Effects of vitamin D3 on glucose metabolism in patients with severe osteoarthritis: A randomized double-blind trial comparing daily 2000 with 800 IU vitamin D3.

AIM: To investigate the effect of daily 800 versus 2000 IU of vitamin D3 supplementation over 24 months on glycaemic control in older adults after unilateral knee replacement. MATERIALS AND METHODS: The Zurich Multiple Endpoint Vitamin D Trial in Knee OA Patients was a randomized, double-blind trial conducted from 2008 to 2014 in Zurich, Switzerland. Participants were randomly allocated to 800 or 2000 IU vitamin D3 daily for 24 months. This study investigates the predefined secondary endpoints of fasting blood glucose (FBG) and homeostatic model assessment for insulin resistance (HOMA-IR) using linear mixed models adjusted for age, sex, baseline vitamin D deficiency and body mass index. RESULTS: A total of 251 participants (age 70.2 ± 6.5 years; 55.4% women; 39% impaired glucose tolerance, mean 25-hydroxyvitamin D 27.48 ± 12.48 ng/mL, mean FBG 5.49 ± 0.71 mmol/L) were included in this analysis. There was no significant difference in FBG between the group receiving 800 versus 2000 IU after 2 years with a least square mean (95% CI) of 5.32 (5.19; 5.44) versus 5.39 (5.27; 5.51) mmol/L (ptreat = .130) and no difference in HOMA-IR (0.44 [0.37; 0.52] vs. 0.49 [0.41; 0.58]; ptreat = .162), respectively. However, FBG decreased significantly over time independent of vitamin D3 dose (800 IU: 5.54 [5.42; 5.66] to 5.32 [5.19; 5.44], ptime < .001; 2000 IU: 5.5 [5.38; 5.62] to 5.39 [5.27; 5.51] mmol/L, ptime = .019). CONCLUSIONS: There was no clinically meaningful difference between 800 and 2000 IU of vitamin D3 over 2 years in FBG or HOMA-IR in community-dwelling older adults. Glycaemic outcomes improved in both groups.

Randomized trial of vitamin D versus placebo supplementation on markers of systemic inflammation in hypertensive patients.

BACKGROUND AND AIMS: Animal and cell models indicated that vitamin D modulates inflammatory activity, which is considered relevant in the pathogenesis of arterial hypertension and cardiovascular diseases. We therefore aimed to investigate the effect of vitamin D supplementation on systemic markers of inflammation in a cohort of hypertensive patients. METHODS AND RESULTS: The Styrian Vitamin D Hypertension Trial is a single-centre, double-blind, placebo-controlled study conducted from 2011 to 2014 in Austria. We enrolled 200 study participants with arterial hypertension and 25-hydroxy-vitamin-D (25(OH)D) concentration below 30 ng/mL. Study participants were randomized to receive either 2800 IU of vitamin D3 per day or placebo for 8 weeks. The present investigation is a post-hoc analysis using analysis of co-variance (ANCOVA). Outcome measures were biomarkers of inflammation including CRP, leukocytes including subtypes and leukocyte-to-lymphocyte ratio, leucine and kynurenic acid. A total of 187 participants (mean age 60.1 ± 11.3years; 47% women; mean baseline 25(OH)D 21.1 ± 5.6 ng/mL) completed the trial. ANCOVA revealed a mean treatment effect for none of the respective outcomes and no significant results were detected in various subgroup analyses. CONCLUSION: Vitamin D3 supplementation in hypertensive patients with insufficient 25(OH)D concentrations has no significant effect on lowering markers of systemic inflammation. Further studies investigating the effect of vitamin D on other inflammatory pathways and in populations with severe vitamin D deficiency and a significant inflammatory burden are required. REGISTRATION: ClinicalTrials.gov Identifier: NCT02136771; EudraCT No. 2009-018,125-70. Start Date: 2011-04-06.

Exposure to disinfection byproducts and risk of type 2 diabetes: a nested case-control study in the HUNT and Lifelines cohorts.

