost-effectiveness ratio. Except for the risk ratio, all of these are absolute effect measures. For constructing externally generalizable absolute measures of effect when there is superior fit of the multiplicative model, we suggest using the multiplicative model to estimate relative risks, which will often be obtained in simple linear form with no interactions, and then converting these to the desired absolute measure. The externally generalizable absolute measure of effect can be obtained by suitably standardizing to the risk factor distribution of the population to which the results are to be generalized. External generalizability will often be compromised when absolute measures are computed from study populations with risk factor distributions different from those of the population to whom the results are to be generalized, even when these risk factors are not confounders of the intervention effect.

Switching to second-line ART in relation to mortality in a large Tanzanian HIV cohort.

Objectives: In a large cohort of HIV-infected Tanzanians, we assessed: (i) rates of first-line treatment failure and switches to second-line ART; (ii) the effect of switching to second-line ART on death and loss to follow-up; and (iii) treatment outcomes on second-line ART by regimen. Methods: HIV-1-infected adults (≥15 years) initiated on first-line ART between November 2004 and September 2012, and who remained on initial therapy for at least 24 weeks before switching, were studied. Survival analyses were conducted to examine the effect of second-line ART on mortality and loss to follow-up in: (i) the whole cohort; (ii) all patients eligible for second-line ART by immunological failure (IF) and/or virological failure (VF) criteria; and (iii) patients eligible by VF criteria. Results: In total, 47 296 HIV-infected patients [mean age 37.5 (SD 9.5) years, CD4 175 (SD 158) cells/mm 3 , 71% female] were included in the analyses. Of these, 1760 (3.7%) patients switched to second-line ART (incidence rate = 1.7/100 person-years). Higher rates of mortality were observed in switchers versus non-switchers in all patients and patients with ART failure using IF/VF criteria. Switching only protected against mortality in patients with ART failure defined virologically and with the highest level of adherence [switching versus non-switching; >95% adherence; adjusted HR = 0.50 (95% CI = 0.26-0.93); P = 0.03]. Conclusions: Switching patients to second-line ART may only be beneficial in a select group of patients who are virologically monitored and demonstrate good adherence. Our data emphasize the need for routine viral load monitoring and aggressive adherence interventions in HIV programmes in sub-Saharan Africa.

Effect of neonatal vitamin A supplementation on mortality in infants in Tanzania (Neovita): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Supplementation of vitamin A in children aged 6-59 months improves child survival and is implemented as global policy. Studies of the efficacy of supplementation of infants in the neonatal period have inconsistent results. We aimed to assess the efficacy of oral supplementation with vitamin A given to infants in the first 3 days of life to reduce mortality between supplementation and 180 days (6 months). METHODS: We did an individually randomised, double-blind, placebo-controlled trial of infants born in the Morogoro and Dar es Salaam regions of Tanzania. Women were identified during antenatal clinic visits or in the labour wards of public health facilities in Dar es Salaam. In Kilombero, Ulanga, and Kilosa districts, women were seen at home as part of the health and demographic surveillance system. Newborn infants were eligible for randomisation if they were able to feed orally and if the family intended to stay in the study area for at least 6 months. We randomly assigned infants to receive one dose of 50,000 IU of vitamin A or placebo in the first 3 days after birth. Infants were randomly assigned in blocks of 20, and investigators, participants' families, and data analysis teams were masked to treatment assignment. We assessed infants on day 1 and day 3 after dosing, as well as at 1, 3, 6, and 12 months after birth. The primary endpoint was mortality at 6 months, assessed by field interviews. The primary analysis included only children who were not lost to follow-up. This trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), number ACTRN12610000636055. FINDINGS: Between Aug 26, 2010, and March 3, 2013, 31,999 newborn babies were randomly assigned to receive vitamin A (n=15,995) or placebo (n=16,004; 15,428 and 15,464 included in analysis of mortality at 6 months, respectively). We did not find any evidence for a beneficial effect of vitamin A supplementation on mortality in infants at 6 months (26 deaths per 1000 livebirths in vitamin A vs 24 deaths per 1000 livebirths in placebo group; risk ratio 1·10, 95% CI 0·95-1·26; p=0·193). There was no evidence of a differential effect for vitamin A supplementation on mortality by sex; risk ratio for mortality at 6 months for boys was 1·08 (0·90-1·29) and for girls was 1·12 (0·91-1·39). There was also no evidence of adverse effects of supplementation within 3 days of dosing. INTERPRETATION: Neonatal vitamin A supplementation did not result in any immediate adverse events, but had no beneficial effect on survival in infants in Tanzania. These results strengthen the evidence against a global policy recommendation for neonatal vitamin A supplementation. FUNDING: Bill & Melinda Gates Foundation to WHO.

