Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis.

Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10-88). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10-12). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10-5) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.

Identifying integration and differentiation in a Hospital's logistical system: a social network analysis of a case study.

BACKGROUND: Integration, the coordination and alignment of tasks, has been promoted widely in order to improve the performance of hospitals. Both organization theory and social network analysis offer perspectives on integration. This exploratory study research aims to understand how a hospital's logistical system works, and in particular to what extent there is integration and differentiation. More specifically, it first describes how a hospital organizes logistical processes; second, it identifies the agents and the interactions for organizing logistical processes, and, third, it establishes the extent to which tasks are segmented into subsystems, which is referred to as differentiation, and whether these tasks are coordinated and aligned, thus achieving integration. METHODS: The study is based on case study research carried out in a hospital in the Netherlands. All logistical tasks that are executed for surgery patients were studied. Using a mixed method, data were collected from the Hospital Information System (HIS), documentation, observations and interviews. These data were used to perform a social network analysis and calculate the network metrics of the hospital network. RESULTS: This paper shows that 23 tasks are executed by 635 different agents who interact through 31,499 interaction links. The social network of the hospital demonstrates both integration and differentiation. The network appears to function differently from what is assumed in literature, as the network does not reflect the formal organizational structure of the hospital, and tasks are mainly executed across functional silos. Nurses and physicians perform integrative tasks and two agents who mainly coordinate the tasks in the network, have no hierarchical position towards other agents. The HIS does not seem to fulfill the interactional needs of agents. CONCLUSIONS: This exploratory study reveals the network structure of a hospital. The cross-functional collaboration, the integration found, and position of managers, coordinators, nurses and doctors suggests a possible gap between organizational perspectives on hospitals and reality. This research sets a basis for further research that should focus on the relation between network structure and performance, on how integration is achieved and in what way organization theory concepts and social network analysis could be used in conjunction with one another.

Use of Selective Serotonin Reuptake Inhibitors and Bone Mineral Density Change: A Population-Based Longitudinal Study in Middle-Aged and Elderly Individuals.

BACKGROUND: Longitudinal studies showed conflicting results regarding the association between use of selective serotonin reuptake inhibitors (SSRIs) and bone mineral density (BMD). Therefore, we investigate the association between-duration of-SSRI use and BMD, and change in BMD ([INCREMENT]BMD). METHODS: Data from the population-based Rotterdam Study cohort (1991-2008) were used. In total, 4915 men and 5831 postmenopausal women, aged 45 years and older, were included, having measurement visits at 4- to 5-year intervals. Multivariable linear mixed models were applied to examine the association between SSRI use, based on pharmacy records, duration of SSRI use, and repeated measures of BMD, and changes in BMD, compared with nonuse. Femoral neck BMD (grams per centimeters squared) was measured at 4 visits, comprising 19,861 BMD measurements. Three [INCREMENT]BMD periods were examined, comprising 7897 [INCREMENT]BMD values. Change in BMD was expressed in the annual percentage [INCREMENT]BMD between 2 consecutive visits. RESULTS: In men and women, we observed no association between SSRI and BMD when compared with nonuse (women: mean difference, 0.007 g/cm; 95% confidence interval, -0.002 to 0.017; P = 0.123). We did not find an association between duration of SSRI use and [INCREMENT]BMD (women: annual percentage change, -0.081; 95% confidence interval, -0.196 to 0.033; P = 0.164). CONCLUSIONS: In conclusion, use of SSRIs is not associated with BMD or [INCREMENT]BMD, after taking duration of treatment into account, in middle-aged and elderly individuals. Therefore, our results question previously raised concerns on the adverse effects of SSRIs on BMD.

Beta-blocker use and fall risk in older individuals: Original results from two studies with meta-analysis.