INTRODUCTION: Environmental chemicals acting as metabolic disruptors have been implicated with diabetogenesis, but evidence is weak among short-lived chemicals, such as disinfection byproducts (trihalomethanes, THM composed of chloroform, TCM and brominated trihalomethanes, BrTHM). OBJECTIVES: We assessed whether THM were associated with type 2 diabetes (T2D) and we explored alterations in metabolic profiles due to THM exposures or T2D status. METHODS: A prospective 1:1 matched case-control study (n = 430) and a cross-sectional 1:1 matched case-control study (n = 362) nested within the HUNT cohort (Norway) and the Lifelines cohort (Netherlands), respectively, were set up. Urinary biomarkers of THM exposure and mass spectrometry-based serum metabolomics were measured. Associations between THM, clinical markers, metabolites and disease status were evaluated using logistic regressions with Least Absolute Shrinkage and Selection Operator procedure. RESULTS: Low median THM exposures (ng/g, IQR) were measured in both cohorts (cases and controls of HUNT and Lifelines, respectively, 193 (76, 470), 208 (77, 502) and 292 (162, 595), 342 (180, 602). Neither BrTHM (OR = 0.87; 95% CI: 0.67, 1.11 | OR = 1.09; 95% CI: 0.73, 1.61), nor TCM (OR = 1.03; 95% CI: 0.88, 1.2 | OR = 1.03; 95% CI: 0.79, 1.35) were associated with incident or prevalent T2D, respectively. Metabolomics showed 48 metabolites associated with incident T2D after adjusting for sex, age and BMI, whereas a total of 244 metabolites were associated with prevalent T2D. A total of 34 metabolites were associated with the progression of T2D. In data driven logistic regression, novel biomarkers, such as cinnamoylglycine or 1-methylurate, being protective of T2D were identified. The incident T2D risk prediction model (HUNT) predicted well incident Lifelines cases (AUC = 0.845; 95% CI: 0.72, 0.97). CONCLUSION: Such exposome-based approaches in cohort-nested studies are warranted to better understand the environmental origins of diabetogenesis.

A Personal, Distributed Exposimeter: Procedure for Design, Calibration, Validation, and Application.

This paper describes, for the first time, the procedure for the full design, calibration, uncertainty analysis, and practical application of a personal, distributed exposimeter (PDE) for the detection of personal exposure in the Global System for Mobile Communications (GSM) downlink (DL) band around 900 MHz (GSM 900 DL). The PDE is a sensor that consists of several body-worn antennas. The on-body location of these antennas is investigated using numerical simulations and calibration measurements in an anechoic chamber. The calibration measurements and the simulations result in a design (or on-body setup) of the PDE. This is used for validation measurements and indoor radio frequency (RF) exposure measurements in Ghent, Belgium. The main achievements of this paper are: first, the demonstration, using both measurements and simulations, that a PDE consisting of multiple on-body textile antennas will have a lower measurement uncertainty for personal RF exposure than existing on-body sensors; second, a validation of the PDE, which proves that the device correctly estimates the incident power densities; and third, a demonstration of the usability of the PDE for real exposure assessment measurements. To this aim, the validated PDE is used for indoor measurements in a residential building in Ghent, Belgium, which yield an average incident power density of 0.018 mW/m².

Effects of vitamin D3, omega-3 s and a simple strength training exercise program on bone health: the DO-HEALTH randomized controlled trial.