A new measure of between-studies heterogeneity in meta-analysis.

Assessing the magnitude of heterogeneity in a meta-analysis is important for determining the appropriateness of combining results. The most popular measure of heterogeneity, I(2) , was derived under an assumption of homogeneity of the within-study variances, which is almost never true, and the alternative estimator, R^I, uses the harmonic mean to estimate the average of the within-study variances, which may also lead to bias. This paper thus presents a new measure for quantifying the extent to which the variance of the pooled random-effects estimator is due to between-studies variation, R^b, that overcomes the limitations of the previous approach. We show that this measure estimates the expected value of the proportion of total variance due to between-studies variation and we present its point and interval estimators. The performance of all three heterogeneity measures is evaluated in an extensive simulation study. A negative bias for R^b was observed when the number of studies was very small and became negligible as the number of studies increased, while R^I and I(2) showed a tendency to overestimate the impact of heterogeneity. The coverage of confidence intervals based upon R^b was good across different simulation scenarios but was substantially lower for R^I and I(2) , especially for high values of heterogeneity and when a large number of studies were included in the meta-analysis. The proposed measure is implemented in a user-friendly function available for routine use in r and sas. R^b will be useful in quantifying the magnitude of heterogeneity in meta-analysis and should supplement the p-value for the test of heterogeneity obtained from the Q test. Copyright © 2016 John Wiley & Sons, Ltd.

The impact of covariate measurement error on risk prediction.

In the development of risk prediction models, predictors are often measured with error. In this paper, we investigate the impact of covariate measurement error on risk prediction. We compare the prediction performance using a costly variable measured without error, along with error-free covariates, to that of a model based on an inexpensive surrogate along with the error-free covariates. We consider continuous error-prone covariates with homoscedastic and heteroscedastic errors, and also a discrete misclassified covariate. Prediction performance is evaluated by the area under the receiver operating characteristic curve (AUC), the Brier score (BS), and the ratio of the observed to the expected number of events (calibration). In an extensive numerical study, we show that (i) the prediction model with the error-prone covariate is very well calibrated, even when it is mis-specified; (ii) using the error-prone covariate instead of the true covariate can reduce the AUC and increase the BS dramatically; (iii) adding an auxiliary variable, which is correlated with the error-prone covariate but conditionally independent of the outcome given all covariates in the true model, can improve the AUC and BS substantially. We conclude that reducing measurement error in covariates will improve the ensuing risk prediction, unless the association between the error-free and error-prone covariates is very high. Finally, we demonstrate how a validation study can be used to assess the effect of mismeasured covariates on risk prediction. These concepts are illustrated in a breast cancer risk prediction model developed in the Nurses' Health Study.

Active or passive exposure to tobacco smoking and allergic rhinitis, allergic dermatitis, and food allergy in adults and children: a systematic review and meta-analysis.