AIMS: To investigate the association between use of ß-blockers and ß-blocker characteristics - selectivity, lipid solubility, intrinsic sympathetic activity (ISA) and CYP2D6 enzyme metabolism - and fall risk. METHODS: Data from two prospective studies were used, including community-dwelling individuals, n = 7662 (the Rotterdam Study) and 2407 (B-PROOF), all aged ≥55 years. Fall incidents were recorded prospectively. Time-varying ß-blocker use was determined using pharmacy dispensing records. Cox proportional hazard models adjusted for age and sex were applied to determine the association between ß-blocker use, their characteristics - selectivity, lipid solubility, ISA and CYP2D6 enzyme metabolism - and fall risk. The results of the studies were combined using meta-analyses. RESULTS: In total 2917 participants encountered a fall during a total follow-up time of 89 529 years. Meta-analysis indicated no association between use of any ß-blocker, compared to nonuse, and fall risk, hazard ratio (HR) = 0.97 [95% confidence interval (CI) 0.88-1.06]. Use of a selective ß-blocker was also not associated with fall risk, HR = 0.92 (95%CI 0.83-1.01). Use of a nonselective ß-blocker was associated with an increased fall risk, HR = 1.22 (95%CI 1.01-1.48). Other ß-blocker characteristics including lipid solubility and CYP2D6 enzyme metabolism were not associated with fall risk. CONCLUSION: Our study suggests that use of a nonselective ß-blocker, contrary to selective ß-blockers, is associated with an increased fall risk in an older population. In clinical practice, ß-blockers have been shown effective for a variety of cardiovascular indications. However, fall risk should be considered when prescribing a ß-blocker in this age group, and the pros and cons for ß-blocker classes should be taken into consideration.

A Randomized Controlled Trial to Examine the Effect of 2-Year Vitamin B12 and Folic Acid Supplementation on Physical Performance, Strength, and Falling: Additional Findings from the B-PROOF Study.

Elevated homocysteine concentrations are associated with a decline in physical function in elderly persons. Homocysteine-lowering therapy may slow down this decline. This study aimed to examine the effect of a 2-year intervention of vitamin B12 and folic acid supplementation on physical performance, handgrip strength, and risk of falling in elderly subjects in a double-blind, randomized placebo-controlled trial. Participants aged ≥65 years with elevated plasma homocysteine concentrations [12-50 µmol/L (n = 2919)] were randomly assigned to daily supplementation of 500 µg vitamin B12, 400 µg folic acid, and 600 IU vitamin D3, or to placebo with 600 IU vitamin D3. Physical performance (range 0-12) and handgrip strength (kg) were measured at baseline and after 2 years. Falls were reported prospectively on a research calendar. Intention-to-treat (primary) and per-protocol (secondary) analyses were performed. Physical performance level and handgrip strength significantly decreased during the follow-up period, but this decline did not differ between groups. Moreover, time to first fall was not significantly different (HR: 1.0, 95% CI 0.9-1.2). Secondary analyses on a per-protocol base identified an interaction effect with age on physical performance. In addition, the treatment was associated with higher follow-up scores on the walking test (cumulative OR: 1.3, 95% CI 1.1-1.5). Two-year supplementation of vitamin B12 and folic acid was neither effective in reducing the age-related decline in physical performance and handgrip strength, nor in the prevention of falling in elderly persons. Despite the overall null-effect, the results provide indications for a positive effect of the intervention on gait, as well as on physical performance among compliant persons >80 years. These effects should be further tested in future studies.

Effect of vitamin B12 and folic acid supplementation on biomarkers of endothelial function and inflammation among elderly individuals with hyperhomocysteinemia.

B-vitamin trials failed to demonstrate beneficial effects on cardiovascular outcomes, but hyperhomocysteinemia still stands out as an independent cardiovascular risk factor, particularly in elderly individuals. B-vitamins may influence early vascular dysfunction, such as endothelial dysfunction, or may have adverse effects, for example on inflammation. We investigated the effect of B-vitamins on endothelial function and inflammation within an interventional study. This study was conducted within the framework of the B-PROOF trial, which included 2919 hyperhomocysteinemic elderly individuals, who received daily vitamin B12 (500 µg) and folic acid (400 µg) or placebo for 2 years. Using an electrochemiluminescence platform, we measured intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), serum amyloid A (SAA), vascular endothelial growth factor (VEGF) and C-reactive protein (CRP) at baseline and follow-up in a subsample of 522 participants (271 intervention group; 251 placebo). Treatment effects were analyzed with ANCOVA. The participants had a mean age of 72 years, and 55% of them were male. At the 2-year follow-up, B-vitamins did not change the ICAM-1 (+36% change in the intervention group versus +32% change in the placebo group; p = 0.72), VCAM-1 (+27% vs +25%; p = 0.39), VEGF (-1% vs +4%; p = 0.40), SAA (+34% vs +38%; p = 0.85) or CRP levels (+26% vs +36%; p = 0.70) as compared to placebo. In conclusion, in elderly patients with hyperhomocysteinemia, vitamin B12 and folic acid are unlikely to influence either endothelial function or low-grade systemic inflammation. ClinicalTrials.gov Identifier: NCT00696514.