INTRODUCTION: Evidence on the effects of Vitamin D, omega-3 s and exercise on aBMD in healthy older adults is limited. We examined whether vitamin D3, omega-3 s, or a simple home-based exercise program (SHEP), alone or in combination, over three years, improve lumbar spine (LS), femoral neck (FN) or total hip (TH) aBMD assessed by DXA. METHODS: aBMD was a secondary outcome in DO-HEALTH, a 3-year, multicenter, double-blind, randomized 2 × 2 × 2 factorial design trial in generally healthy older adults age ≥ 70 years. The study interventions were vitamin D3 (2000IU/d), omega-3 s (1 g/d), and SHEP (3 × 30 min/wk), applied alone or in combination in 8 treatment arms. Mixed effect models were used adjusting for age, sex, BMI, prior fall, study site and baseline level of the outcome. Main effects were assessed in the absence of an interaction between the interventions. Subgroup analyses by sex, physical activity level, dietary calcium intake, serum 25(OH)D levels, and fracture history were conducted. RESULTS: DXA scans were available for 1493 participants (mean age 75 years; 80.4% were physically active, 44% had 25(OH)D levels <20 ng/ml). At the LS and FN sites, none of the treatments showed a benefit. At the TH, vitamin D vs. no vitamin D treatment showed a significant benefit across 3 years (difference in adjusted means [AM]: 0.0035 [95% CI 0.0011, 0.0059] g/cm2). Furthermore, there was a benefit for vitamin D vs. no vitamin D treatment on LS aBMD in the male subgroup of (interaction P = 0.003; ∆AM: 0.0070 [95% CI 0.0007, 0.0132] g/cm2). CONCLUSIONS: Omega-3 and SHEP had no benefit on aBMD in healthy, active and largely vitamin D replete older adults. Our study suggests a small benefit of 2000 IU vitamin D daily on TH aBMD overall and LS aBMD among men, however, effect sizes were very modest and the clinical impact of these findings is unclear.

Vitamin D, omega-3 fatty acids (omega-3 s) and strength training are simple but promising strategies to improve bone health, however, their effect in healthy older adults over a period of three years was unclear. In this study, we examined whether daily vitamin D supplementation (2000 IU/d), daily omega-3 s supplementation (1 g/d) or a simple strength training program performed three times per week, either applied alone (e.g., only vitamin D supplements) or in combination (e.g., vitamin D and omega-3 s supplements) could improve bone density at the spine, hip or femoral neck. We included 1493 healthy older adults from Switzerland, Germany, France and Portugal who were at least 70 years of age and who had not experienced any major health events in the five years before study start. Taking omega-3 s supplements showed no benefit for bone density. Similarly, the simple strength exercise program showed no benefit. In contrast, participants receiving daily vitamin D supplements experienced a benefit at the hip. However, it should be noted that the effect across three years was very small.

Adherence to the Mediterranean Diet and Incidence of Pre-Frailty and Frailty in Community-Dwelling Adults 70+: The 3-Year DO-HEALTH Study.

The Mediterranean diet has been associated with many health benefits. Therefore, we investigated whether the degree of adherence to the Mediterranean diet at baseline, or changes in adherence over time, were associated with the incidence of pre-frailty or frailty in generally healthy older adults. This study used the DO-HEALTH trial data. We evaluated Mediterranean diet adherence with Panagiotakos' MedDietScore at baseline and at 3-year follow-up; frailty was assessed annually with the Fried frailty phenotype. We used minimally and fully adjusted mixed logistic regression models to estimate the exposure-disease relationship. We included 1811 participants without frailty at baseline (mean age 74.7 years; 59.4% women). Baseline adherence, as reflected by the MedDietScore, was not associated with becoming pre-frail [OR(95%CI) = 0.93 (0.83-1.03) for five-point greater adherence] or frail [OR(95%CI) = 0.90 (0.73-1.12) for five points]. However, a five-point increase in the MedDietScore over three years was associated with lower odds of becoming pre-frail [OR(95%CI) = 0.77 (0.68-0.88)] and frail [OR(95%CI) = 0.77 (0.64-0.92)]. In generally healthy and active older adults, baseline adherence to the Mediterranean diet was not associated with the incidence of pre-frailty or frailty over a 3-year follow-up. However, improved adherence to the Mediterranean diet over time was associated with significantly lower odds of becoming pre-frail or frail.

Effects of Vitamin D Supplementation on 24-Hour Blood Pressure in Patients with Low 25-Hydroxyvitamin D Levels: A Randomized Controlled Trial.