BACKGROUND: Allergic rhinitis, allergic dermatitis, and food allergy are extremely common diseases, especially among children, and are frequently associated to each other and to asthma. Smoking is a potential risk factor for these conditions, but so far, results from individual studies have been conflicting. The objective of this study was to examine the evidence for an association between active smoking (AS) or passive exposure to secondhand smoke and allergic conditions. METHODS AND FINDINGS: We retrieved studies published in any language up to June 30th, 2013 by systematically searching Medline, Embase, the five regional bibliographic databases of the World Health Organization, and ISI-Proceedings databases, by manually examining the references of the original articles and reviews retrieved, and by establishing personal contact with clinical researchers. We included cohort, case-control, and cross-sectional studies reporting odds ratio (OR) or relative risk (RR) estimates and confidence intervals of smoking and allergic conditions, first among the general population and then among children. We retrieved 97 studies on allergic rhinitis, 91 on allergic dermatitis, and eight on food allergy published in 139 different articles. When all studies were analyzed together (showing random effects model results and pooled ORs expressed as RR), allergic rhinitis was not associated with active smoking (pooled RR, 1.02 [95% CI 0.92-1.15]), but was associated with passive smoking (pooled RR 1.10 [95% CI 1.06-1.15]). Allergic dermatitis was associated with both active (pooled RR, 1.21 [95% CI 1.14-1.29]) and passive smoking (pooled RR, 1.07 [95% CI 1.03-1.12]). In children and adolescent, allergic rhinitis was associated with active (pooled RR, 1.40 (95% CI 1.24-1.59) and passive smoking (pooled RR, 1.09 [95% CI 1.04-1.14]). Allergic dermatitis was associated with active (pooled RR, 1.36 [95% CI 1.17-1.46]) and passive smoking (pooled RR, 1.06 [95% CI 1.01-1.11]). Food allergy was associated with SHS (1.43 [1.12-1.83]) when cohort studies only were examined, but not when all studies were combined. The findings are limited by the potential for confounding and bias given that most of the individual studies used a cross-sectional design. Furthermore, the studies showed a high degree of heterogeneity and the exposure and outcome measures were assessed by self-report, which may increase the potential for misclassification. CONCLUSIONS: We observed very modest associations between smoking and some allergic diseases among adults. Among children and adolescents, both active and passive exposure to SHS were associated with a modest increased risk for allergic diseases, and passive smoking was associated with an increased risk for food allergy. Additional studies with detailed measurement of exposure and better case definition are needed to further explore the role of smoking in allergic diseases.

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.

Confidence intervals for heterogeneity measures in meta-analysis.

Two methods of quantifying heterogeneity between studies in meta-analysis were studied. One method quantified the proportion of the total variance of the effect estimate due to variation between studies (RI), and the other calibrated the variance between studies to the size of the effect itself through a between-study coefficient of variation (CVB). Bootstrap and asymptotic confidence intervals for RI and CVB were derived and evaluated in an extensive simulation study that covered a wide range of scenarios likely to be encountered in practice. The best performance was given by asymptotic Wald confidence intervals developed for RI and CVB. The use of these heterogeneity measures together with their confidence intervals was illustrated in 5 typical meta-analyses. A new user-friendly SAS macro (SAS Institute, Inc., Cary, North Carolina) is provided to implement these methods for routine use and can be downloaded at the last author's website.

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.

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.

Meta-analysis for linear and nonlinear dose-response relations: examples, an evaluation of approximations, and software.

Two methods for point and interval estimation of relative risk for log-linear exposure-response relations in meta-analyses of published ordinal categorical exposure-response data have been proposed. The authors compared the results of a meta-analysis of published data using each of the 2 methods with the results that would be obtained if the primary data were available and investigated the circumstances under which the approximations required for valid use of each meta-analytic method break down. They then extended the methods to handle nonlinear exposure-response relations. In the present article, methods are illustrated using studies of the relation between alcohol consumption and colorectal and lung cancer risks from the ongoing Pooling Project of Prospective Studies of Diet and Cancer. In these examples, the differences between the results of a meta-analysis of summarized published data and the pooled analysis of the individual original data were small. However, incorrectly assuming no correlation between relative risk estimates for exposure categories from the same study gave biased confidence intervals for the trend and biased P values for the tests for nonlinearity and between-study heterogeneity when there was strong confounding by other model covariates. The authors illustrate the use of 2 publicly available user-friendly programs (Stata and SAS) to implement meta-analysis for dose-response data.