Effect of Vitamin B12 and Folic Acid Supplementation on Bone Mineral Density and Quantitative Ultrasound Parameters in Older People with an Elevated Plasma Homocysteine Level: B-PROOF, a Randomized Controlled Trial.

High plasma homocysteine (Hcy) levels are associated with increased osteoporotic fracture incidence. However, the mechanism remains unclear. We investigated the effect of Hcy-lowering vitamin B12 and folic acid treatment on bone mineral density (BMD) and calcaneal quantitative ultrasound (QUS) parameters. This randomized, double-blind, placebo-controlled trial included participants aged ≥65 years with plasma Hcy levels between 12 and 50 µmol/L. The intervention comprised 2-year supplementation with either a combination of 500 µg B12, 400 µg folic acid, and 600 IU vitamin D or placebo with 600 IU vitamin D only. In total, 1111 participants underwent repeated dual-energy X-ray assessment and 1165 participants underwent QUS. Femoral neck (FN) BMD, lumbar spine (LS) BMD, calcaneal broadband ultrasound attenuation (BUA), and calcaneal speed of sound (SOS) were assessed. After 2 years, FN-BMD and BUA had significantly decreased, while LS-BMD significantly increased (all p < 0.01) and SOS did not change in either treatment arm. No statistically significant differences between the intervention and placebo group were present for FN-BMD (p = 0.24), LS-BMD (p = 0.16), SOS (p = 0.67), and BUA (p = 0.96). However, exploratory subgroup analyses revealed a small positive effect of the intervention on BUA at follow-up among compliant persons >80 years (estimated marginal mean 64.4 dB/MHz for the intervention group and 61.0 dB/MHz for the placebo group, p = 0.04 for difference). In conclusion, this study showed no overall effect of treatment with vitamin B12 and folic acid on BMD or QUS parameters in elderly, mildly hyperhomocysteinemic persons, but suggests a small beneficial effect on BUA in persons >80 years who were compliant in taking the supplement.

Non-linear associations between serum 25-OH vitamin D and indices of arterial stiffness and arteriosclerosis in an older population.

BACKGROUND: several studies have been pointing towards a non-linear relationship between serum 25(OH)D and cardiovascular disease. Next to vitamin D deficiency, also higher levels of 25(OH)D have been reported to be associated with increased cardiovascular risk. We aimed to investigate the nature of the relationship between serum 25(OH)D and measures of arterial stiffness and arteriosclerosis in an elderly population. DESIGN: cross-sectional. SETTING/SUBJECTS: a subgroup of the B-PROOF study was included to determine associations between serum 25(OH)D and arterial stiffness and atherosclerosis (n = 567, 57% male, age 72.6 ± 5.6 years, mean serum 25(OH)D 54.6 ± 24.1 nmol/l). METHODS: carotid intima media thickness (IMT) was assessed using ultrasonography and pulse wave velocity (PWV) was determined with applanation tonometry. Associations were tested using multivariable restricted cubic spline functions and stratified linear regression analysis. RESULTS: the associations between serum 25(OH)D and carotid IMT or PWV were non-linear. Spline functions demonstrated a difference between 25(OH)D deficient and sufficient individuals. In serum 25(OH)D sufficient participants (≥50 nmol/l; n = 287), a positive association with IMT and serum 25(OH)D was present (ß 1.24; 95%CI [0.002; 2.473]). PWV levels were slightly lower in vitamin D deficient individuals, but the association with 25(OH)D was not significant. CONCLUSION: our study demonstrates that associations of serum 25(OH)D and PWV and IMT in an elderly population are not linear. In particular from serum 25(OH)D levels of 50 nmol/l and up, there is a slight increase of IMT with increasing 25(OH)D levels.

