Low Folate Concentrations Research Articles

Association of serum folate concentrations with the mortality of cancer: a prospective cohort study.

The association between serum folate concentrations and the mortality of cancer remains unclear. We aim to investigate the association of serum folate concentrations with all-cause and cause-specific mortality among American adults with cancer. This cohort study included 4535 patients with cancer from National Health and Nutrition Examination Survey (NHANES) 1999 to 2016 and NHANES III (1988-1994). Death outcomes were ascertained by linkage to National Death Index records through 31 December 2019. Cox proportional hazards model and two-piecewise Cox proportional hazards model were used to calculate hazard ratios and 95% confidence intervals for the associations between folate concentrations and the risk of mortality. During a median follow-up of 37,792 person-years, there were 1998 all-cause deaths and 616 cancer deaths. Non-linear and L-shaped associations were observed between serum folate concentrations and the risk of all-cause and cancer mortality among patients with cancer. Notably, the mortality rates reached a plateau at 23.7ng/mL for all-cause mortality and 23.57ng/mL for cancer mortality. When folate levels fell below these thresholds, the risk of all-cause and cancer mortality decreased by approximately 2.1% (HR 0.979; 95% CI 0.969-0.989) and 3.6% (HR 0.964; 95% CI 0.948-0.981), respectively, with each unit increase in the folate concentration up to the thresholds. Our study reveals that low serum folate concentrations are linked to an elevated risk of cancer mortality among individuals with cancer within a certain range and supplementation of folate in cancer patients to achieve specific serum folate level threshold (23.7ng/mL) might reduce the risk of cancer mortality.

Folic Acid Supplementation to Prevent Neural Tube Defects Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

(JAMA. 2023;330(5):460–466) Neural tube defects are among the most commonly recorded birth defects for babies in the United States, and they are typically caused by low folate concentrations during conception and early gestation. These malformations can cause disabilities and even death in fetuses and children. In 2017, the United States Preventative Services Task Force (USPSTF) determined that women who increase their intake of folic acid before becoming pregnant can significantly help reduce the likelihood of their babies developing neural tube defects. The USPSTF also asserted their 2009 recommendation that patients should take 0.4 to 0.8 mg (400 to 800 μg) of folic acid daily if they were planning or capable of pregnancy, and that there was no consistent strong evidence of harmful adverse effects. This evidence report was conducted to analyze studies post-2017 for the USPSTF’s current recommendation on folic acid supplementation.

High red blood cell folate is associated with an increased risk of diabetes death among a hypertensive cohort

The relationship between folate and diabetes remains inconclusive, possibly because of folate measured differentially between studies. Interference from mandatory folic acid fortification (FAF) has also been blamed. With both folate intake and circulating concentration measured, we assessed the relationship between folate and the risk of diabetes death in a hypertensive cohort established before FAF. We hypothesized that the association between folate and diabetes death is measurement dependent. We analyzed the data of 3133 hypertensive adults aged ≥19 years who participated in the Third National Health and Nutrition Examination Survey (1991–1994) and were followed up through December 31, 2010. Hazard ratios of diabetes death were estimated for participants with high (4th quarter) folate compared with those with moderate (2nd and 3rd quarters) or low (1st quarter) concentrations of folate. Dietary folate intake, total folate intake (including folate from supplements), serum, and red blood cell (RBC) folate were measured. After 42,025 person-years of follow-up, 165 diabetes deaths were recorded, and a dose-response positive association was observed between diabetes death and RBC folate. The adjusted hazard ratios of diabetes death were 1.00 (reference), 1.42 (95% CI. 1.20–1.68), and 2.21 (1.73–2.82), respectively, for hypertensive adults with low, moderate, and high RBC folate. No association was detected between diabetes death and serum folate concentration, folate intake, or either dietary intake or total intake. With minimized interference from FAF, neither dietary nor serum folate was associated with diabetes death, but elevated RBC folate was associated with a high risk of diabetes deaths among hypertensive patients.

Folic acid alleviated oxidative stress-induced telomere attrition and inhibited apoptosis of neurocytes in old rats.

