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The impact of zinc and folic acid supplementation on sperm DNA methylation: results from the folic acid and zinc supplementation randomized clinical trial (FAZST).
Jenkins, T, Aston, K, Carrell, D, DeVilbiss, E, Sjaarda, L, Perkins, N, Mills, JL, Chen, Z, Sparks, A, Clemons, T, et al
Fertility and sterility. 2022;(1):75-85
Abstract
OBJECTIVE To determine if 6-month folic acid (5 mg) and zinc (30 mg) supplementation impacts sperm DNA methylation patterns. DESIGN A multicenter, double-blind, block randomized, placebo-controlled trial titled "The Folic Acid and Zinc Supplementation Trial (FAZST)." SETTING Infertility care centers. PATIENT(S): Male partners (18 years and older) from heterosexual couples (female partners aged 18-45 years) seeking fertility treatment were recruited. INTERVENTION(S): Men were randomized 1:1 to receive folic acid (5 mg) and elemental zinc (30 mg) (n = 713) or a matching placebo (n = 757) daily for 6 months. MAIN OUTCOME MEASURE(S): Sperm DNA methylation was analyzed using the EPIC methylation array (Illumina) at 6 months. Differential sperm DNA methylation was assessed at multiple levels (regional, single cytosine phosphate guanine, etc.). We additionally assessed the impact of supplementation on epigenetic age. RESULT(S): No significant differences were identified between the treatment and placebo groups although some trends appeared to be present. To determine if these trends were noteworthy, we implemented various permutations and found that the patterns we identified were no more than would be expected by random chance. CONCLUSION(S): The data presented here strongly suggest that this supplementation regimen is not effective at altering sperm DNA methylation. These data comport well with previous findings from the FAZST study that found no impact of supplementation on basic semen analysis parameters or live birth. CLINICAL TRIAL REGISTRATION NUMBER ClinicalTrials.gov Identifier: NCT01857310.
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A pilot study of thiamin and folic acid in hemodialysis patients with cognitive impairment.
Lu, R, Fang, Y, Zhou, Y, Che, M, Shen, J, Liu, Q, Zhang, H, Pan, S, Lin, Y, Wang, Q, et al
Renal failure. 2021;(1):766-773
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Abstract
OBJECTIVE This study aimed to explore the effectiveness of thiamin and folic acid supplementation on the improvement of the cognitive function in patients with maintenance hemodialysis. METHOD In the present study, we randomly assigned patients undergoing hemodialysis who had the Montreal Cognitive Assessment (MoCA) score lower than 26 to treatment group (n = 25, thiamin 90 mg/day combined with folic acid 30 mg/day) or control group (n = 25, nonintervention). All subjects were followed up for 96 weeks. The primary outcome was the improvement of the MoCA score. The secondary outcomes included homocysteine level, survival and safety. RESULTS Patients in treatment group had an increase of the MoCA score from 21.95 ± 3.81 at baseline to 25.68 ± 1.96 at week 96 (p < 0.001, primary outcome), as compared with the MoCA score from 20.69 ± 3.40 to 19.62 ± 3.58 in control group. Thiamin combined with folic acid treatment also resulted in lower level of serum homocysteine in treatment group compare with control group at week 96 (p < 0.05, secondary outcome). 3 patients and 9 patients died during follow-up period in treatment and control group respectively (p = 0.048). The proportion of adverse events in treatment group was significantly lower than that in control group. CONCLUSION Hemodialysis patients with cognitive impairment treated with thiamin and folic acid had a significant improvement in MoCA score.
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Immunogenicity of an oral rotavirus vaccine administered with prenatal nutritional support in Niger: A cluster randomized clinical trial.
