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The impact of vitamin B2 (riboflavin) intake on cognitive performance among older adults in the United States (US) remains inadequately understood. This study aimed to explore the association between vitamin B2 intake and cognitive performance among non-institutionalized elderly people in the US. Weighted logistic regression was used to evaluate the association between vitamin B2 intake and cognitive performance. Vitamin B2 intake was determined from the mean of two 24-hour dietary recall interviews. Three cognitive ability assessment tests, namely the Immediate Recall Test (IRT), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST), were performed. Participants included all older adults over 60 who underwent cognitive scoring, with cut-offs defined based on the lowest quartile (25th percentile) for each test (the cut-offs for the three scores were 15.625, 12, and 33, respectively). Sensitivity analysis, including dose-response curves, subgroup analyses, interaction effects, per 1 standard deviation (SD), recommended dietary allowance (RDA), and residual energy model analysis, were performed to solidify the solid association between vitamin B2 and cognitive performance. A total of 2893 individuals aged over 60 were included, with a mean age of 69 (7) years, and 46% were men. There was a significant association between vitamin B2 intake and all three cognitive scores (IRT, Odds Ratio = 0.77, 95% confidence interval: [0.65,0.92]; AFT, 0.75, [0.64,0.88]; DSST, 0.72, [0.59,0.88]). Moreover, vitamin B2 intake above the RDA reduced the risk of low cognitive performance (IRT, 0.66, [0.46,0.93]; AFT, 0.83, [0.62,1.11]; DSST, 0.65, [0.45,0.92]) compared to intake below the RDA. Dose-response curves indicated that higher vitamin B2 intake was negatively associated with the risk of low cognitive performance. Physical activity may modify the association between vitamin B2 and cognitive performance. Vitamin B2 intake was positively associated with cognitive performance among older adults. Adequate vitamin B2 intake could help protect cognitive function., (© 2024. The Author(s).)

Brain oxygen deprivation causes morphological damage involved in the formation of serious pathological conditions such as stroke and cerebral palsy. Therapeutic methods for post-hypoxia/anoxia injuries are limited and still have deficiencies in terms of safety and efficacy. Recently, clinical studies of stroke have reported the use of drugs containing riboflavin for post-injury clinical rehabilitation, however, the effects of vitamin B2 on exposure to cerebral oxygen deprivation are not completely elucidated. This review aimed to investigate the potential antioxidant, anti-inflammatory and neuroprotective effects of riboflavin in cerebral hypoxia/anoxia. After a systematic search, 21 articles were selected, 8 preclinical and 12 clinical studies, and 1 translational study. Most preclinical studies used B2 alone in models of hypoxia in rodents, with doses of 1-20 mg/kg (in vivo) and 0.5-5 µM (in vitro). Together, these works suggested greater regulation of lipid peroxidation and apoptosis and an increase in neurotrophins, locomotion, and cognition after treatment. In contrast, several human studies have administered riboflavin (5 mg) in combination with other Krebs cycle metabolites, except one study, which used only B2 (20 mg). A reduction in lactic acidosis and recovery of sensorimotor functions was observed in children after treatment with B2, while adults and the elderly showed a reduction in infarct volume and cognitive rehabilitation. Based on findings from preclinical and clinical studies, we conclude that the use of riboflavin alone or in combination acts beneficially in correcting the underlying brain damage caused by hypoxia/anoxia and its inflammatory, oxidative, and behavioral impairments.

This investigation aimed to evaluate the impact of immersion (IM) riboflavin treatment on the hatchability, production efficiency, and carcass characteristics of Japanese quail eggs. A total of 260 eggs of Japanese quail birds were used for hatching and were randomly divided into 4 treatments with 5 replicates (13 eggs/replicate) in a fully randomized design. Hatching eggs were immersed in riboflavin for 2 min before incubation. The experiment treatments were designed as follows: G1 control group with no treatment, G2 treated with 3 g/L vit. B2 (IM), G3 treated with 4 g/L vit. B2 (IM) and G4 were treated with 5 g/L vit. B2 (IM). After hatching, 128 Japanese quail chicks, aged 7 d, were randomly grouped into 4 treatment groups, with 32 birds in each group. When quails were given vitamin B2 via immersion, they demonstrated significant enhancements in live body weight, body weight gain, feed consumption, and feed conversion ratio at different stages compared to the control group. Compared to control and other groups, the carcass parameters of Japanese quails given a 4 g/L immersion solution showed a significant improvement (P < 0.05). Hatchability and fertility (%) were considerably raised by Vit.B2 treatments of 3, 4, and 5g; the group immersed in 5 g/L had the highest percentages compared to the other groups. Furthermore, treated chickens with all concentrations of vitamin B2 had significantly higher blood indices than the controls. During the exploratory phase (1-6 wk) of age, the highest returns were reported in G4 treated with 5g/L vit. B2 (IM). Treating Japanese quail eggs with different dosages of vitamin B2 by immersion may be recommended to improve their productive and reproductive performance, blood indices, carcass traits, and economic efficiency., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the feasibility of theranostics to determine the riboflavin concentration in the cornea using clinically available ophthalmic formulations during epithelium-off (epi-off) and transepithelial (epi-on) corneal cross-linking procedures., Methods: Thirty-two eye bank human donor corneas were equally randomized in eight groups; groups 1 to 3 and groups 4 to 8 underwent epi-off and epi-on delivery of riboflavin respectively. Riboflavin ophthalmic solutions were applied onto the cornea according to the manufacturers' instructions. The amount of riboflavin into the cornea was estimated, at preset time intervals during imbibition time, using theranostic UV-A device (C4V CHROMO4VIS, Regensight srl, Italy) and expressed as riboflavin score (d.u.). Measurements of corneal riboflavin concentration (expressed as µg/cm 3 ) were also performed by spectroscopy absorbance technique (AvaLight-DH-S-BAL, Avantes) for external validation of theranostic measurements., Results: At the end of imbibition time in epi-off delivery protocols, the average riboflavin score ranged from 0.77 ± 0.38 (the average corneal riboflavin concentration was 213 ± 190 µg/cm 3 ) to 1.79 ± 0.07 (554 ± 103 µg/cm 3 ). In epi-on delivery protocols, the average riboflavin score ranged from 0.17 ± 0.01 to 0.67 ± 0.19 (corneal riboflavin concentration ranged from 6 ± 5 µg/cm 3 to 122 ± 39 µg/cm 3 ) at the end of imbibition time. A statistically significant linear correlation (P ≤ 0.05) was found between the theranostic and spectrophotometry measurements in all groups., Conclusions: Real-time theranostic imaging provided an accurate strategy for assessing permeation of riboflavin into the human cornea during the imbibition phase of corneal cross-linking, regardless of delivery protocol. A large variability in corneal riboflavin concentration exists between clinically available ophthalmic formulations both in epi-off and epi-on delivery protocols., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Accumulating evidence suggests a pivotal role of vitamin B2 in the pathogenesis and progression of prostate cancer (PCa). Vitamin B2 intake has been postulated to modulate the screening rate for PCa by altering the concentration of prostate-specific antigen(PSA). However, the relationship between vitamin B2 and PSA remains indeterminate. Hence, we conducted a comprehensive evaluation of the association between vitamin B2 intake and PSA levels, utilizing data from the National Health and Nutrition Examination Survey (NHANES) database., Methods: From a pool of 20,371 participants in the NHANES survey conducted between 2003 and 2010, a cohort of 2,323 participants was selected for the present study. The male participants were classified into four distinct groups based on their levels of vitamin B2 intake. We employed a multiple linear regression model and a non-parametric regression method to investigate the relationship between vitamin B2 and PSA levels., Results: The study cohort comprised of 2,323 participants with a mean age of 54.95 years (± 11.73). Our findings revealed a statistically significant inverse correlation between vitamin B2 intake (mg) and PSA levels, with a reduction of 0.13 ng/ml PSA concentration for every unit increase in vitamin B2 intake. Furthermore, we employed a fully adjusted model to construct a smooth curve to explore the possible linear relationship between vitamin B2 intake and PSA concentration., Conclusions: Our study in American men has unveiled a notable inverse association between vitamin B2 intake and PSA levels, potentially posing a challenge for the identification of asymptomatic prostate cancer. Specifically, our findings suggest that individuals with higher vitamin B2 intake may be at a greater risk of being diagnosed with advanced prostate cancer in the future, possibly indicating a detection bias. These results may offer a novel explanation for the observed positive correlation between vitamin B2 intake and prostate cancer., (© 2024. The Author(s).)