Exploring changes in integration, differentiation, rules, coordination and performance following the introduction of a hospital planning centre: a case study.

PURPOSE: This study explores how a hospital works, which is important for further enhancing hospital performance. Following the introduction of a Hospital Planning Centre (HPC), changes are explored in a hospital in terms of integration (the coordination and alignment of tasks), differentiation (the extent to which tasks are segmented into subsystems), rules, coordination mechanisms and hospital performance. DESIGN/METHODOLOGY/APPROACH: A case study was conducted examining the hospital's social network, rules, coordination mechanisms and performance both before and after the introduction of the HPC. All planning and execution tasks for surgery patients were studied using a naturalistic inquiry and mixed-method approach. FINDINGS: After the introduction of the HPC, the overall network structure and coordination mechanisms and coordination mechanisms remained largely the same. Integration and certain rules changed for specific planning tasks. Differentiation based on medical discipline remained. The number of local rules decreased and hospital-wide rules increased, and these remained largely in people's minds. Coordination mechanisms remained largely unchanged, primarily involving mutual adjustment and standardization of work both before and after the introduction of the HPC. Overall, the hospital's performance did not change substantially. The findings suggest that integration seems to "emerge" instead of being designed. Hospitals could benefit, we argue, from a more conscious system-wide approach that includes collective learning and information sharing. ORIGINALITY/VALUE: This exploratory study provides in-depth insight into how a hospital works, yielding important knowledge for further research and the enhancement of hospital performance.

Explaining integration and differentiation by identifying the rules and coordination mechanisms in a hospital's logistical system.

PURPOSE: Integration, that is, the coordination and alignment of tasks, is widely promoted as a means to improve hospital performance. A previous study examined integration and differentiation, that is, the extent to which tasks are segmented into subsystems, in a hospital's social network. The current study carries this research further, aiming to explain integration and differentiation by studying the rules and coordination mechanisms that agents in a hospital network use. DESIGN/METHODOLOGY/APPROACH: The current case study deepens the analysis of the social network in a hospital. All planning tasks and tasks for surgery performance were studied, using a naturalistic inquiry approach and a mixed method. FINDINGS: Of the 314 rules found, 85% predominantly exist in people's minds, 31% are in documents and 7% are in the information system. In the early planning stages for a surgery procedure, mutual adjustment based on hospital-wide rules is dominant. Closer to the day of surgery, local rules are used and open loops are closed through mutual adjustment, thus achieving integration. On the day of surgery, there is mainly standardization of work and output, based on hospital-wide rules. The authors propose topics for future research, focusing on increasing the hospital's robustness and stability. ORIGINALITY/VALUE: This exploratory case study provides an overview of the rules and coordination mechanisms that are used for organizing hospital-wide logistics for surgery patients. The findings are important for future research on how integration and differentiation are effectively achieved in hospitals.

Genetic variants modify the associations of concentrations of methylmalonic acid, vitamin B-12, vitamin B-6, and folate with bone mineral density.

BACKGROUND: Elevated plasma homocysteine has been found to be associated with an increased risk of osteoporosis, especially hip and vertebral fractures. The plasma concentration of homocysteine is dependent on the activities of several B vitamin-dependent enzymes, such as methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), and cystathionine ß-synthase (CBS). OBJECTIVES: We investigated whether genetic variants in some of the genes involved in 1 carbon metabolism modify the association of B vitamin-related measures with bone mineral density (BMD) and strength. METHODS: We measured several B vitamins and biomarkers in participants of the Framingham Offspring Study, and performed analyses of methylmalonic acid (MMA) continuously and <210 nmol/L; pyridoxal-5'-phosphate; vitamin B-12 continuously and ≥258 pmol/L; and folate. The outcomes of interest included areal and volumetric BMD, measured by DXA and quantitative computed tomography (QCT), respectively. We evaluated associations between the bone measures and interactions of single nucleotide polymorphism with a B vitamin or biomarker in Framingham participants (n = 4310 for DXA and n = 3127 for QCT). For analysis of DXA, we validated the association results in the B-PROOF cohort (n = 1072). Bonferroni-corrected locus-wide significant thresholds were defined to account for multiple testing. RESULTS: The interactions between rs2274976 and vitamin B-12 and rs34671784 and MMA <210 nmol/L were associated with lumbar spine BMD, and the interaction between rs6586281 and vitamin B-12 ≥258 pmol/L was associated with femoral neck BMD. For QCT-derived traits, 62 interactions between genetic variants and B vitamins and biomarkers were identified. CONCLUSIONS: Some genetic variants in the 1-carbon methylation pathway modify the association of B vitamin and biomarker concentrations with bone density and strength.  These interactions require further replication and functional validation for a mechanistic understanding of the role of the 1-carbon metabolism pathway on BMD and risks of fracture.

