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Frontiers in Endocrinology 2023Metabolic syndrome (MetS) is associated with life-threatening conditions. Several studies have reported an association of vitamin B12, folic acid, or homocysteine (Hcy)... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND & AIMS
Metabolic syndrome (MetS) is associated with life-threatening conditions. Several studies have reported an association of vitamin B12, folic acid, or homocysteine (Hcy) levels with MetS. This systematic review and meta-analysis assessed the association of vitamin B12, folic acid, and Hcy levels with MetS.
METHODS
PubMed, Scopus, Embase, Ovid/Medline, and Web of Science were searched up to February 13, 2023. Cross-sectional, case-control, or cohort studies were included. A random-effects model was performed using the DerSimonian and Laird method to estimate the between-study variance. Effect measures were expressed as odds ratios (OR) with their corresponding 95% confidence intervals (95% CI). Between-study heterogeneity was evaluated using Cochran's Q test and the I statistic.
RESULTS
Sixty-six articles (n = 87,988 patients) were included. Higher vitamin B12 levels were inversely associated with MetS (OR = 0.87; 95% CI: 0.81-0.93; p < 0.01; I= 90%). Higher Hcy levels were associated with MetS (OR = 1.19; 95% CI: 1.14-1.24; p < 0.01; I= 90%). Folate levels were not associated with MetS (OR = 0.83; 95% CI: 0.66-1.03; p = 0.09; I= 90%).
CONCLUSION
Higher vitamin B12 levels were inversely associated with MetS, whereas higher Hcy levels were associated with MetS. Studies assessing the pathways underlying this association are required.
Topics: Humans; Vitamin B 12; Folic Acid; Metabolic Syndrome; Homocysteine; Cross-Sectional Studies
PubMed: 37772082
DOI: 10.3389/fendo.2023.1221259 -
Frontiers in Immunology 2023Glucose metabolism, specifically, hexokinase 2 (HK2), has a critical role in rheumatoid arthritis (RA) fibroblast-like synoviocyte (FLS) phenotype. HK2 localizes not...
BACKGROUND
Glucose metabolism, specifically, hexokinase 2 (HK2), has a critical role in rheumatoid arthritis (RA) fibroblast-like synoviocyte (FLS) phenotype. HK2 localizes not only in the cytosol but also in the mitochondria, where it protects mitochondria against stress. We hypothesize that mitochondria-bound HK2 is a key regulator of RA FLS phenotype.
METHODS
HK2 localization was evaluated by confocal microscopy after FLS stimulation. RA FLSs were infected with Green fluorescent protein (GFP), full-length (FL)-HK2, or HK2 lacking its mitochondrial binding motif (HK2ΔN) expressing adenovirus (Ad). RA FLS was also incubated with methyl jasmonate (MJ; 2.5 mM), tofacitinib (1 µM), or methotrexate (1 µM). RA FLS was tested for migration and invasion and gene expression. Gene associations with HK2 expression were identified by examining single-cell RNA sequencing (scRNA-seq) data from murine models of arthritis. Mice were injected with K/BxN serum and given MJ. Ad-FLHK2 or Ad-HK2ΔN was injected into the knee of wild-type mice.
RESULTS
Cobalt chloride (CoCl) and platelet-derived growth factor (PDGF) stimulation induced HK2 mitochondrial translocation. Overexpression of the HK2 mutant and MJ incubation reversed the invasive and migrative phenotype induced by FL-HK2 after PDGF stimulation, and MJ also decreased the expression of C-X-C Motif Chemokine Ligand 1 (CXCL1) and Collagen Type I Alpha 1 Chain (COL1A1). Of interest, tofacitinib but not methotrexate had an effect on HK2 dissociation from the mitochondria. In murine models, MJ treatment significantly decreased arthritis severity, whereas HK2FL was able to induce synovial hypertrophy as opposed to HK2ΔN.
CONCLUSION
Our results suggest that mitochondrial HK2 regulates the aggressive phenotype of RA FLS. New therapeutic approaches to dissociate HK2 from mitochondria offer a safer approach than global glycolysis inhibition.