Oxidative stress has been reported to cause telomere attrition, which triggers cell apoptosis. Apoptosis of neurocytes may play an essential role in the pathogenesis of neurodegenerative diseases. This study hypothesized that folic acid (FA) supplementation decreased neurocyte apoptosis by alleviating oxidative stress-induced telomere attrition in 25-month-old Sprague Dawley (SD) rats. Three-month-old male SD rats were randomly divided into four diet groups by different concentrations of folic acid in equal numbers, with intervention for 22months. Folate, homocysteine (Hcy), reactive oxygen species (ROS) levels, antioxidant activities, and telomere length in the brain tissues were tested at 11, 18, and 22months of intervention, and 8-hydroxy-deoxyguanosine (8-OHdG) levels, neurocyte apoptosis and telomere length in the cerebral cortex and hippocampal regions were tested during the 22-month intervention. An automated chemiluminescence system, auto-chemistry analyzer, Q-FISH, qPCR, and TUNEL assay were used in this study. The rats had lower folate concentrations and higher Hcy, ROS, and 8-OHdG concentrations in brain tissue with aging. However, FA supplementation increased folate concentrations and antioxidant activities while decreasing Hcy, ROS, and 8-OHdG levels in rat brain tissue after 11, 18, and 22months of intervention. Furthermore, FA supplementation alleviated telomere length shortening and inhibited neurocyte apoptosis during the 22-month intervention. FA supplementation alleviated oxidative stress-induced telomere attrition and inhibited apoptosis of neurocytes in 25-month-old rats.

Micronutrients and socio-demographic factors were major predictors of anaemia among the Ethiopian population.

Anaemia is characterised by low hemoglobin (Hb) concentration. Despite being a public health concern in Ethiopia, the role of micronutrients and non-nutritional factors as a determinant of Hb concentrations has been inadequately explored. This study focused on the assessment of serum micronutrient and Hb concentrations and a range of non-nutritional factors, to evaluate their associations with the risk of anaemia among the Ethiopian population (n 2046). It also explored the mediation effect of Zn on the relation between se and Hb. Bivariate and multivariate regression analyses were performed to identify the relationship between serum micronutrients concentration, inflammation biomarkers, nutritional status, presence of parasitic infection and socio-demographic factors with Hb concentration (n 2046). Sobel-Goodman test was applied to investigate the mediation of Zn on relations between serum se and Hb. In total, 18·6 % of participants were anaemic, 5·8 % had iron deficiency (ID), 2·6 % had ID anaemia and 0·6 % had tissue ID. Younger age, household head illiteracy and low serum concentrations of ferritin, Co, Cu and folate were associated with anaemia. Serum se had an indirect effect that was mediated by Zn, with a significant effect of se on Zn (P < 0·001) and Zn on Hb (P < 0·001). The findings of this study suggest the need for designing a multi-sectorial intervention to address anaemia based on demographic group.

Does maternal genetic liability to folate deficiency influence the risk of antiseizure medication-associated language impairment and autistic traits in children of women with epilepsy?

BackgroundPrenatal exposure to antiseizure medication (ASM) may lead to low plasma folate concentrations and is associated with impaired neurodevelopment. ObjectivesTo examine whether maternal genetic liability to folate deficiency interacts with ASM-associated risk of language impairment and autistic traits in children of women with epilepsy. MethodsWe included children of women with and without epilepsy and with available genetic data enrolled in the Norwegian Mother, Father, and Child Cohort Study. Information on ASM use, folic acid supplement use and dose, dietary folate intake, child autistic traits, and child language impairment was obtained from parent-reported questionnaires. Using logistic regression, we examined the interaction between prenatal ASM exposure and maternal genetic liability to folate deficiency expressed as polygenic risk score of low folate concentrations or maternal rs1801133 genotype (CC or CT/TT) on risk of language impairment or autistic traits. ResultsWe included 96 children of women with ASM-treated epilepsy, 131 children of women with ASM-untreated epilepsy, and 37,249 children of women without epilepsy. The polygenic risk score of low folate concentrations did not interact with the ASM-associated risk of language impairment or autistic traits in ASM-exposed children of women with epilepsy compared with ASM-unexposed children aged 1.5–8 y. ASM-exposed children had increased risk of adverse neurodevelopment regardless of maternal rs1801133 genotype {adjusted odds ratio [aOR] for language impairment aged 8 y was 2.88 [95% confidence interval (CI): 1.00, 8.26] if CC and aOR 2.88 [95% CI: 1.10, 7.53] if CT/TT genotypes}. In children of women without epilepsy aged 3 y, those with maternal rs1801133 CT/TT compared with CC genotype had increased risk of language impairment (aOR: 1.18; 95% CI: 1.05, 1.34). ConclusionsIn this cohort of pregnant women reporting widespread use of folic acid supplements, maternal genetic liability to folate deficiency did not significantly influence the ASM-associated risk of impaired neurodevelopment.