No independent associations between preconception paternal dietary patterns and embryonic growth; the Predict Study.

BACKGROUND & AIM: Several studies show the importance of periconceptional maternal dietary patterns on human embryonic growth. Healthy paternal nutrition has been associated with better semen quality and fecundability, however, evidence on the impact on pregnancy outcome is limited. Therefore, the aim of this study was to investigate the association between preconception paternal dietary patterns and first trimester embryonic growth using the parameters longitudinal crown-rump length (CRL) and embryonic volume (EV). METHODS: A total of 638 couples were enrolled in the Rotterdam Periconceptional Cohort and received longitudinal three dimensional transvaginal ultrasound scans from 7+0 up to 12+0 weeks of gestation. Virtual reality software was used to perform offline measurements of the embryonic CRL and EV. Food frequency questionnaires (FFQ) were used to estimate habitual food intake in couples. Principal component analysis (PCA) was performed to identify paternal and maternal dietary patterns. Linear mixed models adjusted for potential confounders were applied to analyze associations between paternal and maternal dietary patterns and embryonic growth parameters. RESULTS: The paternal dietary patterns retrieved were identified as "Whole wheat grains and Vegetables", "Sauces and Snacks Refined Grains", "Fish and Legumes" and explained 27.5% of the total variance of the dietary intake. No significant additional effects, independent of maternal dietary patters and other maternal and paternal potential confounders, were shown of these paternal dietary patterns on embryonic growth in spontaneous or IVF/ICSI pregnancies. CONCLUSION: No significant effects of paternal dietary patterns independent of maternal dietary patters and other parental potential confounders on embryonic growth parameters could be established in spontaneous or IVF/ICSI pregnancies. The biological importance of paternal nutrition on semen quality, however, supports the need of periconceptional tailored nutritional counselling of couples trying to conceive.

CYP2C9 Genotypes Modify Benzodiazepine-Related Fall Risk: Original Results From Three Studies With Meta-Analysis.

OBJECTIVE: To investigate whether the CYP2C9*2 and *3 variants modify benzodiazepine-related fall risk. DESIGN: Three prospective studies; the Rotterdam Study, B-PROOF, and LASA. SETTING: Community-dwelling individuals living in or near five Dutch cities. PARTICIPANTS: There were 11,485 participants aged ≥55 years. MEASUREMENTS: Fall incidents were recorded prospectively. Benzodiazepine use was determined using pharmacy dispensing records or interviews. Cox proportional hazard models adjusted for age and sex were applied to determine the association between benzodiazepine use and fall risk stratified for CYP2C9 genotype and comparing benzodiazepine users to nonusers. The results of the three studies were combined applying meta-analysis. Within benzodiazepine users, the association between genotypes and fall risk was also assessed. RESULTS: Three thousand seven hundred five participants (32%) encountered a fall during 91,996 follow-up years, and 4% to 15% (depending on the study population) used benzodiazepines. CYP2C9 variants had frequencies of 13% for the *2 allele and 6% for the *3 allele. Compared to nonusers, current benzodiazepine use was associated with an 18% to 36% increased fall risk across studies with a combined hazard ratio (HR) = 1.26 (95% confidence interval [CI], 1.13; 1.40). CYP2C9*2 or *3 allele variants modified benzodiazepine-related fall risk. Compared to nonusers, those carrying a CYP2C9*2 or *3 allele and using benzodiazepines had a 45% increased fall risk (HR, 1.45 95% CI, 1.21; 1.73), whereas CYP2C9*1 homozygotes using benzodiazepines had no increased fall risk (HR, 1.14; 95% CI, 0.90; 1.45). Within benzodiazepine users, having a CYP2C9*2 or *3 allele was associated with an increased fall risk (HR, 1.35; 95% CI, 1.06; 1.72). Additionally, we observed an allele dose effect; heterozygous allele carriers had a fall risk of (HR = 1.30; 95% CI, 1.05; 1.61), and homozygous allele carriers of (HR = 1.91 95% CI, 1.23; 2.96). CONCLUSIONS: CYP2C9*2 and *3 allele variants modify benzodiazepine-related fall risk. Those using benzodiazepines and having reduced CYP2C9 enzyme activity based on their genotype are at increased fall risk. In clinical practice, genotyping might be considered for elderly patients with an indication for benzodiazepine use. However, because the exact role of CYP2C9 in benzodiazepine metabolism is still unclear, additional research is warranted.