Topics: Mice; Animals; Synoviocytes; Hexokinase; Arthritis, Rheumatoid; Synovitis; Methotrexate; Fibroblasts
PubMed: 37529037
DOI: 10.3389/fimmu.2023.1103231 -
RMD Open Jul 2023Interstitial lung disease (ILD) is an important cause of mortality in some patients with rheumatoid arthritis (RA). Patient-level factors may predict which patients...
Interstitial lung disease (ILD) is an important cause of mortality in some patients with rheumatoid arthritis (RA). Patient-level factors may predict which patients with RA are at the highest risk of developing ILD and are therefore candidates for screening for this complication of the underlying disease. A systematic literature review was performed using PubMed, Embase and Scopus over a 10-year period up to July 2021. Publications reporting patient-level factors in patients with RA with and without ILD that were assessed before development of ILD (or were unchanged over time and therefore could be extrapolated to before development of ILD) were retrieved for assessment of evidence. Genetic variation in and treatment with methotrexate were not included in the assessment of evidence because these factors have already been widely investigated for association with ILD. We found consistent associations of age, sex, smoking status and autoantibodies with development of ILD. For biomarkers such as Krebs von den Lungen 6, which have been shown to be diagnostic for ILD, there were no publications meeting criteria for this study. This analysis provides an initial step in the identification of patient-level factors for potential development of a risk algorithm to identify patients with RA who may be candidates for screening for ILD. The findings represent a useful basis for future research leading to an improved understanding of the disease course and improved care for patients with RA at risk of development and progression of ILD.
Topics: Humans; Arthritis, Rheumatoid; Lung Diseases, Interstitial; Methotrexate; Autoantibodies; Smoking
PubMed: 37507209
DOI: 10.1136/rmdopen-2023-003059 -
BMC Infectious Diseases Nov 2023In recent years, observational studies have been conducted to investigate the potential impact of vitamins on sepsis. However, many of these studies have produced...
BACKGROUND
In recent years, observational studies have been conducted to investigate the potential impact of vitamins on sepsis. However, many of these studies have produced inconsistent results. Our Mendelian randomization (MR) study aims to evaluate the causality between vitamins and sepsis from a genetic perspective.
METHODS
Our MR study was designed following the STROBE-MR guidelines. Genetic instrumental variables for vitamins including folate, vitamin B12, B6, A (Retinol), C, D, and K were obtained from previous genome-wide association studies (GWAS) and MR studies. Five different sepsis severity levels were included in the analysis. The genetic instrumental variables were screened for potential confounders using PhenoScanner V2. MR analysis was performed using MR-egger, inverse-variance weighted multiplicative random effects (IVW-RE), inverse-variance weighted multiplicative fixed-effects (IVW-FE), and wald ratio methods to assess the relationship between vitamins and sepsis. Sensitivity analysis was performed using the MR-egger_intercept method, and the MR-PRESSO package and Cochran's Q test were used to evaluate the heterogeneity of the instrumental variables.
RESULTS
Our MR study found no statistically significant association between vitamins and sepsis risk, regardless of the type of vitamin (P-value > 0.05). The odds ratios (ORs) for folate, vitamin B6, vitamin B12, vitamin A, vitamin D, vitamin K, and vitamin C were 1.164 (95% CI: 0.895-1.514), 0.987 (95% CI: 0.969-1.005), 0.975 (95% CI: 0.914-1.041), 0.993 (95% CI: 0.797-1.238), 0.861 (95% CI: 0.522-1.42), 0.955 (95% CI: 0.86-1.059), and 1.049 (95% CI: 0.911-1.208), respectively. Similar results were observed in subgroups of different sepsis severity levels.
CONCLUSIONS
Our MR study found no evidence of a causal association between vitamins and sepsis risk from a genetic perspective. Further randomized controlled trials are necessary to confirm these results.
Topics: Humans; Vitamins; Vitamin A; Genome-Wide Association Study; Mendelian Randomization Analysis; Vitamin K; Vitamin B 12; Folic Acid; Sepsis
PubMed: 37936083
DOI: 10.1186/s12879-023-08778-9 -
Journal of Translational Medicine Nov 2023To scrutinize the relationship between vitamin B2 consumption and cognitive function based on the NHANES database.
BACKGROUND
To scrutinize the relationship between vitamin B2 consumption and cognitive function based on the NHANES database.