Contrasting Association of Maternal Plasma Biomarkers of Smoking and 1-Carbon Micronutrients with Offspring DNA Methylation: Evidence of Aryl Hydrocarbon Receptor Repressor Gene–Smoking–Folate Interaction

BackgroundMaternal prenatal smoking is known to alter offspring DNA methylation (DNAm). However, there are no effective interventions to mitigate smoking-induced DNAm alteration. ObjectivesThis study investigated whether 1-carbon nutrients (folate, vitamins B6, and B12) can protect against prenatal smoking-induced offspring DNAm alterations in the aryl hydrocarbon receptor repressor (AHRR) (cg05575921), GFI1 (cg09935388), and CYP1A1 (cg05549655) genes. MethodsThis study included mother-newborn dyads from a racially diverse US birth cohort. The cord blood DNAm at the above 3 sites were derived from a previous study using the Illumina Infinium MethylationEPIC BeadChip. Maternal smoking was assessed by self-report and plasma biomarkers (hydroxycotinine and cotinine). Maternal plasma folate, and vitamins B6 and B12 concentrations were obtained shortly after delivery. Linear regressions, Bayesian kernel machine regression, and quantile g-computation were applied to test the study hypothesis by adjusting for covariables and multiple testing. ResultsThe study included 834 mother-newborn dyads (16.7% of newborns exposed to maternal smoking). DNAm at cg05575921 (AHRR) and at cg09935388 (GFI1) was inversely associated with maternal smoking biomarkers in a dose-response fashion (all P < 7.01 × 10−13). In contrast, cg05549655 (CYP1A1) was positively associated with maternal smoking biomarkers (P < 2.4 × 10−6). Folate concentrations only affected DNAm levels at cg05575921 (AHRR, P = 0.014). Regression analyses showed that compared with offspring with low hydroxycotinine exposure (<0.494) and adequate maternal folate concentrations (quartiles 2–4), an offspring with high hydroxycotinine exposure (≥0.494) and low folate concentrations (quartile 1) had a significant reduction in DNAm at cg05575921 (M-value, ß ± SE = −0.801 ± 0.117, P = 1.44 × 10−11), whereas adequate folate concentrations could cut smoking-induced hypomethylation by almost half. Exposure mixture models further supported the protective role of adequate folate concentrations against smoking-induced aryl hydrocarbon receptor repressor (AHRR) hypomethylation. ConclusionsThis study found that adequate maternal folate can attenuate maternal smoking-induced offspring AHRR cg05575921 hypomethylation, which has been previously linked to a range of pediatric and adult diseases.

Potential mechanism for hyperhomocysteinemia in Greyhound dogs.