Purpose: To present the outcome of the interrupted iontophoresis-assisted treatment arm in an ongoing randomised clinical trial (NCT04427956)., Methods: A randomised clinical study of corneal cross-linking (CXL) using continuous UV-A irradiation at a rate of 9 mW/cm 2 and three different types of riboflavin and riboflavin delivery mode: (1) iso-osmolar dextran-based riboflavin (epithelium-off), (2) hypo-osmolar dextran-free riboflavin (epithelium-off) and (3) iontophoresis-assisted delivery of riboflavin (epithelium-on) for the treatment of progressive keratoconus. Inclusion criteria were an increase in the maximum keratometry value (Kmax) of 1.0 dioptre over 12 months or 0.5 dioptre over 6 months. The primary outcome in evaluating treatment efficacy was Kmax. Recently presented stratified detection limits were used post hoc to confirm the enrolment of patients with truly progressive keratoconus and in the assessment of the need for re-CXL., Results: Thirteen patients had been randomised to iontophoresis-assisted CXL when the treatment arm was interrupted; two patients dropped out. Of the remaining 11 patients, 7 were deemed as having truly progressive disease according to the more recent stratified detection limits. The disease continued to progress in three patients according to the original definition (increase in Kmax≥1 D), necessitating re-CXL with epithelium-off CXL. This progression was confirmed by post hoc analysis using the stratified detection limits for progression., Conclusions: The iontophoresis-assisted CXL protocol failed to halt further disease progression in 27% of the patients. The failure rate increased to 38% when considering only the patients deemed to have truly progressive disease using the stratified detection limits., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Avoiding damage of the endothelial cells, especially in thin corneas, remains a challenge in corneal collagen crosslinking (CXL). Knowledge of the riboflavin gradients and the UV absorption characteristics after topical application of riboflavin in concentrations ranging from 0.1% to 0.5% could optimize the treatment. In this study, we present a model to calculate the UV-intensity depending on the corneal thickness. Ten groups of de-epithelialized porcine corneas were divided into 2 subgroups. Five groups received an imbibition of 10 min and the other five groups for 30 min. The applied riboflavin concentrations were 0.1%, 0.2%, 0.3%, 0.4% and 0.5% diluted in a 15% dextran solution for each subgroup. After the imbibition process, two-photon fluorescence microscopy was used to determine fluorescence intensity, which was compared to samples after saturation, yielding the absolute riboflavin concentration gradient of the cornea. The extinction coefficient of riboflavin solutions was measured using a spectrophotometer. Combining the obtained riboflavin concentrations and the extinction coefficients, a depth-dependent UV-intensity profile was calculated for each group. With increasing corneal depth, the riboflavin concentration decreased for all imbibition solutions and application times. The diffusion coefficients of 10 min imbibition time were higher than for 30 min. A higher RF concentration and a longer imbibition time resulted in higher UV-absorption and a lower UV-intensity in the depth of the cornea. Calculated UV-transmission was 6 percentage points lower compared to the measured transmission. By increasing the riboflavin concentration of the imbibition solution, a substantially higher UV-absorption inside the cornea is achieved. This offers a simple treatment option to control the depth of crosslinking e.g. in thin corneas, resulting in a lower risk of endothelial damage., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

To investigate the influences of dietary riboflavin (RF) addition on nutrient digestion and rumen fermentation, eight rumen cannulated Holstein bulls were randomly allocated into four treatments in a repeated 4 × 4 Latin square design. Daily addition level of RF for each bull in control, low RF, medium RF and high RF was 0, 300, 600 and 900 mg, respectively. Increasing the addition level of RF, DM intake was not affected, average daily gain tended to be increased linearly and feed conversion ratio decreased linearly. Total tract digestibilities of DM, organic matter, crude protein (CP) and neutral-detergent fibre (NDF) increased linearly. Rumen pH decreased quadratically, and total volatile fatty acids (VFA) increased quadratically. Acetate molar percentage and acetate:propionate ratio increased linearly, but propionate molar percentage and ammonia-N content decreased linearly. Rumen effective degradability of DM increased linearly, NDF increased quadratically but CP was unaltered. Activity of cellulase and populations of total bacteria, protozoa, fungi, dominant cellulolytic bacteria, Prevotella ruminicola and Ruminobacter amylophilus increased linearly. Linear increase was observed for urinary total purine derivatives excretion. The data suggested that dietary RF addition was essential for rumen microbial growth, and no further increase in performance and rumen total VFA concentration was observed when increasing RF level from 600 to 900 mg/d in dairy bulls.

Objective: To determine whether B vitamin treatment was sufficient to reduce cognitive impairment associated with high-fat diets in rats and to modulate transketolase (TK) expression and activity., Methods: To test this, we separated 50 rats into five groups that were either fed a standard chow diet (controls) or a high-fat diet (experimental groups H0, H1, H2, and H3). H0 group animals received no additional dietary supplementation, while H1 group animals were administered 100 mg/kg body weight (BW) thiamine, 100 mg/kg BW riboflavin, and 250 mg/kg BW niacin each day, and group H2 animals received daily doses of 100 mg/kg BW pyridoxine, 100 mg/kg BW cobalamin, and 5 mg/kg BW folate. Animals in the H3 group received the B vitamin regimens administered to both H1 and H2 each day., Results: Over time, group H0 exhibited greater increases in BW and fat mass relative to other groups. When spatial and memory capabilities in these animals were evaluated via conditioned taste aversion (CTA) and Morris Water Maze (MWM), we found B vitamin treatment was associated with significant improvements relative to untreated H0 controls. Similarly, B vitamin supplementation was associated with elevated TK expression in erythrocytes and hypothalamus of treated animals relative to those in H0 (P<0.05)., Conclusion: Together, these findings suggest B vitamin can modulate hypothalamic TK activity to reduce the severity of cognitive deficits in a rat model of obesity. As such, B vitamin supplementation may be a beneficial method for reducing cognitive dysfunction in clinical settings associated with high-fat diets., (© 2021. Huazhong University of Science and Technology.)