METHODS
This cross-sectional study included eligible older adults from the NHANES 2011-2014. Vitamin B2 intake was determined from dietary interview data for two 24-h periods. Cognitive function was evaluated through the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). The regression analyses were used to evaluate the association of vitamin B2 intake with cognitive performance. Stratified analyses based on gender, race, and body mass index (BMI) were conducted.
RESULTS
Higher vitamin B2 intake was correlated with higher scores on each test. As compared to the lowest quartile, the highest quartile of vitamin B2 intake was related to a 45.1-fold increase (P = 0.004) on the DSST test sores. Moreover, those who were males, non-Hispanic whites, or had a BMI of 18.5 to 30 kg/m had a stronger relationship between total vitamin B2 consumption and cognitive function.
CONCLUSION
It's possible that older persons who consume more vitamin B2 have enhanced performance in some areas of cognitive function. To determine the causal link between vitamin B2 consumption and cognitive performance, further long-term research is required.
Topics: Male; Humans; Female; Aged; Aged, 80 and over; Cross-Sectional Studies; Nutrition Surveys; Cognition; Nutritional Status; Riboflavin
PubMed: 38037028
DOI: 10.1186/s12967-023-04749-5 -
Nutrients Sep 2023Depressive disorders pose significant challenges to global public health, necessitating effective prevention and management strategies. Notably, the occurrence of... (Review)
Review
Depressive disorders pose significant challenges to global public health, necessitating effective prevention and management strategies. Notably, the occurrence of suicide frequently coincides with depressive episodes. Suicide is as a paramount global health concern that demands efficacious preventive strategies. Current psychiatric approaches heavily rely on pharmacological interventions but have had limited success in addressing the global burden of mental health issues. Suboptimal nutrition, with its impact on the neuroendocrine system, has been implicated in the underlying pathology of depressive disorders. Folate, a group of water-soluble compounds, plays a crucial role in various central nervous system functions. Depressed individuals often exhibit low levels of serum and red blood cell folate. Multiple studies and systematic reviews have investigated the efficacy of folic acid and its derivative, L-methylfolate, which can cross the blood-brain barrier, as stand-alone or adjunct therapies for depression. Although findings have been mixed, the available evidence generally supports the use of these compounds in depressed individuals. Recent studies have established links between the one-carbon cycle, folate-homocysteine balance, immune system function, glutamate excitation via NMDA (N-methyl-D-aspartate) receptors, and gut microbiome eubiosis in mood regulation. These findings provide insights into the complex neurobiological mechanisms underlying the effects of folate and related compounds in depression. Through a comprehensive review of the existing literature, this study aims to advance our understanding of the therapeutic potential of folic acid and related compounds in depression treatment. It also seeks to explore their role in addressing suicidal tendencies and shed light on the neurobiological mechanisms involved, leveraging the latest discoveries in depression research.
Topics: Humans; Suicidal Ideation; Suicide; Folic Acid; Glutamic Acid; Depressive Disorder
PubMed: 37686891
DOI: 10.3390/nu15173859 -
PLoS Medicine Dec 2023Maternal vitamin status preconception and during pregnancy has important consequences for pregnancy outcome and offspring development. Changes in vitamin status from... (Randomized Controlled Trial)
Randomized Controlled Trial
Maternal B-vitamin and vitamin D status before, during, and after pregnancy and the influence of supplementation preconception and during pregnancy: Prespecified secondary analysis of the NiPPeR double-blind randomized controlled trial.
BACKGROUND
Maternal vitamin status preconception and during pregnancy has important consequences for pregnancy outcome and offspring development. Changes in vitamin status from preconception through early and late pregnancy and postpartum have been inferred from cross-sectional data, but longitudinal data on vitamin status from preconception throughout pregnancy and postdelivery are sparse. As such, the influence of vitamin supplementation on vitamin status during pregnancy remains uncertain. This study presents one prespecified outcome from the randomized controlled NiPPeR trial, aiming to identify longitudinal patterns of maternal vitamin status from preconception, through early and late pregnancy, to 6 months postdelivery, and determine the influence of vitamin supplementation.