Greyhounds have been reported to have hyperhomocysteinemia (HHC), but the underlying mechanisms and clinical implications are unclear. Our primary aim was to assess serum concentrations of homocysteine (HCy) and related analytes in Greyhounds and to identify a likely metabolic pathway for HHC. A secondary aim was to determine whether HHC is associated with evidence of oxidative stress. Healthy pet Greyhounds (n = 31) and non-sighthound control dogs (n = 15). Analysis of serum HCy, cobalamin, folate, and methionine, and plasma cysteine, glutathione, and total 8-isoprostane concentrations. Homocysteine concentrations were higher in Greyhounds (median, 25.0 μmol/L) compared to controls (13.9 μmol/L; P < .0001). Cobalamin concentrations were lower in Greyhounds (median, 416 ng/L) compared to controls (644 ng/L; P = .004) and were inversely correlated with HCy (r = -0.40, P = .004). Serum concentrations of folate, which is regenerated when HCy is converted to methionine, also were inversely correlated with HCy (r = -0.47, P = .002). Serum methionine concentrations were more than 4-fold lower in Greyhounds (median, 3.2 μmol/L) compared to controls (median, 15.0 μmol/L), but this difference was not significant (P = .3). Plasma cysteine, glutathione, and 8-isoprostane concentrations did not differ significantly between groups. Our findings suggest a primary defect in conversion of HCy to methionine in Greyhounds, with related impaired folate generation. Ineffective cycling by methionine synthase could lead to secondary cobalamin depletion. Notably, low serum folate and cobalamin concentrations can be observed in Greyhounds without signs of intestinal disease.

Sustaining an ageing population: the role of micronutrients in frailty and cognitive impairment.

Age-related frailty and cognitive decline are complex multidimensional conditions that significantly impact the ability of older adults to sustain functional capacity and independence. While underlying causes remain poorly understood, nutrition continually emerges as one associated risk element. Many studies have addressed the importance of adequate nutrition in delaying the onset of these conditions, but the specific role of micronutrients is not well established. The consideration of pre-frailty as an outcome variable is also limited in the current literature. In this review, we focus on the potential value of maintaining micronutrient sufficiency to sustaining the health of the ageing population. Using data from the Irish longitudinal study on ageing, we consider several vitamins known to have a high prevalence of low status in older adults and their impact on pre-frailty, frailty and cognitive impairment. They include vitamin B12 and folate, both of which are associated with multiple biological mechanisms involved in long-term health, in particular in cognitive function; vitamin D, which has been associated with increased risk of musculoskeletal disorders, depression and other chronic diseases; and the carotenoids, lutein and zeaxanthin, that may help mitigate the risk of frailty and cognitive decline via their antioxidant and anti-inflammatory properties. We show that low concentrations of folate and carotenoids are implicated in poorer cognitive health and that the co-occurrence of multiple nutrient deficiencies confers greatest risk for frailty and pre-frailty in the Irish longitudinal study on ageing cohort. These health associations contribute to evidence needed to optimise micronutrient status for health in the older adult population.

Simultaneous Measurement of One-Carbon and Polyglutamate Derivatives of Folic Acid in Rat Liver Using Enzymatic Interconversions of Folates Followed by Ternary Complex Formation with Thymidylate Synthetase and 5-Fluorodeoxyuridylic Acid: Standardization of the Method

A sensitive assay is needed for the measurement of individual folate derivatives in samples that contain low concentrations of folate. The ternary complex method for the determination of folylpolyglutamates has been combined with procedures for interconverting folate derivatives to provide a method capable of measuring 28 different folate derivatives in biological samples. The method takes advantage of the properties of the ternary complex formed with thymidylate synthetase, fluorodeoxyuridylic acid and 5,10-methylenetetrahydrofolic acid. In the presence of excess purified thymidylate synthetase and excess [3H]fluorodeoxyuridylic acid, limiting concentrations of folates were converted to 5,10-methylenetetrahydrofolate using purified folate interconverting enzymes. This process separated folate derivatives into four groups: Tetrahydrofolate + 5,10-methylenetetrahydrofolate; dihydrofolate; 5,10-methenyl-, 5-formyl-, and 10-formyltetrahydrofolates and 5-methyltetrahydrofolate. Within groups specificity was good, showing little overlap between folates. Sensitivities to 100 fmol of folate were achievable and to 1 pmol were standard. Recoveries were linear for each of the groups in this system to 50 pmol of folate. Ternary complexes containing different polyglutamates were separated by isoelectric focusing, visualized by fluorography and measured by densitometry. The densitometry was linear with folate concentration in the range 20–200 fmol for each of the polyglutamates. Primary and secondary coefficients of variation were determined. This method provides the sensitivity to measure individual folates in the femtomole range and the flexibility to determine the concentrations of 28 separate pools of folate derivatives, differentiating between derivatives of the pteridine moiety and glutamate chain length simultaneously.