Evaluation of the pharmacokinetics of trazpiroben (TAK-906) in the presence and absence of the proton pump inhibitor esomeprazole.

Trazpiroben, a dopamine D2 /D3 receptor antagonist under development to treat gastroparesis, displays decreasing solubility with increasing pH. This single-sequence, open-label, two-period, crossover study evaluated the effect of esomeprazole, a proton pump inhibitor that raises gastric pH, on the single-dose pharmacokinetics, safety, and tolerability of trazpiroben in healthy adults (NCT03849690). In total, 12 participants were enrolled and entered period 1 (days 1-3), receiving a single oral dose of trazpiroben 25 mg on day 1. After a 4-day washout, participants then entered period 2 (days 8-13) and received esomeprazole 40 mg once daily on days 8-12, with a single oral dose of trazpiroben 25 mg co-administered 1 h post esomeprazole dosing on day 11. Geometric mean area under the curve from time 0 extrapolated to infinity (AUC∞ ) and maximum plasma concentration (Cmax ) values were generally similar when trazpiroben was administered alone versus alongside esomeprazole (AUC∞ , 44.03 vs. 38.85 ng h/ml; Cmax , 19.76 vs. 17.24 ng/ml). Additionally, the associated geometric mean ratio (GMR; co-administration: administration alone) 90% confidence intervals (CIs) suggested no clinically meaningful difference between treatment groups (AUC∞ , GMR 0.88, 90% CI 0.78-1.00; Cmax , 0.87, 90% CI 0.70-1.09). Mean apparent first-order terminal elimination half-life values were similar between treatments, illustrating co-administration with esomeprazole had minimal effect on trazpiroben elimination. Trazpiroben was well-tolerated in healthy adults following administration alone and alongside esomeprazole, with no clinically relevant adverse events reported. The lack of evidence of any clinically meaningful drug-drug interaction supports the co-administration of esomeprazole with trazpiroben.

The Moderate Alcohol and Cardiovascular Health Trial (MACH15): Design and methods for a randomized trial of moderate alcohol consumption and cardiometabolic risk.

BACKGROUND: Observational studies have documented lower risks of coronary heart disease and diabetes among moderate alcohol consumers relative to abstainers, but only a randomized clinical trial can provide conclusive evidence for or against these associations. AIM: The purpose of this study was to describe the rationale and design of the Moderate Alcohol and Cardiovascular Health Trial, aimed to assess the cardiometabolic effects of one alcoholic drink daily over an average of six years among adults 50 years or older. METHODS: This multicenter, parallel-arm randomized trial was designed to compare the effects of one standard serving (∼11-15 g) daily of a preferred alcoholic beverage to abstention. The trial aimed to enroll 7800 people at high risk of cardiovascular disease. The primary composite endpoint comprised time to the first occurrence of non-fatal myocardial infarction, non-fatal ischemic stroke, hospitalized angina, coronary/carotid revascularization, or total mortality. The trial was designed to provide >80% power to detect a 15% reduction in the risk of the primary outcome. Secondary outcomes included diabetes. Adverse effects of special interest included injuries, congestive heart failure, alcohol use disorders, and cancer. RESULTS: We describe the design, governance, masking issues, and data handling. In three months of field center activity until termination by the funder, the trial randomized 32 participants, successfully screened another 70, and identified ∼400 additional interested individuals. CONCLUSIONS: We describe a feasible design for a long-term randomized trial of moderate alcohol consumption. Such a study will provide the highest level of evidence for the effects of moderate alcohol consumption on cardiovascular disease and diabetes, and will directly inform clinical and public health guidelines.