METHODS AND FINDINGS
In the NiPPeR trial, 1,729 women (from the United Kingdom, Singapore, and New Zealand) aged 18 to 38 years and planning conception were randomized to receive a standard vitamin supplement (control; n = 859) or an enhanced vitamin supplement (intervention; n = 870) starting in preconception and continued throughout pregnancy, with blinding of participants and research staff. Supplement components common to both treatment groups included folic acid, β-carotene, iron, calcium, and iodine; components additionally included in the intervention group were riboflavin, vitamins B6, B12, and D (in amounts available in over-the-counter supplements), myo-inositol, probiotics, and zinc. The primary outcome of the study was glucose tolerance at 28 weeks' gestation, measured by oral glucose tolerance test. The secondary outcome reported in this study was the reduction in maternal micronutrient insufficiency in riboflavin, vitamin B6, vitamin B12, and vitamin D, before and during pregnancy. We measured maternal plasma concentrations of B-vitamins, vitamin D, and markers of insufficiency/deficiency (homocysteine, hydroxykynurenine-ratio, methylmalonic acid) at recruitment, 1 month after commencing intervention preconception, in early pregnancy (7 to 11 weeks' gestation) and late pregnancy (around 28 weeks' gestation), and postdelivery (6 months after supplement discontinuation). We derived standard deviation scores (SDS) to characterize longitudinal changes among participants in the control group and measured differences between the 2 groups. At recruitment, the proportion of patients with marginal or low plasma status was 29.2% for folate (<13.6 nmol/L), 7.5% and 82.0% for riboflavin (<5 nmol/L and ≤26.5 nmol/L, respectively), 9.1% for vitamin B12 (<221 pmol/L), and 48.7% for vitamin D (<50 nmol/L); these proportions were balanced between the groups. Over 90% of all participants had low or marginal status for one or more of these vitamins at recruitment. Among participants in the control group, plasma concentrations of riboflavin declined through early and late pregnancy, whereas concentrations of 25-hydroxyvitamin D were unchanged in early pregnancy, and concentrations of vitamin B6 and B12 declined throughout pregnancy, becoming >1 SDS lower than baseline by 28 weeks gestation. In the control group, 54.2% of participants developed low late-pregnancy vitamin B6 concentrations (pyridoxal 5-phosphate <20 nmol/L). After 1 month of supplementation, plasma concentrations of supplement components were substantially higher among participants in the intervention group than those in the control group: riboflavin by 0.77 SDS (95% CI 0.68 to 0.87, p < 0.0001), vitamin B6 by 1.07 SDS (0.99 to 1.14, p < 0.0001), vitamin B12 by 0.55 SDS (0.46 to 0.64, p < 0.0001), and vitamin D by 0.51 SDS (0.43 to 0.60, p < 0.0001), with higher levels in the intervention group maintained during pregnancy. Markers of vitamin insufficiency/deficiency were reduced in the intervention group, and the proportion of participants with vitamin D insufficiency (<50 nmol/L) during late pregnancy was lower in the intervention group (35.1% versus 8.5%; p < 0.0001). Plasma vitamin B12 remained higher in the intervention group than in the control group 6 months postdelivery (by 0.30 SDS (0.14, 0.46), p = 0.0003). The main limitation is that generalizability to the global population is limited by the high-resource settings and the lack of African and Amerindian women in particular.
CONCLUSIONS
Over 90% of the trial participants had marginal or low concentrations of one or more of folate, riboflavin, vitamin B12, or vitamin D during preconception, and many developed markers of vitamin B6 deficiency in late pregnancy. Preconception/pregnancy supplementation in amounts available in over-the-counter supplements substantially reduces the prevalence of vitamin deficiency and depletion markers before and during pregnancy, with higher maternal plasma vitamin B12 maintained during the recommended lactational period.
TRIAL REGISTRATION
ClinicalTrials.gov NCT02509988; U1111-1171-8056.