Accumulating evidence suggests that potential cardiovascular benefits of vitamin D supplementation may be restricted to individuals with very low 25-hydroxyvitamin D (25(OH)D) concentrations; the effect of vitamin D on blood pressure (BP) remains unclear. We addressed this issue in a post hoc analysis of the double-blind, randomized, placebo-controlled Styrian Vitamin D Hypertension Trial (2011−2014) with 200 hypertensive patients with 25(OH)D levels <30 ng/mL. We evaluated whether 2800 IU of vitamin D3/day or placebo (1:1) for 8 weeks affects 24-hour systolic ambulatory BP in patients with 25(OH)D concentrations <20 ng/mL, <16 ng/mL, and <12 ng/mL and whether achieved 25(OH)D concentrations were associated with BP measures. Taking into account correction for multiple testing, p values < 0.0026 were considered significant. No significant treatment effects on 24-hour BP were observed when different baseline 25(OH)D thresholds were used (all p-values > 0.30). However, there was a marginally significant trend towards an inverse association between the achieved 25(OH)D level with 24-hour systolic BP (−0.196 per ng/mL 25(OH)D, 95% CI (−0.325 to −0.067); p = 0.003). In conclusion, we could not document the antihypertensive effects of vitamin D in vitamin D-deficient individuals, but the association between achieved 25(OH)D concentrations and BP warrants further investigations on cardiovascular benefits of vitamin D in severe vitamin D deficiency.

Coupling external with internal exposure metrics of trihalomethanes in young females from Kuwait and Cyprus.

The Eastern Mediterranean and the Middle Eastern regions are both understudied in terms of possible environmental health risks for their populations. Water scarcity and desalination treatment provide the general population of countries from these regions (e.g., Kuwait and Cyprus) with unique tap water characteristics. This study investigated the association between external (tap water and 24 h personal air samples) and internal (urine) THM exposure metrics that reflected information about THM-related habits and activities collected using questionnaires and time activity diaries. The study population comprised of young females residing in either Kuwait (n=13) or Cyprus (n=22). First morning urine voids were collected on 2 consecutive days. Urinary creatinine-adjusted total THM (TTHM) levels were higher in Kuwait (median (interquartile range): 1044 (814, 1270) ng/g) than in Cyprus (691 (510, 919) ng/g, P<0.05). Median personal air TTHM levels in Kuwait (1.4 (0.7, 1.7) µg/m3) were higher than those in Cyprus (0.9 (0.5, 1.4) µg/m3), but did not reach statistical significance (P=0.17). Median tap water TTHM in Kuwait (6.7 (5.4, 11.6) µg/l) did not correlate with urinary or air THM and they were lower than those in Cyprus (29.5 (20.1, 48.0) µg/l; P<0.01). Despite that tap water did not contain chloroform (TCM), TCM was detected in both air and urine samples in Kuwait, suggesting other TCM exposure sources, such as household cleaning activities. Total duration of activities and mopping were significantly correlated with air and urine THM in Kuwait, as reported in the time activity diary. Personal air and urine exposure metrics were correlated in Kuwait (TTHM ρ=0.62, P<0.05), but not in Cyprus (TTHM ρ=-0.32, P>0.05). Time-activity diaries and urinary THM seemed to be useful measures of THM exposures in Kuwait. Coupling both external with internal exposure metrics could find use in population health studies towards further refining the association between environmental exposures and health outcomes.

Time of the day dictates the variability of biomarkers of exposure to disinfection byproducts.