Isanaka, S, Garba, S, Plikaytis, B, Malone McNeal, M, Guindo, O, Langendorf, C, Adehossi, E, Ciglenecki, I, Grais, RF
PLoS medicine. 2021;(8):e1003720
Abstract
BACKGROUND Nutritional status may play a role in infant immune development. To identify potential boosters of immunogenicity in low-income countries where oral vaccine efficacy is low, we tested the effect of prenatal nutritional supplementation on immune response to 3 doses of a live oral rotavirus vaccine. METHODS AND FINDINGS We nested a cluster randomized trial within a double-blind, placebo-controlled randomized efficacy trial to assess the effect of 3 prenatal nutritional supplements (lipid-based nutrient supplement [LNS], multiple micronutrient supplement [MMS], or iron-folic acid [IFA]) on infant immune response (n = 53 villages and 1,525 infants with valid serology results: 794 in the vaccine group and 731 in the placebo group). From September 2015 to February 2017, participating women received prenatal nutrient supplement during pregnancy. Eligible infants were then randomized to receive 3 doses of an oral rotavirus vaccine or placebo at 6-8 weeks of age (mean age: 6.3 weeks, 50% female). Infant sera (pre-Dose 1 and 28 days post-Dose 3) were analyzed for anti-rotavirus immunoglobulin A (IgA) using enzyme-linked immunosorbent assay (ELISA). The primary immunogenicity end point, seroconversion defined as ≥3-fold increase in IgA, was compared in vaccinated infants among the 3 supplement groups and between vaccine/placebo groups using mixed model analysis of variance procedures. Seroconversion did not differ by supplementation group (41.1% (94/229) with LNS vs. 39.1% (102/261) with multiple micronutrients (MMN) vs. 38.8% (118/304) with IFA, p = 0.91). Overall, 39.6% (n = 314/794) of infants who received vaccine seroconverted, compared to 29.0% (n = 212/731) of infants who received placebo (relative risk [RR]: 1.36; 95% confidence interval [CI]: 1.18, 1.57, p < 0.001). This study was conducted in a high rotavirus transmission setting. Study limitations include the absence of an immune correlate of protection for rotavirus vaccines, with the implications of using serum anti-rotavirus IgA for the assessment of immunogenicity and efficacy in low-income countries unclear. CONCLUSIONS This study showed no effect of the type of prenatal nutrient supplementation on immune response in this setting. Immune response varied depending on previous exposure to rotavirus, suggesting that alternative delivery modalities and schedules may be considered to improve vaccine performance in high transmission settings. TRIAL REGISTRATION ClinicalTrials.gov NCT02145000.
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Cobalamin and folate status in women during early pregnancy in Bhaktapur, Nepal.
Schwinger, C, Sharma, S, Chandyo, RK, Hysing, M, Kvestad, I, Ulak, M, Ranjitkar, S, Shrestha, M, Shrestha, LP, McCann, A, et al
Journal of nutritional science. 2021;:e57
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The demand for cobalamin (vitamin B12) and folate is increased during pregnancy, and deficiency during pregnancy may lead to complications and adverse outcomes. Yet, the status of these micronutrients is unknown in many populations. We assessed the concentration of cobalamin, folate and their functional biomarkers, total homocysteine (tHcy) and methylmalonic acid (MMA), in 561 pregnant women enrolled in a community-based randomised controlled trial in Bhaktapur, Nepal. Plasma concentrations of cobalamin, folate, tHcy and MMA were measured and a combined indicator of vitamin B12 status (3cB12) was calculated. We report mean or median concentrations and the prevalence of deficiency according to commonly used cut-offs, and assessed their association with indicators of socio-economic status, and maternal and dietary characteristics by linear regression. Among the women at gestational week less than 15, deficiencies of cobalamin and folate were seen in 24 and 1 %, respectively. Being a vegetarian was associated with lower plasma cobalamin, and a higher socio-economic status was associated with a better micronutrient status. We conclude that cobalamin deficiency defined by commonly used cut-offs was common in Nepalese women in early pregnancy. In contrast, folate deficiency was rare. As there is no consensus on cut-off points for vitamin B12 deficiency during pregnancy, future studies are needed to assess the potential functional consequences of these low values.
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Feasibility and acceptability of a nutritional intervention testing the effects of nitrate-rich beetroot juice and folic acid on blood pressure in Tanzanian adults with elevated blood pressure.