Topics: Female; Humans; Pregnancy; Cross-Sectional Studies; Dietary Supplements; Folic Acid; Pregnancy Outcome; Riboflavin; Vitamin B 12; Vitamin B 6; Vitamin B Complex; Vitamin D; Adolescent; Young Adult; Adult
PubMed: 38051700
DOI: 10.1371/journal.pmed.1004260 -
BMC Neurology Jul 2023Anti-N-methyl-d-aspartate "anti-NMDA" receptor encephalitis is one of the most common autoimmune encephalitis for which first- and second-line therapies have been... (Review)
Review
BACKGROUND
Anti-N-methyl-d-aspartate "anti-NMDA" receptor encephalitis is one of the most common autoimmune encephalitis for which first- and second-line therapies have been recommended following international consensus. However, some refractory cases do not respond to the first- and second-line therapy and require further immune-modulatory therapies such as intra-thecal methotrexate. In this study, we reviewed six confirmed cases of refractory anti-NMDA receptor encephalitis from two tertiary centers in Saudi Arabia that required escalation of treatment and received a six-month course of intra-thecal methotrexate. The aim of this study was to evaluate the effectiveness of intra-thecal methotrexate as immunomodulatory therapy for refractory anti-NMDA receptor encephalitis.
METHODS
We retrospectively evaluated six confirmed cases of refractory anti-NMDA receptor encephalitis who did not improve after first- and second-line therapy and received monthly intra-thecal methotrexate treatment course for six consecutive months. We reviewed patient demography, underlying etiologies, and compared their modified Rankin score prior to receiving intra-thecal methotrexate and six months after completing the treatment.
RESULTS
Three of the six patients showed a marked response to intra-thecal methotrexate with a modified Rankin scale of 0-1 at 6-month follow-up. None of the patients experienced any side effects during or after intra-thecal methotrexate treatment, and no flareups were observed.
CONCLUSION
Intra-thecal methotrexate may be a potentially effective and relatively safe escalation option for immunomodulatory therapy of refractory anti-NMDA receptor encephalitis. Future studies on intra-thecal methotrexate -specific treatment regimens may further support its utility, efficacy, and safety in treating refractory anti-NMDA receptor encephalitis.
Topics: Humans; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Methotrexate; Retrospective Studies; Antibodies; Hashimoto Disease; Receptors, N-Methyl-D-Aspartate
PubMed: 37420168
DOI: 10.1186/s12883-023-03301-8 -
JAMA Network Open Sep 2023The optimal maintenance strategy after induction chemotherapy with anti-epidermal growth factor receptor antibody for patients with RAS wild-type metastatic colorectal... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
The optimal maintenance strategy after induction chemotherapy with anti-epidermal growth factor receptor antibody for patients with RAS wild-type metastatic colorectal cancer (mCRC) remains to be debated.
OBJECTIVE
To evaluate the efficacy and safety of maintenance therapy with single-agent cetuximab after FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) plus cetuximab induction therapy.
DESIGN, SETTING, AND PARTICIPANTS
The TIME (Treatment After Irinotecan-Based Frontline Therapy: Maintenance With Erbitux]) (PRODIGE 28 [Partenariat de Recherche en Oncologie Digestive]-UCGI 27 [UniCancer GastroIntestinal Group]) phase 2 noncomparative, multicenter randomized clinical trial was conducted from January 15, 2014, to November 23, 2018, among 139 patients with unresectable RAS wild-type mCRC. The cutoff date for analysis was July 21, 2022.
INTERVENTIONS
After first-line induction therapy with 8 cycles of FOLFIRI plus cetuximab, patients without disease progression were randomized (1:1) to biweekly maintenance with cetuximab or observation. On disease progression, the same induction regimen was recommended for 16 weeks followed by further maintenance with cetuximab or observation until disease progression under the full induction regimen.
MAIN OUTCOMES AND MEASURES
The primary end point was the 6-month progression-free rate from randomization. Analysis was performed on an intention-to-treat basis. An exploratory biomolecular analysis, using next-generation sequencing, investigated the putative prognostic value of the tumor mutation profile.