Circulating homocysteine and folate concentrations and risk of type 2 diabetes: A retrospective observational study in Chinese adults and a Mendelian randomization analysis.

The relation between circulating homocysteine (hcy) and folate concentrations and risk of type 2 diabetes mellitus (T2DM) has been evaluated in several observational studies with inconsistent results; and it is unclear about their causal relationships. Our aim was to assess the causality association between circulating hcy or folate concentrations and the development of T2DM using Mendelian randomization (MR) analysis, based on results of an observational study in Chinese adults. We conducted an observational study of 370 patients with T2DM and 402 controls after routine physical examination who consulted at the Zhongnan Hospital of Wuhan University between March 2021 and December 2021. Correlations between hcy and folate and the incidence of T2DM were quantified using logistic regression models. Two-sample MR analysis was conducted using summary statistics of genetic variants gained from 2 genome-wide association studies (GWAS) on circulating hcy and folate concentrations in individuals of European ancestry and from an independent GWAS study based on DIAMANTE meta-analysis. In the observational study, after logistic regression with multiple adjustment, lower hcy and higher folate levels were identified to be associated with the risk of T2DM, with OR (95% CI) for hcy of 1.032 (1.003-1.060); while 0.909 (0.840-0.983) for folate. In the MR analysis, the OR for T2DM was 1.08 (95% CI: 0.95, 1.21; P = 0.249) for each SD unit increase in genetically predicted homocysteinemia and the OR for T2DM per SD increase in genetically predicted folate elevation was 0.80 (95% CI: 0.60, 1.00, P = 0.026). We discovered that high circulating hcy and low folate concentrations were related with an increased risk of developing T2DM in Chinese adults. Moreover, MR analysis provided genetic evidence for a possible causal relationship between serum folate and the risk of T2DM.

Quality of Life and Nutritional Parameters of Celiac Patients in Mar Del Plata, Argentina

Background: Celiac disease (CD) is one of the most common causes of chronic malabsorption. The changes that occur in the diet due to the influence of gluten free diet (GFD) lead to a lower content in the intake of fiber and vitamins. Some authors point out that the higher cost of GF foods, the lower availability of those in social events, the impaired patient’s quality of life, could influence the degree of adherence to the GFD. Our aims were to evaluate the nutritional status, identifying the factors that are associated with adherence to the gluten-free diet (DLG) and the quality of life of a group of CD patients in Mar del Plata. Methods: CD patients were recruited from outpatient of clinic and gastroenterology unit of Oscar Alende Hospital, Mar del Plata and Argentina Celiac Association and had blood drawn for micronutrients concentration. Quality of life was evaluated by SF12 questionnaire, factors and adherence to GFD were determined by factors questionnaire and the Celiac Dietary Adherence Test (CDAT). Results: 47% of the participants had high adherence to GFD. The large supply of gluten-free foods without options during social events was significantly associated with the worst adherence to GFD. The average concentrations of folic acid, magnesium, iron and vitamin B12 were within the normal ranges; however, 6.7, 7.0 and 33.3% of the low adherent group showed low serum concentrations of iron, vitamin B12 and folate, respectively, while 7.7 and 53.8% of the high adherent exhibited low serum concentrations of iron and folate, respectively. Approximately 14.2% had anemia, only 7.1% had iron deficiency anemia. 54% of patients reported eating corn-based foods 3 or more times per week. The general perception of health was low in the age range between 18 and 40 years (34.3 ± 22.0) and the energy and vitality values were low in the same group (37.5 ± 25.2). Conclusions: Evaluation of quality of life and micronutrients indicate the need to support the patients in their treatment and to increase the supply of GF foods and the supplementation with vitamins and micronutrients of the GFD.