Kandhari, N, Prabhakar, M, Shannon, O, Fostier, W, Koehl, C, Rogathi, J, Temu, G, Stephan, BCM, Gray, WK, Haule, I, et al
International journal of food sciences and nutrition. 2021;(2):195-207
Abstract
Sub-Saharan African countries are experiencing an alarming increase in hypertension prevalence. This study evaluated the feasibility and acceptability of nitrate-rich beetroot and folate supplementation, alone or combined, for the reduction of blood pressure (BP) in Tanzanian adults with elevated BP. This was a three-arm double-blind, placebo-controlled, parallel randomised clinical trial. Forty-eight participants were randomised to one of three groups to follow a specific 60-day intervention which included a: (1) combined intervention (beetroot juice + folate), (2) single intervention (beetroot juice + placebo), and (3) control group (nitrate-depleted beetroot juice + placebo). Forty-seven participants (age: 50-70 years) completed the study. The acceptability of the interventions was high. Self-reported compliance to the interventions was more than 90% which was confirmed by the significant increase in nitrate and folate concentrations in plasma and saliva samples in the treatment arms. This study provides important information for the design of high-nitrate interventions to reduce BP in Sub-Saharan African countries.
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Interaction of serum calcium and folic acid treatment on first stroke in hypertensive males.
Wu, H, Zhang, Y, Li, H, Li, J, Zhang, Y, Liang, M, Nie, J, Wang, B, Wang, X, Huo, Y, et al
Clinical nutrition (Edinburgh, Scotland). 2021;(4):2381-2388
Abstract
BACKGROUND & AIMS The role of serum calcium on the risk of stroke is still uncertain. We aimed to evaluate the effect of serum calcium on first stroke risk, and on the efficacy of folic acid treatment in prevention of first stroke among hypertensive patients. METHODS Our analyses included a total of 19,644 eligible hypertensive adults from the China Stroke Primary Prevention Trial (CSPPT). In the CSPPT, a total of 20,702 hypertensive patients were randomly assigned to a double-blind, daily treatment with either 10 mg enalapril and 0.8 mg folic acid or 10 mg enalapril alone. The primary outcome was a first stroke. RESULTS Over a median of 4.5 years, among those not receiving folic acid, a significantly higher risk of first stroke was found in hypertensive males with baseline albumin-corrected serum calcium ≥2.43 mmol/L (median) (vs. <2.43 mmol/L; 6.5% vs. 2.3%; adjusted HR, 2.47; 95% CI: 1.72, 3.55). For those with enalapril and folic acid treatment, compared with the enalapril only group, the risk of first stroke was reduced from 6.5% to 3.0% (adjusted HR, 0.49; 95% CI: 0.35, 0.68) in hypertensive males with baseline albumin-corrected serum calcium ≥2.43 mmol/L, whereas there was no significant effect among hypertensive males with baseline albumin-corrected serum calcium <2.43 mmol/L. However, among hypertensive females, serum calcium did not significantly affect the first stroke risk and the efficacy of folic acid in prevention of first stroke. CONCLUSIONS Among Chinese hypertensive males, those with elevated serum calcium levels had increased risk of first stroke, and this risk was reduced by 51% with folic acid treatment.
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Positive effects of folic acid supplementation on cognitive aging are dependent on ω-3 fatty acid status: a post hoc analysis of the FACIT trial.