RESULTS
Of 214 patients enrolled (141 men [65.9%]; median age, 67 years [range, 23-85 years]), 139 were randomized to receive cetuximab (n = 67; 45 men [67.2%]; median age, 64 years [range, 34-85 years]) or to be observed (n = 72; 50 men [69.4%]; median age, 68 years [23-85 years]). The 6-month progression-free rate was 38.8% ([26 of 67] 95% CI, 27.1%-51.5%) in the cetuximab group and 5.6% ([4 of 72] 95% CI, 1.5%-13.6%) in the observation group. At a median follow-up of 40.5 months (95% CI, 33.6-47.5 months), median progression-free survival (PFS) from randomization was 5.3 months (95% CI, 3.7-7.4 months) in the cetuximab group and 2.0 months (95% CI, 1.8-2.7 months) in the observation group. Median overall survival (OS) was 24.8 months (95% CI, 18.7-30.4 months) in the cetuximab group and 19.7 months (95% CI, 13.3-24.4 months) in the observation group. In an exploratory multivariate analysis, any tumor-activating mutation in the mitogen-activated protein kinase (MAPK) pathway genes was associated with shorter PFS from randomization regardless of treatment group (hazard ratio, 1.63 [95% CI, 1.01-2.62]; P = .04). The most frequent grade 3 or 4 treatment-related toxic effect in the cetuximab group during maintenance therapy was rash (8 of 67 [11.9%]).
CONCLUSION AND RELEVANCE
The randomized clinical trial did not meet its primary end point but suggests clinically meaningful PFS and OS benefits associated with cetuximab maintenance therapy. However, maintenance cetuximab or treatment breaks after first-line combination FOLFIRI-cetuximab therapy seems inappropriate for patients with MAPK-mutated independently of the side of primary tumor. A more complete assessment of MAPK pathway mutations warrants further investigation to the refine treatment strategy for patients with RAS wild-type mCRC.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02404935.
Topics: Male; Humans; Aged; Middle Aged; Cetuximab; Irinotecan; Colonic Neoplasms; Rectal Neoplasms; Leucovorin; Disease Progression
PubMed: 37721754
DOI: 10.1001/jamanetworkopen.2023.33533 -
Nutrients Jul 2023Micronutrition in pregnancy is critical to impact not only fetal growth and development but also long-term physical and psychiatric health outcomes. (Clinical Trial)
Clinical Trial
BACKGROUND
Micronutrition in pregnancy is critical to impact not only fetal growth and development but also long-term physical and psychiatric health outcomes.
OBJECTIVE
Estimate micronutrient intake from food and dietary supplements in a diverse cohort of pregnant women and compare intake to the Dietary Reference Intakes (DRIs).
DESIGN
Secondary analysis of women enrolled in a multi-site clinical trial of docosahexaenoic acid (DHA) supplementation who provided their dietary intake using the diet history questionnaire-II ( = 843) or multiple 24 h recalls ( = 178) at baseline and their intake of nutritional supplements at baseline through 30 days postpartum.
PARTICIPANTS/SETTING
1021 participants from the parent trial who had reliable data for dietary intake, supplement intake, or both.
MAIN OUTCOME MEASURES
Micronutrient intake from dietary and supplement sources and percentage of intakes meeting the DRIs for pregnancy.
STATISTICAL ANALYSES PERFORMED
Percent of participants whose intake was below the estimated average requirement (EAR) or adequate intake (AI) and above the tolerable upper limit (UL).
RESULTS
Dietary intakes of choline, folate, iron, vitamin D, zinc, vitamin E, magnesium, and potassium, were below the AI or EAR for 30-91% of the participants; thiamin and vitamin B6 were also below the AI or EAR for non-Hispanic/Latina women. Supplement intake improved the intake for most; however, 80% of the group remained below the AI for choline and 52.5% for potassium while 30% remained below the EAR for magnesium. Folate and iron intakes were above the UL for 80% and 19%, respectively.
CONCLUSIONS
Dietary supplements, despite their variability, allowed the majority of this cohort of pregnant women to achieve adequate intakes for most micronutrients. Choline, magnesium, and potassium were exceptions. Of interest, folate intake was above the tolerable UL for the majority and iron for 16.8% of the participants. Clinicians have the opportunity to address the most common nutrient deficits and limits with advice on food sources that provide choline, magnesium, and potassium and to ensure folate is not overabundant. More research is needed to determine if these findings are similar in a cross-sectional population.
Topics: Female; Humans; Pregnancy; Choline; Cross-Sectional Studies; Diet; Dietary Supplements; Folic Acid; Iron; Magnesium; Micronutrients; Nutritional Requirements; Potassium; Pregnant Women; Trace Elements
PubMed: 37513643
DOI: 10.3390/nu15143228