Maintaining nutritional adequacy contributes to successful ageing. B vitamins involved in one-carbon metabolism regulation (folate, riboflavin, vitamins B6 and B12) are critical nutrients contributing to homocysteine and epigenetic regulation. Although cross-sectional B vitamin intake in ageing populations is characterised, longitudinal changes are infrequently reported. This systematic review explores age-related changes in dietary adequacy of folate, riboflavin, vitamins B6 and B12 in community-dwelling older adults (≥65 years at follow-up). Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, databases (MEDLINE, Embase, BIOSIS, CINAHL) were systematically screened, yielding 1579 records; eight studies were included (n 3119 participants, 2–25 years of follow-up). Quality assessment (modified Newcastle–Ottawa quality scale) rated all of moderate–high quality. The estimated average requirement cut-point method estimated the baseline and follow-up population prevalence of dietary inadequacy. Riboflavin (seven studies, n 1953) inadequacy progressively increased with age; the prevalence of inadequacy increased from baseline by up to 22·6 and 9·3 % in males and females, respectively. Dietary folate adequacy (three studies, n 2321) improved in two studies (by up to 22·4 %), but the third showed increasing (8·1 %) inadequacy. Evidence was similarly limited (two studies, respectively) and inconsistent for vitamins B6 (n 559; −9·9 to 47·9 %) and B12 (n 1410; −4·6 to 7·2 %). This review emphasises the scarcity of evidence regarding micronutrient intake changes with age, highlighting the demand for improved reporting of longitudinal changes in nutrient intake that can better direct micronutrient recommendations for older adults. This review was registered with PROSPERO (CRD42018104364).

Mitochondrial complex I (CI) deficiencies (OMIM 252010) are the commonest inherited mitochondrial disorders in children. Acyl-CoA dehydrogenase 9 (ACAD9) is a flavoenzyme involved chiefly in CI assembly and possibly in fatty acid oxidation. Biallelic pathogenic variants result in CI dysfunction, with a phenotype ranging from early onset and sometimes fatal mitochondrial encephalopathy with lactic acidosis to late-onset exercise intolerance. Cardiomyopathy is often associated. We report a patient with childhood-onset optic and peripheral neuropathy without cardiac involvement, related to CI deficiency. Genetic analysis revealed compound heterozygous pathogenic variants in ACAD9, expanding the clinical spectrum associated to ACAD9 mutations. Importantly, riboflavin treatment (15 mg/kg/day) improved long-distance visual acuity and demonstrated significant rescue of CI activity in vitro., (Copyright © 2021 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Corneal cross-linking has been described as an effective treatment to slow the progression of keratoconus. The standard protocol entails corneal epithelial removal to allow the diffusion of riboflavin into the stroma. Although, de-epithelization can generate risks or complications that transepithelial cross-linking tries to solve or avoid. Different formulations were developed after verifying that hydroxypropyl-β-cyclodextrin (HPβCD) and sulfobuthylether-β-cyclodextrin (SBEβCD) in a 20% concentration, increased the solubility of practically insoluble in water drugs such as riboflavin from 0.12 mg/mL to 0.35 mg/mL and 0.29 mg/mL respectively. These values were higher when chitosan and arginine were added to the formulation, showing solubility of 0.78 mg/mL when HPβCD concentration was not modified. Ex vivo corneal permeability was measured after having kept in contact bovine corneas with intact epithelium for 5 h with the 0.1 mg/mL riboflavin solution, the formulations developed and a reproduced nanoemulsion from another work. Riboflavin's permeability was increased when cyclodextrins, chitosan, and arginine were part of the formulations, compared to the control drug solution. The best permeability coefficient was reached when riboflavin was combined with 40% (w/v) HPβCD, 0.5% (w/w) arginine, and 0.5% (w/w) chitosan. After having carried out toxicity studies as bovine corneal opacity and permeability (BCOP) and Heńs Egg Test - Chorioallantoic Membrane Test (HET-CAM) it was verified that both, the active ingredients and the excipients of the different formulations were not harmful without generating irritation, loss of transparency or corneal permeability alterations. The results show the great potential of the ocular developed solution for their use in transepithelial cross-linking for keratoconus treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: The present study investigated whether the pulmonary intersegmental planes could be identified with the intravenous injection of vitamin B 2 using a fluorescent camera and whether this method can be used instead of the inflation-deflation technique or the intravenous indocyanine green (ICG) method., Methods: In experiment 1, the vitamin B 2 was intravenously injected to visualize the pulmonary intersegmental plane and perform segmentectomy, and the visualized pulmonary intersegmental line was then compared to the inflation-deflation line in six pigs. In experiment 2, using six pigs, the fluorescent area and duration of fluorescence were compared after the intravenous injection of vitamin B 2 and ICG in the same animals., Results: In all animals in experiment 1, it was possible to clearly detect yellow-green fluorescence in the lung, in segments other than the one intended for resection, for at least 60 min. Moreover, the line visualized with vitamin B 2 fluorescence matched the inflation-deflation line in all animals. In experiment 2, the area of vitamin B 2 fluorescence corresponded to the area of ICG fluorescence in each animal., Conclusions: The visualization of fluorescence after the intravenous injection of vitamin B 2 using a fluorescent camera was a simple, safe, and accurate method for detecting intersegmental planes in a pig model. This method can be an alternative to the inflation-deflation technique and the intravenous ICG method.