Relative importance of summer sun exposure, vitamin D intake, and genes to vitamin D status in Dutch older adults: The B-PROOF study.

BACKGROUND/OBJECTIVES: The prevalence of vitamin D deficiency among seniors is high. Whereas sun exposure, vitamin D intake, genes, demographics, and lifestyle have been identified as being important determinants of vitamin D status, the impact of these factors is expected to differ across populations. To improve current prevention and treatment strategies, this study aimed to explore the main determinants of vitamin D status and its relative importance in a population of community-dwelling Dutch older adults. METHODS/SUBJECTS: Serum 25-hydroxyvitamin D (25(OH)D) was measured in 2857 adults aged ≥65 years. Sun exposure was assessed with a structured questionnaire (n=1012), vitamin D intake using a Food Frequency Questionnaire (n=596), and data on genetic variation that may affect 25(OH)D status was obtained for 4 genes, DHCR7 (rs12785878), CYP2R1 (rs10741657), GC (rs2282679), and CYP24A1 (rs6013897) (n=2530). RESULTS: Serum 25(OH)D concentrations <50nmol/L were observed in 45% of the population; only 6% of these participants used vitamin D supplements. Sun exposure (being outside daily during summer: 66±25nmol/L vs not being outside daily during summer: 58±27nmol/L, P=0.02) and vitamin D intake (per unit µg/day during winter/spring: 3.1±0.75nmol/L, P<0.0001) were associated with higher 25(OH)D concentrations. Major allele carriers of SNPs related to DHCR7, CYP24A1, and GC, as well as CYP2R1 minor allele carriers had the highest 25(OH)D concentrations. Together, sun (R2=0.29), vitamin D intake (R2=0.24), and genes (R2=0.28) explained 35% (R2=0.35) of the variation in 25(OH)D concentrations during summer/autumn period, when adjusted for age, sex, BMI, education, alcohol consumption, smoking, physical activity, and self-rated health status (n=185). CONCLUSION: The investigated determinants explained 35% of 25(OH)D status. Of the three main determinants under study, sun exposure still appeared to be an important determinant of serum 25(OH)D in older individuals, closely followed by genes, and vitamin D intake. Given the low frequency of vitamin D supplement use in this population, promoting supplement use may be an inexpensive, easy, and effective strategy to fight vitamin D deficiency.

Effects of Two-Year Vitamin B12 and Folic Acid Supplementation on Depressive Symptoms and Quality of Life in Older Adults with Elevated Homocysteine Concentrations: Additional Results from the B-PROOF Study, an RCT.