Circulating folate concentrations and the risk of mild cognitive impairment: A prospective study on the older Chinese population without folic acid fortification.

The longitudinal association between serum folate concentrations and the risk of cognitive impairment remains unclear in populations with low folate levels. We examined the association between serum folate concentrations and mild cognitive impairment (MCI) in older adults in China, where mandatory fortification of foods with folic acid has not been implemented. We further explored if homocysteine (Hcy) and leukocyte telomere length (LTL) mediate the association between serum folate and MCI. We performed a longitudinal analysis of 3974 participants aged ≥60 years from the Tianjin Elderly Nutrition and Cognition (TENC) cohort study. The associations between serum folate level and the risk of cognitive impairment overall and stratified by apolipoprotein E (APOE) ε4 genotypes were evaluated using multivariable Cox proportional hazards models. The mediating effects of Hcy and LTL on the folate-MCI association were explored via a path analysis approach. Within a 3-year follow-up, we documented 560 incident MCI cases. After multivariable adjustment, higher serum folate concentrations were associated with lower incidence of MCI, with hazard ratios (95% confidence interval) across quartiles of folate (from lowest to highest concentrations) of 1.00 (reference), 0.66 (0.52, 0.83), 0.57 (0.45, 0.73), 0.66 (0.52, 0.84), respectively (p for trend &lt;0.001). In mediation analyses, the status of serum folate deficiency and MCI were correlated via two intermediary pathways, Hcy and Hcy-telomere (p &lt; 0.05). Lower folate concentrations, independently of APOE genotype, were associated with increased risk of MCI among elderly Chinese people, a population with relatively low folate intake. Our data were compatible with the mediation hypothesis that the association between folate status and MCI was mediated by Hcy and LTL.

Folate Deficiency Is Spatially Dependent and Associated with Local Farming Systems among Women in Ethiopia

ABSTRACTBackgroundFolate is essential for the synthesis and integrity of DNA, normal cell formation, and body growth. Folate deficiency among women of reproductive age (WRA) increases the risk of poor birth outcomes including neural tube defect (NTD)-affected pregnancies. Folate status is largely dependent on dietary intakes.ObjectivesWe aimed to explore the spatial distribution of biomarkers of folate status and their association with farming systems among nonpregnant WRA in Ethiopia.MethodsSerum and RBC folate concentration data were derived from the Ethiopia National Micronutrient Survey of 2015. The spatial dependencies of folate concentration of WRA were investigated and its relation with the dominant local farming system was explored.ResultsThe median serum folate and RBC folate concentrations were 12.3 nmol/L and 567.3 nmol/L, respectively. The national prevalence of folate deficiency using homocysteine concentration as a metabolic indicator based on serum and RBC folate concentration was 11.6% and 5.7%, respectively. The majority of women (77.9%) had low RBC folate concentrations consistent with increased risk of NTD-affected pregnancies. Folate nutrition was spatially dependent at distances of ≤ 300 km. A marked variability in folate concentration was observed between farming systems: greater RBC folate concentration (median: 1036 nmol/L) was found among women from the Lake Tana fish-based system, whereas the lowest RBC folate concentration (median: 386.7 nmol/L) was observed in the highland sorghum chat mixed system.ConclusionsThe majority (78%) of WRA in Ethiopia had low folate status potentially increasing the risk of NTD-affected pregnancies. These findings may help national and subnational nutrition intervention strategies to target the most affected areas in the country.

Plasma folate deficiency increases the risk for abnormal blood pressure in Chinese women of childbearing age