Background: Keratoconus is the most common corneal dystrophy. It can cause loss of uncorrected and best-corrected visual acuity through ectasia (thinning) of the central or paracentral cornea, irregular corneal scarring, or corneal perforation. Disease onset usually occurs in the second to fourth decade of life, periods of peak educational attainment or career development. The condition is lifelong and sight-threatening. Corneal collagen crosslinking (CXL) using ultraviolet A (UVA) light applied to the cornea is the only treatment that has been shown to slow progression of disease. The original, more widely known technique involves application of UVA light to de-epithelialized cornea, to which a photosensitizer (riboflavin) is added topically throughout the irradiation process. Transepithelial CXL is a recently advocated alternative to the standard CXL procedure, in that the epithelium is kept intact during CXL. Retention of the epithelium offers the putative advantages of faster healing, less patient discomfort, faster visual rehabilitation, and less risk of corneal haze., Objectives: To assess the short- and long-term effectiveness and safety of transepithelial CXL compared with epithelium-off CXL for progressive keratoconus., Search Methods: To identify potentially eligible studies, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature database (LILACS); ClinicalTrials.gov; and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not impose any date or language restrictions. We last searched the electronic databases on 15 January 2020., Selection Criteria: We included randomized controlled trials (RCTs) in which transepithelial CXL had been compared with epithelium-off CXL in participants with progressive keratoconus., Data Collection and Analysis: We used standard Cochrane methodology., Main Results: We included 13 studies with 723 eyes of 578 participants enrolled; 13 to 119 participants were enrolled per study. Seven studies were conducted in Europe, three in the Middle East, and one each in India, Russia, and Turkey. Seven studies were parallel-group RCTs, one study was an RCT with a paired-eyes design, and five studies were RCTs in which both eyes of some or all participants were assigned to the same intervention. Eleven studies compared transepithelial CXL with epithelium-off CXL in participants with progressive keratoconus. There was no evidence of an important difference between intervention groups in maximum keratometry (denoted 'maximum K' or 'Kmax'; also known as steepest keratometry measurement) at 12 months or later (mean difference (MD) 0.99 diopters (D), 95% CI -0.11 to 2.09; 5 studies; 177 eyes; I 2 = 41%; very low certainty evidence). Few studies described other outcomes of interest. The evidence is very uncertain that epithelium-off CXL may have a small (data from two studies were not pooled due to considerable heterogeneity (I 2 = 92%)) or no effect on stabilization of progressive keratoconus compared with transepithelial CXL; comparison of the estimated proportions of eyes with decreases or increases of 2 or more diopters in maximum K at 12 months from one study with 61 eyes was RR 0.32 (95% CI 0.09 to 1.12) and RR (non-event) 0.86 (95% CI 0.74 to 1.00), respectively (very low certainty). We did not estimate an overall effect on corrected-distance visual acuity (CDVA) because substantial heterogeneity was detected (I 2 = 70%). No study evaluated CDVA gain or loss of 10 or more letters on a logarithm of the minimum angle of resolution (logMAR) chart. Transepithelial CXL may result in little to no difference in CDVA at 12 months or beyond. Four studies reported that either no adverse events or no serious adverse events had been observed. Another study noted no change in endothelial cell count after either procedure. Moderate certainty evidence from 4 studies (221 eyes) found that epithelium-off CXL resulted in a slight increase in corneal haze or scarring when compared to transepithelial CXL (RR (non-event) 1.07, 95% CI 1.01 to 1.14). Three studies, one of which had three arms, compared outcomes among participants assigned to transepithelial CXL using iontophoresis versus those assigned to epithelium-off CXL. No conclusive evidence was found for either keratometry or visual acuity outcomes at 12 months or later after surgery. Low certainty evidence suggests that transepithelial CXL using iontophoresis results in no difference in logMAR CDVA (MD 0.00 letter, 95% CI -0.04 to 0.04; 2 studies; 51 eyes). Only one study examined gain or loss of 10 or more logMAR letters. In terms of adverse events, one case of subepithelial infiltrate was reported after transepithelial CXL with iontophoresis, whereas two cases of faint corneal scars and four cases of permanent haze were observed after epithelium-off CXL. Vogt's striae were found in one eye after each intervention. The certainty of the evidence was low or very low for the outcomes in this comparison due to imprecision of estimates for all outcomes and risk of bias in the studies from which data have been reported., Authors' Conclusions: Because of lack of precision, frequent indeterminate risk of bias due to inadequate reporting, and inconsistency in outcomes measured and reported among studies in this systematic review, it remains unknown whether transepithelial CXL, or any other approach, may confer an advantage over epithelium-off CXL for patients with progressive keratoconus with respect to further progression of keratoconus, visual acuity outcomes, and patient-reported outcomes (PROs). Arrest of the progression of keratoconus should be the primary outcome of interest in future trials of CXL, particularly when comparing the effectiveness of different approaches to CXL. Furthermore, methods of assessing and defining progressive keratoconus should be standardized. Trials with longer follow-up are required in order to assure that outcomes are measured after corneal wound-healing and stabilization of keratoconus. In addition, perioperative, intraoperative, and postoperative care should be standardized to permit meaningful comparisons of CXL methods. Methods to increase penetration of riboflavin through intact epithelium as well as delivery of increased dose of UVA may be needed to improve outcomes. PROs should be measured and reported. The visual significance of adverse outcomes, such as corneal haze, should be assessed and correlated with other outcomes, including PROs., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

An increasing body of evidence has shown that gut microbiota imbalances are linked to diseases. Currently, the possibility of regulating gut microbiota to reverse these perturbations by developing novel therapeutic and preventive strategies is being extensively investigated. The modulatory effect of vitamins on the gut microbiome and related host health benefits remain largely unclear. We investigated the effects of colon-delivered vitamins A, B2, C, D, and E on the gut microbiota using a human clinical study and batch fermentation experiments, in combination with cell models for the assessment of barrier and immune functions. Vitamins C, B2, and D may modulate the human gut microbiome in terms of metabolic activity and bacterial composition. The most distinct effect was that of vitamin C, which significantly increased microbial alpha diversity and fecal short-chain fatty acids compared to the placebo. The remaining vitamins tested showed similar effects on microbial diversity, composition, and/or metabolic activity in vitro , but in varying degrees. Here, we showed that vitamins may modulate the human gut microbiome. Follow-up studies investigating targeted delivery of vitamins to the colon may help clarify the clinical significance of this novel concept for treating and preventing dysbiotic microbiota-related human diseases. Trial registration: ClinicalTrials.gov, NCT03668964. Registered 13 September 2018 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03668964.

Background: We evaluated the efficacy of riboflavin in pediatric migraineurs., Methods: A retrospective observational study was performed on 42 patients (aged six to 18 years) with migraine who were evaluated from January to December 2019 at Dell Children's Medical Center in Austin, Texas. Weight-based dosing of riboflavin was recommended for migraine prevention. Descriptive statistics were used to study the population demographics. Nonparametric tests were used for inferential statistics to study the effect of riboflavin on headache frequency, intensity, and duration., Results: Patients treated with riboflavin had a significant reduction in headache days per month (frequency) at the first follow-up visit at 2 to 4 months (T1) (11.07 ± 10.52 days) compared with the baseline T0 (21.90 ± 9.85 days); P < 0.001 in regard to the primary outcome in 42 patients (mean age, 13.38 ± 3.38). Mean headache intensity decreased from 8.85 (±6.41; T0) to 2.30 (±2.51; T1); P < 0.001 on a 0 to 10 scale. The headache duration also reduced significantly from 18.23 ± 17.07 hours (T0) to 10.18 ± 10.49 hours (T1); P = 0.001. There was a positive correlation between riboflavin efficacy and reduced use of acute medications (r s  = 0.304; P = 0.05). Riboflavin was useful in reducing the frequency and intensity in two patients with new daily persistent headache., Conclusions: Patients treated with riboflavin had a reduction in headache frequency, use of acute medications, and days of school missed. Riboflavin prophylaxis also reduced migraine intensity and duration. Riboflavin is recommended as a safe, inexpensive, and effective nutraceutical in the treatment of pediatric migraine., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The prospective relation of dietary riboflavin intake with hypertension remains uncertain. We aimed to investigate the relationship of dietary riboflavin intake with new-onset hypertension and examine possible effect modifiers in general population. A total of 12 245 participants who were free of hypertension at baseline from China Health and Nutrition Survey were included. Dietary intake was measured by 3 consecutive 24-hour dietary recalls combined with a household food inventory. The study outcome was new-onset hypertension, defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg or diagnosed by physician or under antihypertensive treatment during the follow-up. A total of 4303 (35.1%) subjects developed hypertension during 95 573 person-years of follow-up. Overall, there was a nonlinear, inverse association between total, plant-based, or animal-based riboflavin intake and new-onset hypertension (all P for nonlinearity, <0.001). The risk of new-onset hypertension was increased only in participants with relatively lower riboflavin intake. Accordingly, a significantly lower risk of new-onset hypertension was found in participants in quartiles 2 to 4 of total riboflavin intake (hazard ratio, 0.74 [95% CI, 0.68-0.80]), plant-derived riboflavin intake (hazard ratio, 0.77 [95% CI, 0.71-0.84]), or animal-derived riboflavin intake (hazard ratio, 0.70 [95% CI, 0.65-0.77]), compared with those in quartile 1. In addition, the association between total riboflavin intake and new-onset hypertension was particularly evident in those with lower dietary sodium/potassium intake ratio ( P interaction, <0.001). In summary, there was an inverse association between riboflavin intake and new-onset hypertension in general Chinese adults. Our results emphasized the importance of maintaining relatively higher riboflavin intake levels for the prevention of hypertension.