van Soest, APM, van de Rest, O, Witkamp, RF, de Groot, LCPGM
The American journal of clinical nutrition. 2021;(4):801-809
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BACKGROUND Although epidemiological studies suggest a protective role of B vitamins and omega-3 (ω-3) fatty acids in cognitive decline, findings from intervention studies are conflicting. Mechanistic studies suggest that the ω-3 (n-3) fatty acid status can modulate the effects of B vitamins on cognitive decline. OBJECTIVES We investigated the interaction between baseline ω-3 fatty acid statuses and folic acid treatment on cognitive decline in a placebo-controlled trial [FACIT (Folic Acid and Carotid Intima-media Thickness)]. METHODS This post hoc analysis included 791 older adults aged 50-70 y with plasma total homocysteine ≥13 µmol/L and ≤26 µmol/L and serum vitamin B12 ≥200 pmol/L. Participants received 800 µg folic acid or placebo daily for 3 y. Global cognitive functioning and domain-specific functioning (episodic memory, information processing speed, executive functioning) were assessed at baseline and after 3 y. The effect of the folic acid supplementation was analyzed according to tertiles of baseline ω-3 fatty acid concentrations using linear multiple regression. RESULTS The mean ± SD age of the study population was 60.2 ± 5.6 y, and the mean ± SD Mini-Mental State Examination score was 28.6 ± 1.5. The treatment effect of folic acid was significantly larger in participants in the low compared to high ω-3 fatty acid tertile for global cognition (difference in z-score: mean ± SE = 0.16 ± 0.059; P < 0.01). Regarding domain-specific functioning, similar results were observed for information processing speed (mean ± SE = 0.167 ± 0.068; P = 0.01). There were no overall interactions between folic acid treatment and ω-3 fatty acid tertiles for episodic memory (P = 0.14) and executive functioning (P = 0.21). CONCLUSIONS This post hoc analysis revealed that the efficacy of folic acid treatment on cognitive functioning is dependent on the ω-3 fatty acid status. Individuals with a lower ω-3 fatty acid status at baseline benefited from folic acid treatment, while individuals with a higher ω-3 fatty acid status did not. The results potentially explain the inconsistency in outcomes of B-vitamin supplementation trials and emphasize the importance of a personalized approach. This trial was registered at clinicaltrials.gov as NCT00110604.
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Unexpected interactions between dolutegravir and folate: randomized trial evidence from South Africa.
Chandiwana, NC, Chersich, M, Venter, WDF, Akpomiemie, G, Hill, A, Simmons, B, Lockman, S, Serenata, CM, Fairlie, L, Moorhouse, MA
AIDS (London, England). 2021;(2):205-211
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OBJECTIVE Dolutegravir exposure at conception was associated with a preliminary signal of increased infant neural tube defect risk. As low maternal folate levels are linked with neural tube defects, we aimed to assess serum folate concentrations in women starting dolutegravir. DESIGN We analysed serum folate concentrations from stored plasma among women enrolled in the South African ADVANCE trial. METHODS We compared changes in mean serum folate and occurrence of low serum folate (<14.0 nmol/l) at weeks 0, 12 and 24 across study arms. In ADVANCE, 1053 treatment-naïve participants were randomized to initiate tenofovir-alafenamide/emtricitabine + dolutegravir (TAF/FTC + DTG), tenofovir-disoproxil-fumarate (TDF)/FTC + DTG or TDF/FTC/efavirenz (EFV). RESULTS Analysis includes 406 females, mean age 31.5 years and baseline CD4+ cell count 356 cells/μl. At baseline, folate concentrations were similar across treatment arms. However, serum folate increased over 12 weeks in the TAF/FTC + DTG arm (+4.0 ± 8.1 nmol/l), while folate concentrations decreased slightly in the TDF/FTC + DTG arm (-1.8 ± 8.9 nmol/l) and decreased in the TDF/FTC/EFV arm (-5.9 ± 8.1 nmol/l). Women taking TDF/FTC/EFV had low folate concentrations at both 12 and 24 weeks compared with the other arms (P < 0.001). Of 26 women who became pregnant on study before week 24, folate concentrations increased between baseline and 12 weeks by a mean 2.4 ± 7.1 nmol/l in the TAF/FTC + DTG arm and 2.3 ± 8.4 nmol/l in the TDF/FTC + DTG arm, but decreased by -3.3 ± 8.1 with TDF/FTC/EFV arm. CONCLUSION Unexpectedly, no declines were noted in the dolutegravir-containing arms, and concentrations were considerably higher than in the EFV arm. The possibility that dolutegravir may block cellular uptake of folate warrants investigation.
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Effects of Folic Acid and Vitamin B12 Supplementation on Cognitive Impairment and Inflammation in Patients with Alzheimer's Disease: A Randomized, Single-Blinded, Placebo-Controlled Trial.