Lowering elevated plasma homocysteine (Hcy) concentrations by supplementing vitamin B12 and folic acid may reduce depressive symptoms and improve health-related quality of life (HR-QoL) in older adults. This study aimed to test this hypothesis in a randomized controlled trial. Participants (N = 2919, ≥65 years, Hcy concentrations ≥12 µmol/L) received either 500 µg vitamin B12 and 400 µg folic acid daily or placebo for two years. Both tablets contained 15 µg vitamin D3. Depressive symptoms were measured with the Geriatric Depression Scale-15 (GDS-15). HR-QoL was assessed with the SF-12 Mental and Physical component summary scores and the EQ-5D Index score and Visual Analogue Scale. Differences in two-year change scores were analyzed with Analysis of Covariance (ANCOVA). Hcy concentrations decreased more in the intervention group, but two-year change scores of the GDS-15 and three of four HR-QoL measures did not differ between groups. The EQ-5D Index score declined less in the intervention group than in the placebo group (mean change 0.00 vs. -0.02, p = 0.004). In conclusion, two-year supplementation with vitamin B12 and folic acid in older adults with hyperhomocysteinemia showed that lowering Hcy concentrations does not reduce depressive symptoms, but it may have a small positive effect on HR-QoL.

Effects of 2-year vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly on arterial stiffness and cardiovascular outcomes within the B-PROOF trial.

INTRODUCTION: Hyperhomocysteinemia is an important cardiovascular risk indicator in the oldest old, and is associated with elevated arterial stiffness in this age group. Since several intervention trials reported a lack of benefit of B-vitamin supplementation on cardiovascular outcomes, we aimed to investigate the effect of B-vitamin supplementation on arterial stiffness and atherosclerosis in hyperhomocysteinemic elderly patients. METHODS: The B-PROOF study is a double-blind, randomized controlled trial, including 2919 elderly aged at least 65 years, with hyperhomocysteinemia (12-50  µmol/l), treated with B-vitamins (500  µg vitamin B12 and 400  µg folic acid) or placebo for 2 years. In a subgroup (n = 569), the effect of B-vitamins on pulse wave velocity (PWV) was investigated as a measurement of arterial stiffness. To measure atherosclerosis, carotid intima-media thickness (IMT) measures had been used. Incidents of cardiovascular and cerebrovascular events were determined via structured questionnaires, and blood pressure was also measured. RESULTS: Compared to placebo, B-vitamin supplementation lowered serum homocysteine by 3.6  µmol/l (P < 0.001). Analysis of covariance showed no effect of supplementation on PWV levels, and this was not different for patients without increased arterial stiffness at baseline. Furthermore, no effect on carotid IMT was observed. DISCUSSION: Vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly patients have no effect on PWV or carotid IMT. Further research will still be necessary to unravel the effects and pathways of homocysteine-lowering treatment on cardiovascular outcomes.

Cognitive Performance: A Cross-Sectional Study on Serum Vitamin D and Its Interplay With Glucose Homeostasis in Dutch Older Adults.

OBJECTIVES: First, the association between serum 25-hydroxyvitamin D (25[OH]D) and cognitive performance was examined. Second, we assessed whether there was evidence for an interplay between 25(OH)D and glucose homeostasis in the association with cognitive performance. DESIGN, SETTING, AND PARTICIPANTS: Associations were studied using cross-sectional data of 776 (3 domains) up to 2722 (1 domain) Dutch community-dwelling older adults, aged 65 years or older. MEASUREMENTS: Serum 25(OH)D, plasma glucose, and insulin concentrations were obtained. Cognitive performance was assessed with an extensive cognitive test battery. Prevalence ratios (PRs) were calculated to quantify the association between 25(OH)D and cognition; poor performance was defined as the worst 10% of the distribution of the cognitive scores. RESULTS: The overall median MMSE score was 29 (IQR 28-30). Higher serum 25(OH)D was associated with better attention and working memory, PR 0.50 (95% CI 0.29-0.84) for the third serum 25(OH)D tertile, indicating a 50% lower probability of being a poor performer than participants in the lowest tertile. Beneficial trends were shown for 25(OH)D with executive function and episodic memory. Serum 25(OH)D was not associated with plasma glucose or insulin. Plasma insulin only modified the association between serum 25(OH)D and executive function (P for interaction: .001), suggesting that the improvement in executive function with high 25(OH)D concentrations is stronger in participants with high plasma insulin concentrations compared with those with low plasma insulin concentrations. CONCLUSION: Higher 25(OH)D concentrations significantly associated with better attention and working memory performance. This study does not demonstrate an interplay between serum 25(OH)D and glucose homeostasis in the association with cognitive performance.