Background: Recessive mutations in ETFDH gene have been associated with Multiple Acyl-CoA dehydrogenase deficiency (MADD). The late-onset MADD is often muscle involved, presenting with lipid storage myopathy (LSM). The symptoms of LSM were heterogeneous and definite diagnosis of this disease depends on the pathology and gene test. Methods: Neurological examination, muscle biopsy, and MRI examinations were performed in a patient with a novel missense ETFDH mutation. Results: We describe a patient with lipid storage myopathy complicated with skin damage. In addition, the next generation revealed a novel missense mutation (c.970G > T, p.Val324Leu) in exon 8, which was predicted to be a disease-causing mutation by Mutation-taster, and destroy the function of the protein by Sift. Conclusion: These findings expand the known mutational spectrum of ETFDH and phenotype of MADD.

Climate change impact has disturbed the rainfall pattern worsening the problems of water availability in the aquatic ecosystem of India and other parts of the world. Arsenic pollution, mainly through excessive use of groundwater and other anthropogenic activities, is aggravating in many parts of the world, particularly in South Asia. We evaluated the efficacy of selenium nanoparticles (Se-NPs) and riboflavin (RF) to ameliorate the adverse impacts of elevated temperature and arsenic pollution on growth, anti-oxidative status and immuno-modulation in Pangasianodon hypophthalmus. Se-NPs were synthesized using fish gill employing green synthesis method. Four diets i.e., Se-NPs (0 mg kg -1 ) + RF (0 mg kg -1 ); Se-NPs (0.5 mg kg -1 ) + RF (5 mg kg -1 ); Se-NPs (0.5 mg kg -1 ) + RF (10 mg kg -1 ); and Se-NPs (0.5 mg kg -1 ) + RF (15 mg kg -1 ) were given in triplicate in a completely randomized block design. The fish were treated in arsenic (1/10th of LC 50 , 2.68 mg L -1 ) and high temperature (34 °C). Supplementation of the Se-NPs and RF in the diets significantly (p < 0.01) enhanced growth performance (weight gain, feed efficiency ratio, protein efficiency ratio, and specific growth rate), anti-oxidative status and immunity of the fish. Nitroblue tetrazolium (NBT), total immunoglobulin, myeloperoxidase and globulin enhanced (p < 0.01) with supplementation (Se-NPs + RF) whereas, albumin and albumin globulin (A:G) ratio (p < 0.01) reduced. Stress biomarkers such as lipid peroxidation in the liver, gill and kidney, blood glucose, heat shock protein 70 in gill and liver as well as serum cortisol reduced (p < 0.01) with supplementation of Se-NPs and RF, whereas, acetylcholine esterase and vitamin C level in both brain and muscle significantly enhanced (p < 0.01) in compared to control and stressors group (As + T) fed with control diet. The fish were treated with pathogenic bacteria after 90 days of experimental trial to observe cumulative mortality and relative survival for a week. The arsenic concentration in experimental water and bioaccumulation in fish tissues was also determined, which indicated that supplementation of Se-NPs and RF significantly reduced (p < 0.01) bioaccumulation. The study concluded that a combination of Se-NPs and RF has the potential to mitigate the stresses of high temperature and As pollution in P. hypophthalmus.

Deficient intake of micronutrients involved in one-carbon metabolism (eg, choline, methionine, vitamin B 12 and folic acid) leads to hepatocellular carcinoma (HCC) development in rodents, but is under-investigated in humans. We investigated the association between one-carbon metabolism-related micronutrient intake and HCC risk in a prospective cohort of 494 860 participants with 16 years of follow-up in the NIH-AARP study. Dietary intakes and supplement use were ascertained at baseline using a food-frequency questionnaire. Total intake (diet plus supplements) of the following one-carbon metabolism-related micronutrients were calculated: folate, methionine and vitamins B 2 (riboflavin), B 3 (niacin), B 6 and B 12 . These micronutrients were examined both individually and simultaneously, with adjustment for covariates. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over the 16-year follow-up period, 647 incident HCC cases were diagnosed. When examined individually, higher total vitamin B 3 intake was associated with a lower HCC risk (HR Q5 vs Q1 = 0.60; 95% CI = 0.42-0.85; P trend = .008), and the association remained significant when all six micronutrients were examined simultaneously (HR Q5 vs Q1 = 0.32; 95% CI = 0.18-0.55; P trend < .0001). Among participants with >3 years of follow-up, higher total vitamin B 3 intake was again associated with lower risk (HR Q5 vs Q1 = 0.37; 95% CI = 0.20-0.68; P trend = .001), whereas higher total vitamin B 6 intake was associated with higher risk (HR Q5 vs Q1 = 2.04; 95% CI = 1.02-4.07; P trend = .04). Restricted cubic spline analyses showed a dose-response inverse association between total vitamin B 3 intake and HCC risk, and dose-response positive association between total vitamin B 6 intake and HCC risk. The study suggests that higher vitamin B 3 intake is associated with lower HCC risk, whereas higher vitamin B 6 intake is associated with increased risk., (© 2020 UICC.)

Changes in the barrier mechanisms in the eye should determine the rational route for the administration and dosage of each drug in the treatment of traumatic injuries and other pathologies. The aim of this study was to examine the efficacy of intra-arterial delivery of 14 C-riboflavin (as an "indicator") and compare it with intravenous and intramuscular administration in an animal model of chemical eye burn. 14 C-riboflavin ( 14 C-I) was administered by intra-arterial (carotid artery), intravenous (femoral vein) and intramuscular (femoral muscle) routes. The total radioactivity was determined over 2 h in the plasma and structures of the rabbit's eyes using a scintillation counter. The results of the study show that intravascular administration of 14 C-I gives significantly higher concentrations of total radioactivity in the blood and is accompanied by a significant increase in the permeability of the blood-barrier and barrier in eyes suffering from burns. The highest concentration in the plasma and aqueous humour of the anterior chamber of the eye was observed during the first hour with the intra-arterial route of administration of 14 C-I in either burnt and unburnt eyes. The distribution of total radioactivity in the structures of the eye over the 2 h of the experiment showed a higher level of the drug under intra-arterial administered in the uveal regions, namely: the iris, ciliary body, choroid, retina and also the sclera and cornea. This experimental model shows that intra-arterial administration can increase the bioavailability of a drug to the structures of the eye within a short period of time.