In this study, we investigated the association between folate deficiency and abnormal blood pressure (including prehypertension and hypertension) in nonpregnant Chinese women of childbearing age. We hypothesized that lower plasma folate would be positively correlated with a higher risk for abnormal blood pressure. Data were obtained from a national cross-sectional study conducted in 2005-2006 among 3464 nonpregnant women of childbearing age from 9 provinces in China. Sociodemographic characteristics and lifestyle data were obtained from a researcher-designed questionnaire. Dietary folate intake was determined by 24-hour dietary recall. Prehypertension was defined as systolic blood pressure/diastolic blood pressure 120-139/80-89 mmHg, and hypertension was defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg. Plasma folate concentration was measured with a microbiological assay, and folate deficiency was defined as a plasma folate concentration <10.5 nmol/L. Log-binomial generalized linear modeling was used to examine the association between plasma folate and prehypertension/hypertension after adjustment for confounding factors. The prevalence of prehypertension and hypertension were 20.6% (713/3464) and 3.3% (116/3464), respectively, in Chinese women of childbearing age. The median plasma folate concentration was 14.49 nmol/L (interquartile range: 9.48-22.58), and 30.8% (1067/3464) of women had folate deficiency. Women with folate deficiency were 1.715 times (95% CI, 1.331-2.209) as likely to develop prehypertension or hypertension compared with women with folate sufficiency. In conclusion, a low folate concentration (<10.5 nmol/L) was significantly associated with a higher risk for prehypertension and hypertension in these nonpregnant Chinese women of childbearing age.

Association between preoperative serum homocysteine and delayed neurocognitive recovery after non-cardiac surgery in elderly patients: a prospective observational study

BackgroundHomocysteine, folate, and vitamin B12 involved in 1-carbon metabolism are associated with cognitive disorders. We sought to investigate the relationships between these factors and delayed neurocognitive recovery (dNCR) after non-cardiac surgery.MethodsThis was a prospective observational study of patients (n = 175) who were ≥ 60 years of age undergoing non-cardiac surgery. Patients were evaluated preoperatively and for 1 week postoperatively by using neuropsychological tests and were divided into dNCR or non-dNCR groups according to a Z-score ≤ − 1.96 on at least two of the tests. The relationship between the occurrence of dNCR and preoperative levels of homocysteine, folate, and vitamin B12 was analyzed. Univariate and multivariable logistic regression analyses were conducted to identify factors associated with dNCR.ResultsDelayed neurocognitive recovery was observed in 36 of 175 patients (20.6%; 95% confidence interval [CI], 14.5–26.6%) 1 week postoperatively. Patients who developed dNCR had significantly higher median [interquartile range (IQR)] homocysteine concentrations (12.8 [10.9,14.4] μmol/L vs 10.6 [8.6,14.7] μmol/L; P = 0.02) and lower folate concentrations (5.3 [4.2,7.3] ng/mL vs 6.9 [5.3,9.5] ng/mL; P = 0.01) than those without dNCR. Compared to the lowest tertile, the highest homocysteine tertile predicted dNCR onset (odds ratio [OR], 3.9; 95% CI, 1. 3 to 11.6; P = 0.02), even after adjusting for age, sex, education, and baseline Mini Mental State Examination.ConclusionsElderly patients with high homocysteine levels who underwent general anesthesia for non-cardiac surgery have an increased risk of dNCR. This knowledge could potentially assist in the development of preventative and/or therapeutic measures.Trial registrationNCT03084393 (https://www.clinicaltrials.gov)

Low serum folate concentrations in dogs with non-associative immune-mediated haemolytic anaemia.

Folate deficiency in people can occur in conditions causing increased demand, including haemolytic anaemia. This has not been investigated in dogs with non-associative immune-mediated haemolytic anaemia (IMHA). Cohort study of 15 dogs with non-associative IMHA. Haematocrit (HCT) and serum folate concentrations were measured at presentation and each subsequent venipuncture performed for monitoring. The relationship between serum folate concentrations and HCT was investigated using linear and logistic mixed-effects regression models and in paired samples using a one-tailed paired t-test. Low serum folate concentrations occurred in five of 15 dogs. In 126 samples, a significant positive relationship was found between HCT and corresponding serum folate concentrations. A significant relationship was found between dichotomised folate concentrations (below the reference interval or within/above the reference interval) and HCT and between serum folate concentrations and dichotomised HCT (less than or equal/above 0.30 L/L). For paired samples (available in eight dogs), the mean serum folate concentration of samples with the lowest HCT was significantly lower than that of samples in which the HCT first exceeded 0.30 L/L. Low serum folate concentrations were observed in some dogs with non-associative IMHA. Further studies are needed to determine the cause and investigate whether folate supplementation would be beneficial.