Chen, H, Liu, S, Ge, B, Zhou, D, Li, M, Li, W, Ma, F, Liu, Z, Ji, Y, Huang, G
The journal of prevention of Alzheimer's disease. 2021;(3):249-256
Abstract
OBJECTIVES To evaluate the combined action of folic acid and vitamin B12 supplementation on cognitive performance and inflammation in patients with Alzheimer's disease (AD). DESIGN This was a randomized, single-blind, placebo-controlled trial. PARTICIPANTS Patients (n=120) diagnosed clinically as probable AD and in stable condition from Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Diseases. MEASUREMENTS Individuals were randomly divided into the intervention group (n=60, folic acid 1.2 mg/d + vitamin B12 50 μg/d) and the placebo group (n=60). Cognitive performance, blood folate, vitamin B12, one carbon cycle metabolite, and inflammatory cytokine levels were measured at baseline and after 6 months. The data were analyzed using linear mixed models for repeated measures. RESULTS A total of 101 participants (51 in the intervention group and 50 in the placebo group) completed the trial. Folic acid plus vitamin B12 supplementation had a beneficial effect on the MoCA total scores (P=0.029), naming scores (P=0.013), orientation scores (P=0.004), and ADAS-Cog domain score of attention (P=0.008), as compared to those of the control subjects. Moreover, supplementation significantly increased plasma SAM (P<0.001) and SAM/SAH (P<0.001), and significantly decreased the levels of serum Hcy (P<0.001), plasma SAH (P<0.001), and serum TNFα (P<0.001) compared to in the control subjects. CONCLUSIONS Folic acid and vitamin B12 supplementation showed a positive therapeutic effect in AD patients who were not on a folic acid-fortified diet. The findings of this study help to delineate nutrient intervention as far as public health management for the prevention of dementia is concerned.
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Long-term effects of folic acid and vitamin-B12 supplementation on fracture risk and cardiovascular disease: Extended follow-up of the B-PROOF trial.
Oliai Araghi, S, Kiefte-de Jong, JC, van Dijk, SC, Swart, KMA, Ploegmakers, KJ, Zillikens, MC, van Schoor, NM, de Groot, LCPGM, Lips, P, Stricker, BH, et al
Clinical nutrition (Edinburgh, Scotland). 2021;(3):1199-1206
Abstract
BACKGROUND & AIMS In the initial B-proof, we found inconsistent results of B vitamin supplementation. However, the debate regarding the effects of B vitamins on age-related diseases continues. Therefore, our aim was to investigate the long-term effects (5-7 years follow-up) of an intervention with folic acid and vitamin-B12 supplementation on fracture and cardiovascular disease risk. METHODS Extended follow-up of the B-PROOF trial, a multi-center, double-blind randomized placebo-controlled trial designed to assess the effect of 2-3 years daily supplementation with folic acid (400 μg) and vitamin-B12 (500 μg) versus placebo (n = 2,919). Primary outcome was verified self-reported fracture incidence and secondary outcomes were self-reported cardiovascular endpoints, which were collected through a follow-up questionnaires Proportional hazard analyses was used for the effect of the intervention on risk of fracture(s) and logistic regression for the effect of the intervention on risk of cardiovascular disease. RESULTS A total of 1,298 individuals (44.5%) participated in the second follow-up round with median of 54 months [51-58], (n = 662 and n = 636, treatment versus placebo group). Median age at baseline was 71.0 years [68.0-76.0] for both groups. No effect was observed of the intervention on osteoporotic fracture or any fracture risk after a follow-up (HR: 0.99, 95% CI: 0.62-1.59 and HR: 0.77; 95% CI: 0.50-1.19, respectively), nor on cardiovascular or cerebrovascular disease risk (OR: 1.05; 95%CI: 0.80-1.44 and OR: 0.85; 95%CI: 0.50-1.45, respectively). Potential interaction by baseline homocysteine concentration was observed for osteoporotic- and any fracture (p = 0.10 and 0.06 respectively), which indicated a significantly lower risk of any fracture in the treatment group with higher total homocysteine concentrations (>15.1 μmol/l). No age-dependent effects were present. CONCLUSIONS This study supports and extends previous null-findings of the B-PROOF trial and shows that supplementation of folic acid and vitamin-B12 has no effect on fracture risk, nor on cardiovascular disease in older individuals over a longer follow-up period. However, B-vitamin supplementation may be beneficial in reducing fractures in individuals with high total homocysteine concentrations, a finding which needs to be replicated.