Background: Riboflavin is required to generate the active form of vitamin B-6 (pyridoxal 5'-phosphate; PLP) in tissues, but the relevance of this metabolic interaction for nutritional status of vitamin B-6 is unclear because riboflavin biomarkers are rarely measured in human studies., Objectives: The purpose of this study was to identify the determinants of biomarkers of vitamin B-6 and riboflavin status and to examine the relationship between these nutrients in healthy adults., Methods: Multiple linear regression was performed on observational data in 407 healthy adults aged 18-92 y who did not use B-vitamin supplements. Vitamin B-6 status was assessed by plasma PLP concentrations and erythrocyte glutathione reductase activation coefficient (EGRac) was used as a functional indicator of riboflavin status., Results: Dietary intakes of vitamin B-6 and riboflavin were below the average requirements in 10% and 29% of participants, respectively. Suboptimal status of vitamin B-6 (PLP ≤30.0 nmol/L) was more prevalent in adults aged ≥60 y than in younger participants (i.e., 14% compared with 5%), whereas a high proportion (i.e., overall 37%) of both age groups had deficient riboflavin status (EGRac ≥1.40). In multiple regression analysis, EGRac (P = 0.019) was a significant determinant of plasma PLP, along with dietary vitamin B-6 intake (P = 0.003), age (P < 0.001), BMI (kg/m2) (P = 0.031), and methylenetetrahydrofolate reductase gene (MTHFR) genotype (P < 0.001). Significant determinants of EGRac were dietary riboflavin intake (P < 0.001), age (P < 0.001) and MTHFR genotype (P = 0.020). Plasma PLP showed a stepwise decrease across riboflavin status categories from optimal (EGRac ≤1.26) to low (EGRac 1.27-1.39) to deficient status (P = 0.001), independent of dietary vitamin B-6 intake., Conclusions: The findings are consistent with the known metabolic dependency of vitamin B-6 on riboflavin status and indicate that riboflavin may be the limiting nutrient, particularly in older people, for maintaining adequate vitamin B-6 status., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

The study used the data from the National Health and Nutrition Examination Survey (NHANES) 2007-2014 to analyse the relationship of dietary vitamin B1, B2, niacin, B6, B12 and dietary folate equivalent (DEF) intakes with metabolic syndrome. In the multivariate-adjusted model 2, compared with the lowest quartile of dietary intake, the odd ratios (ORs;95% confidence intervals (CIs)) were 0.73 (0.59-0.91), 0.76 (0.61-0.95), 0.76 (0.59-0.98) and 0.77 (0.62-0.96) for the highest quartile of vitamin B1, niacin, B6 and DFE, respectively. The ORs (95%CIs) for the third and the highest quartile of vitamin B2 were 0.78 (0.61-0.99) and 0.62 (0.47-0.83). A linear inverse relationship was found between dietary vitamin B1, niacin, B6, DFE and metabolic syndrome, and a non-linear inverse relationship was found between dietary vitamin B2 and metabolic syndrome. Our results suggested that higher intake of vitamin B1, B2, niacin, B6 and DFE were all associated with reduced risk of metabolic syndrome.

Background: Maternal supplementation during lactation could increase milk B-vitamin concentrations, but little is known about the kinetics of milk vitamin responses., Objectives: We compared acute effects of maternal lipid-based nutrient supplement (LNS) consumption (n = 22 nutrients, 175%-212% of the RDA intake for the nutrients examined), as a single dose or at spaced intervals during 8 h, on milk concentrations and infant intake from milk of B-vitamins., Methods: This randomized crossover trial in Quetzaltenango, Guatemala included 26 mother-infant dyads 4-6 mo postpartum who were randomly assigned to receive 3 treatments in a random order: bolus 30-g dose of LNS (Bolus); 3 × 10-g doses of LNS (Divided); and no LNS (Control), with control meals. Mothers attended three 8-h visits during which infant milk consumption was measured and milk samples were collected at every feed. Infant intake was assessed as $\mathop \sum \nolimits&#95;{i\ = \ 1}^n ( {{\rm{milk\ volum}}{{\rm{e}}&#95;{{\rm{feed\ }}n}} \times \ {\rm{nutrient\ concentratio}}{{\rm{n}}&#95;{{\rm{feed}}\ n}}} )$ over 8 h., Results: Maternal supplementation with the Bolus or Divided dose increased least-squares mean (95% CI) milk and infant intakes of riboflavin [milk: Bolus: 154.4 (138.2, 172.5) μg · min-1 · mL-1; Control: 84.5 (75.8, 94.3) μg · min-1 · mL-1; infant: Bolus: 64.5 (56.1, 74.3) μg; Control: 34.5 (30.0, 39.6) μg], thiamin [milk: Bolus: 10.9 (10.1, 11.7) μg · min-1 · mL-1; Control: 7.7 (7.2, 8.3) μg · min-1 · mL-1; infant: Bolus: 5.1 (4.4, 6.0) μg; Control: 3.4 (2.9, 4.0) μg], and pyridoxal [milk: Bolus: 90.5 (82.8, 98.9) μg · min-1 · mL-1; Control: 60.8 (55.8, 66.3) μg · min-1 · mL-1; infant: Bolus: 39.4 (33.5, 46.4) μg; Control: 25.0 (21.4, 29.2) μg] (all P < 0.001). Only the Bolus dose increased cobalamin in milk [Bolus: 0.054 (0.047, 0.061) μg · min-1 · mL-1; Control: 0.041 (0.035, 0.048) μg · min-1 · mL-1, P = 0.039] and infant cobalamin intake [Bolus: 0.023 (0.020, 0.027) μg; Control: 0.015 (0.013, 0.018) μg, P = 0.001] compared with Control. Niacin was unaffected., Conclusions: Maternal supplementation with LNS as a Bolus or Divided dose was similarly effective at increasing milk riboflavin, thiamin, and pyridoxal and infant intakes, whereas only the Bolus dose increased cobalamin. Niacin was unaffected in 8 h. This trial was registered at clinicaltrials.gov as NCT02464111., (Published by Oxford University Press on behalf of the American Society for Nutrition 2020.)