Vitamin B12, folate and homocysteine concentrations during pregnancy and early signs of atherosclerosis at school-age

SummaryBackground & aimsSuboptimal circulating vitamin B12, folate and homocysteine concentrations during fetal life seem to be associated with cardiometabolic health at school-age. We examined whether fetal exposure to lower circulating vitamin B12 and folate concentrations and higher circulating homocysteine concentrations is also associated with early signs of atherosclerosis at school-age.MethodsThis study among 3826 school-age children and their mothers was embedded in the Generation R Study, a population-based prospective cohort study from early pregnancy onwards. We examined the associations of early-pregnancy and cord blood serum total and active B12 and plasma folate and homocysteine concentrations with common carotid artery intima-media thickness and distensibility in the children aged ten years.ResultsAs compared to normal early-pregnancy serum total B12 concentrations (≥145 pmol/L), low serum total B12 concentrations (<145 pmol/L) were associated with higher carotid intima-media thickness in the children at school-age (difference 0.09 standard deviations score (SDS); 95% confidence interval (CI): 0.01, 0.16). As compared to normal early-pregnancy plasma folate concentrations (≥8 nmol/L), low plasma folate concentrations (<8 nmol/L) were associated with lower carotid disten-sibility in the children at school-age (difference −0.16 SDS; 95% CI: −0.28, −0.04). Early-pregnancy circulating total and active B12, folate and homocysteine concentrations measured continuously were not associated with carotid intima-media thickness or carotid distensibility in the children at school-age. One SDS higher plasma homocysteine concentrations measured in cord blood at birth was associated with a −0.05 SDS (95% CI: −0.09, −0.02) lower carotid distensibility at school-age. Cord blood total and active B12 and folate concentrations were not associated with carotid intima-media thickness or carotid distensibility at school-age.ConclusionsCirculating total B12, folate and homocysteine concentrations during fetal life seem to be associated with markers of subclinical atherosclerosis at school-age. Further studies need to examine the causality and mechanisms underlying these associations.

Potential role of folate status on pulmonary function in pediatric asthma

ObjectiveThe aim of this study was to explore the relationship between plasma folate status and measures of airway disease (as reflected by spirometry) in children with asthma on a traditional Mediterranean diet. We hypothesized that folate deficiency is associated with lung function impairment in this group of children. MethodsThis cross-sectional study included 64 children with mild asthma (52% boys, mean age 8 ± 2 y) residing in Athens, Greece. Clinical assessments included spirometry and fractional exhaled nitric oxide (FeNO). Plasma 5-methyltetrahydrofolate (5-MTHF) was analyzed using high performance-liquid chromatography assay and examined in participants using quartiles (Q1–Q4). ResultsOf the 64 children, 45.3% were folate deficient (5-MTHF <10 nmol/L). A positive relationship was observed between 5-MTHF and forced vital capacity (FVC; β = 0.79, 95% confidence interval (CI), 0.14–1.44; adjusted P = 0.019), forced expiratory volume in 1s (FEV1) (β = 0.78; 95% CI, 0.01–1.55; adjusted P = 0.046), and peak expiratory flow (PEF; β = 1.64; 95% CI, 0.14–3.15; adjusted P = 0.033) in girls only, adjusting for body mass index and regular exercise. Girls with low plasma folate concentrations (Q1), compared with girls with high concentrations (Q4) had 8.64% lower FVC (β = –8.64; 95% CI, –16.18 to –1.09; adjusted P = 0.027), 10.35% FEV1 (β = –10.35; 95% CI, –18.82 to –1.89; adjusted P = 0.019), and 18.72% PEF (β = –18.72; 95% CI, –36.30 to –1.14; adjusted P = 0.038). ConclusionThe findings of this study highlighted the potential negative effects of folate deficiency on pulmonary function in girls with asthma, the importance of monitoring folate status in children with asthma, and early prevention strategies.

Unexpected interactions between dolutegravir and folate: randomized trial evidence from South Africa.

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.