Non-persistent environmental chemicals (NOPEC) are xenobiotics with short half-lives of elimination (<7h). Similar to chronopharmacokinetics, NOPEC metabolism may follow diurnal patterns of cytochrome P450 activity. The role of circadian liver clock in shaping NOPEC metabolism and their concomitant measurements of biomarkers of exposure and effect remains poorly understood in real-life human settings. Metabolic activation (toxication) by CYP2E1 converts trihalomethanes (THM) to harmful metabolites. We investigated the diurnal variation of urinary THM exposures and their metabolism patterns as catalyzed by CYP2E1 redox activity, using the surrogate marker of 4-hydroxynonenal (4HNE). We implemented three time-series trials with adult volunteers conducting specific household cleaning activities at predefined times of a day. Circadia variation of 4HNE was assessed with a cosinor model and its mesor levels increased with THM exposure. The time of exposure within the day dictated the magnitude of urinary THM levels and their toxication effect; in all three trials and relative to urinary THM levels before the activity, lower and higher median THM were measured right after the activity in morning and afternoon/night, respectively. This is consistent with higher reported CYP2E1 redox activity in light/active phase. Population health studies should incorporate time-stamped biomarker data to improve the understanding of chronic disease processes.

Analysis of personal and bedroom exposure to ELF-MFs in children in Italy and Switzerland.

Little is known about the real everyday exposure of children in Europe to extremely low-frequency magnetic fields (ELF-MFs). The aims of this study are to (i) assess personal ELF-MF exposure in children; (ii) to identify factors determining personal and bedroom ELF-MF exposure measurements in children; (iii) to evaluate the reproducibility of exposure summary measures; and (iv) to compare personal with bedroom measurements. In Switzerland and Italy, 172 children aged between 5 and 13 years were equipped with ELF-MF measurement devices (EMDEX II, measuring 40-800 Hz) during 24-72 h twice, in the warm and the cold season. In addition, 24-h measurements were taken in the bedroom of children. In our study, sample geometric mean ELF-MF exposure was 0.04 µT for personal and 0.05 µT for bedroom measurements. Living within 100 m of a highest voltage power line increased geometric mean personal exposure by a factor of 3.3, and bedroom measurements by a factor 6.8 compared to a control group. Repeated measurements within the same subject showed high reproducibility for the geometric mean (Spearman's correlation 0.78 for personal and 0.86 for bedroom measurements) but less for the 95th and 99th percentile of the personal measurements (≤0.42). Spearman's correlation between bedroom and personal exposure was 0.86 for the geometric mean but considerably lower for the 95th and 99th percentiles (≤0.60). Most previous studies on ELF-MF childhood leukaemia used mean bedroom exposure. Our study demonstrates that geometric mean bedroom measurements is well correlated with personal geometric mean exposure, and has high temporal reproducibility.

Human Exposures to Bisphenol A, Bisphenol F and Chlorinated Bisphenol A Derivatives and Thyroid Function.

Although the increasing prevalence of thyroid nodular disease (TND) has been partially attributed to the more frequent usage of improved diagnostics, environmental factors, such as exposures to thyroid-disrupting chemicals may contribute to TND and altered thyroid function. We investigated the association between exposures to bisphenol A (BPA), its chlorinated derivatives (ClxBPA), and bisphenol F (BPF) with TND and thyroid measures in adult women. A case-control study in Cyprus and Romania (n = 212) was conducted, where cases were those with thyroid nodules (diameter >3mm), and controls without nodules. Serum TSH and free thyroxine and urinary levels of BPA, BPF and ClxBPA were measured using immunoassays and tandem mass spectrometry, respectively. The association between exposures to BPA compounds and TND, adjusting for age, BMI, thyroid hormones and urinary iodine was assessed using logistic regression. Linear regression was used to explore associations between urinary BPA, BPF and ClxBPA and serum thyroid hormones. With the exception of a chlorinated BPA compound (30%), the rest of bisphenols were quantified in 100% of urine samples. A positive and significant (p<0.05) association was observed between urinary BPA and serum TSH that remained after adjusting for urinary creatinine, age, BMI, study site and disease status; there was no significant association between BPF or ClxBPA with TSH. None of the BPA compounds were associated with higher odds of TND. Our study found associations of urinary BPA with TSH but not with BPF or ClxBPA. A larger study would be justified.