Purpose: Determine optimal iontophoresis times for riboflavin delivery to the corneal stroma across different species and compare these to corneal injection., Methods: Ex vivo horse, dog, rabbit, and pig globes were treated with riboflavin administered with either iontophoresis for 2.5-20 minutes with or without corneal epithelium; or with purpose-designed precise corneal injection (PCI) application with intact epithelium. Immediately following riboflavin administration, samples were harvested, frozen, and sectioned. Riboflavin penetration was imaged using fluorescence microscopy., Results: Horse samples processed with iontophoresis without epithelium for 2.5, 5, and 7.5 minutes, and processed with intact epithelium for 20 minutes, had mean percent stromal penetration (%SP mean ) of 63.4%, 93.8%, 100.0%, and 0.0% (respectively). Dog samples processed with iontophoresis without epithelium for 2.5 and 5 minutes, had %SP mean of 60.7% and 82.1% (respectively). Pig samples processed with iontophoresis for 5 minutes without and with epithelium had %SP mean of 63.3% and 35.1% (respectively). Rabbit samples processed with iontophoresis without epithelium for 2.5 and 5 minutes, had %SP mean of 81.8% and 100.0% (respectively). For all injected volumes, riboflavin was observed spanning throughout the corneal stroma, and lamellar separation was noted surrounding all sites of injection., Conclusions: Both iontophoresis and injection via PCI needles provide efficient and effective means of riboflavin administration in ex vivo horse, dog, rabbit, and pig corneas. Epithelial debridement is required for stromal delivery of riboflavin using iontophoresis in horses. Following epithelial removal, riboflavin penetrated through the horse corneal stroma faster than all other species tested., (© 2020 American College of Veterinary Ophthalmologists.)

Nutritional optic neuropathy is a cause of bilateral, symmetrical, and progressive visual impairment with loss of central visual acuity and contrast sensitivity, dyschromatopsia, and a central or centrocecal scotoma. The clinical features are not pathognomonic, since hereditary and toxic forms share similar signs and symptoms. It is becoming increasingly common due to the widespread of bariatric surgery and strict vegetarian or vegan diets, so even the scientific interest has recently increased. In particular, recent studies have focused on possible pathogenetic mechanisms, and on novel diagnostic and therapeutic strategies in order to prevent the onset, make a prompt diagnosis and an accurate nutritional supplementation, and to avoid irreversible optic nerve atrophy. Nowadays, there is clear evidence of the role of cobalamin, folic acid, thiamine, and copper, whereas further studies are needed to define the role of niacin, riboflavin, and pyridoxine. This review aims to summarize the etiology, diagnosis, and treatment of nutritional optic neuropathy, and it is addressed not only to ophthalmologists, but to all physicians who could come in contact with a patient with a possible nutritional optic neuropathy, being a fundamental multidisciplinary approach.

Background: Untreated antenatal depression and anxiety can be associated with short and long term health impacts on the pregnant woman, her infant and the rest of the family. Alternative interventions to those currently available are needed. This clinical trial aims to investigate the efficacy and safety of a broad-spectrum multinutrient formula as a treatment for symptoms of depression and anxiety in pregnant women and to determine the impact supplementation has on the general health and development of the infant., Methods: This randomised, controlled trial will be conducted in Canterbury, New Zealand between April 2017 and June 2022. One hundred and twenty women aged over 16 years, between 12 and 24 weeks gestation and who score ≥ 13 on the Edinburgh Postnatal Depression Scale (EPDS) will be randomly assigned to take the intervention (n = 60) or an active control formula containing iodine and riboflavin (n = 60) for 12 weeks. After 12 weeks, participants can enter an open-label phase until the birth of their infant and naturalistically followed for the first 12 months postpartum. Infants will be followed until 12 months of age. Randomisation will be computer-generated, with allocation concealment by opaque sequentially numbered envelopes. Participants and the research team including data analysts will be blinded to group assignment. The EPDS and the Clinical Global Impressions Scale of Improvement (CGI-I) will be the maternal primary outcome measures of this study and will assess the incidence of depression and anxiety and the improvement of symptomatology respectively. Generalized linear mixed effects regression models will analyse statistical differences between the multinutrient and active control group on an intent-to-treat basis. A minimum of a three-point difference in EPDS scores between the groups will identify clinical significance. Pregnancy outcomes, adverse events and side effects will also be monitored and reported., Discussion: Should the multinutrient formula be shown to be beneficial for both the mother and the infant, then an alternative treatment option that may also improve the biopsychosocial development of their infants can be provided for pregnant women experiencing symptoms of depression and anxiety., Trial Registration: Trial ID: ACTRN12617000354381 ; prospectively registered at Australian New Zealand Clinical Trials Registry on 08/03/2017.

Aim: Keratoconus is a common and progressive eye disease characterized by thinning and tapering of the cornea. This degenerative eye disease is currently treated in the clinic with an interventional technique ("epi-off") that can cause serious side effects as a result of the surgical procedure. The aim of this project is to design innovative formulations for the development of a riboflavin-containing medicinal product to develop a non-invasive ("epi-on") keratoconus treatment as an alternative to current treatment modalities., Methods: Nanostructured lipid carriers (NLCs) were successfully loaded with either riboflavin base of riboflavin-5-phosphate sodium and designed with either Stearylamine (positive charge) or Trancutol P (permeation enhancer). In vitro characterization studies, cytotoxicity and permeability studies were performed. Selected formulations and commercial preparations were applied and compared in ex-vivo corneal drug accumulation and transition studies. Furthermore, in vivo studies were performed to assess drug accumulation in the rat cornea and the corneal stability after NLC treatment was investigated via a biomechanical study on isolated rabbit corneas., Results: Both in vitro and ex-vivo as well as in vivo data showed that from the prepared NLC formulations, the most effective formulation was riboflavin-5-phosphate sodium containing NLC with Transcutol P as permeation enhancer. It possessed the highest drug loading content, low accumulation in the cornea but high permeability through the cornea as well as the highest functional performance in corneal crosslinking., Conclusion: Topical application of riboflavin-5-phosphate sodium loaded NLC systems designed with permeation enhancer Transcutol P may act as a potential alternative for non-invasive keratoconus treatments., Competing Interests: Declaration of Competing Interest Authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Riboflavin may prevent migraine episodes; however, there is limited evidence of its effectiveness in pediatric populations. This study investigated the effectiveness of riboflavin and clinical predictors of response in children with migraines., Methods: We retrospectively reviewed data from 68 Japanese children with migraines, of whom 52 also exhibited another type of headache. Patients received 10 or 40 mg/day of riboflavin. We evaluated the average migraine frequency per month as a baseline and after 3 months of riboflavin therapy to determine the effectiveness and clinical predictors of response., Results: The frequency of migraine episodes was significantly lower at 3 months than at baseline (median, [interquartile range], 5.2 (3-7) vs. 4.0 (2-5); p < 0.01). Twenty-five patients (36.7%) showed 50% or greater reduction in episode frequency (responders), while 18 (26.5%) showed a 25%-50% reduction. We compared responders (n = 25) and non-responders (n = 43) and found no significant differences in sex, familial history, riboflavin dose, migraine type (i.e., presence or absence of aura), age at headache onset, or age at consultation. However, non-responders were more likely to have co-morbid non-migraine headaches (odds ratio, 4.11; 95% confidence interval [CI], 1.27-13.33; p = 0.02); this variable was also significant in a multivariate analysis (adjusted odds ratio, 3.8; 95% CI, 1.16-12.6; p = 0.03). Of the co-morbid headache types, only tension headaches were significant (odds ratio, 0.176; 95% CI, 0.04-0.73; p = 0.013). No adverse effects of riboflavin were identified., Conclusions: Low-dose riboflavin is safe and modestly effective for migraines in children. It may be especially beneficial for children without other co-morbid headache types., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Epidemiologic studies focusing on the association between 1-carbon metabolism-related vitamins (ie, folate, vitamin B 6 , vitamin B 2 , vitamin B 12 ) and breast cancer risk have reported inconsistent findings. We conducted a systematic search of the reported data and performed a meta-analysis of prospective case-control and cohort studies to derive a more precise evaluation. The PubMed and EMBASE databases were searched to identify eligible studies. A total of 27 studies involving 49,707 cases and 1,274,060 individuals were included in the meta-analysis. The results indicated that a high intake of folate, vitamin B 6 , and vitamin B 2 might decrease the risk of breast cancer. The corresponding pooled relative risks (RRs) for the highest intake compared with the lowest were 0.93 (95% confidence interval [CI], 0.88-0.99; P = .018), 0.94 (95% CI, 0.89-1.00; P = .037) and 0.90 (95% CI, 0.82-0.99; P = .026). No significant association between vitamin B 12 and breast cancer risk was found (RR, 0.99; 95% CI, 0.94-1.04; P = .604). Further study showed that folate and vitamin B 6 might decrease the risk of estrogen receptor-negative (ER - )/progesterone receptor-negative (PR - ) breast cancer but not ER + /PR + breast cancer. The dose-response meta-analysis indicated a significant linearity relationship between folate intake and a reduced risk of ER - /PR - breast cancer. An increment of folate intake (100 μg/d) corresponded to a 7% deceased risk of ER - /PR - breast cancer (RR, 0.93; 95% CI, 0.89-0.98; P = .007). In conclusion, a high intake of 1-carbon metabolism-related vitamins might contribute to the prevention of breast cancer, especially ER - /PR - breast cancer., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Nutrition plays a key role in blood pressure (BP) regulation. Here, we examine associations between nutrient intakes and BP in a large predominantly female population-based cohort. We assessed the correlation between 45 nutrients (from food frequency questionnaires) and systolic BP/diastolic BP (SBP/DBP) in 3889 individuals from TwinsUK not on hypertensive treatments and replicated in an independent subset of monozygotic twins discordant for nutrient intake (17-242 pairs). Results from both analyses were meta-analysed. For significant nutrients, we calculated heritability using structural equation modelling. We identified and replicated 15 nutrients associated with SBP, 9 also being associated with DBP, adjusting for covariates and multiple testing. 14 of those had a heritable component ( h 2 : 27.1-57.6%). Strong associations with SBP were observed for riboflavin (Beta(SE) = -1.49(0.38), P = 1.00 × 10 -4 ) and tryptophan (-0.31(0.01), P = 5 × 10 -4 ), while with DBP for alcohol (0.05(0.07), P = 1.00 × 10 -4 ) and lactose (-0.05(0.0), P = 1.3 × 10 -3 ). Two multivariable nutrient scores, combining independently SBP/DBP-associated nutrients, explained 22% of the variance in SBP and 13.6% of the variance in DBP. Moreover, bivariate heritability analysis suggested that nutrients and BP share some genetic influences. We confirm current understanding and extend the panel of dietary nutrients implicated in BP regulation underscoring the value of nutrient focused dietary research in preventing and managing hypertension.

Homozygosity for the C677T polymorphism in MTHFR (TT genotype) is associated with a 24-87% increased risk of hypertension. Blood pressure (BP) lowering was previously reported in adults with the TT genotype, in response to supplementation with the MTHFR cofactor, riboflavin. Whether the BP phenotype associated with the polymorphism is related to perturbed one-carbon metabolism is unknown. This study investigated one-carbon metabolites and their responsiveness to riboflavin in adults with the TT genotype. Plasma samples from adults (n 115) screened for the MTHFR genotype, who previously participated in RCTs to lower BP, were analysed for methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), betaine, choline and cystathionine by liquid chromatography tandem mass spectrometry (LC-MS/MS). The one-carbon metabolite response to riboflavin (1.6 mg/d; n 24) or placebo (n 23) for 16 weeks in adults with the TT genotype was also investigated. Plasma SAM (74.7 ± 21.0 vs 85.2 ± 22.6 nmol/L, P = 0.013) and SAM:SAH ratio (1.66 ± 0.55 vs 1.85 ± 0.51, P = 0.043) were lower and plasma homocysteine was higher (P = 0.043) in TT, compared to CC individuals. In response to riboflavin, SAM (P = 0.008) and cystathionine (P = 0.045) concentrations increased, with no responses in other one-carbon metabolites observed. These findings confirm perturbed one-carbon metabolism in individuals with the MTHFR 677TT genotype, and for the first time demonstrate that SAM, and cystathionine, increase in response to riboflavin supplementation in this genotype group. The genotype-specific, one-carbon metabolite responses to riboflavin intervention observed could offer some insight into the role of this gene-nutrient interaction in blood pressure., (Copyright © 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Background: Dietary intakes of B vitamins (eg, folate) are related to cognitive function according to epidemiological studies in western countries. But prospective studies in Asian populations are scarce. This study evaluated the relationships of dietary intakes of six B vitamins in midlife with cognitive impairment in old age in a Chinese population living in Singapore., Methods: This study included 16,948 participants from the Singapore Chinese Health Study, a population-based prospective cohort. Baseline dietary intakes of B vitamins were assessed using a validated 165-item food frequency questionnaire when the participants were aged 45-74 years (1993-1998). After an average follow-up of 20 years, cognitive function was examined using a Singapore-modified version of Mini-Mental State Examination scale in 2014-2016, and cognitive impairment was defined using education-specific cutoffs. Logistic regression models were applied to estimate the association between B vitamins and cognitive impairment. All the six B vitamins were mutually adjusted in the final model., Results: In the 2014-2016 interview, 2,443 participants were defined as cognitive impairment. Riboflavin and folate were significantly and independently associated with cognitive impairment in a dose-dependent manner: the odds ratio (95% confidence interval) comparing the highest with the lowest quartile was 0.82 (0.69, 0.97) for riboflavin and 0.83 (0.70, 0.98) for folate (both p-trend <.05). Dietary intakes of thiamine, niacin, vitamin B-6, and B-12 were not significantly associated with risk of cognitive impairment., Conclusions: Higher dietary intakes of riboflavin and folate in midlife were associated with a lower risk of cognitive impairment in late-life in the Chinese population., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Tissue-engineered heart valves are a promising alternative to current valve substitutes. As the main scaffold of tissue-engineered heart valves, the decellularized heart valve (DHV) has problems such as biomechanical property damage and rapid degradation. In this study, we applied a photo-crosslinking reaction induced by riboflavin and ultraviolet light A (UVA) in the DHV for improving its biomechanical properties and stability. The results showed that the biomechanical properties of the DHV significantly improved following riboflavin-UVA (R-UVA) crosslinking. Moreover, the R-UVA-crosslinked DHV (R-UV-DHV) showed better resistance to enzymatic degradation in vitro, with significantly higher thermal denaturation temperature compared to that of the untreated DHV, indicating that the stability of the R-UV-DHV improved. Histological staining and scanning electron microscopy showed that the leaflet ultrastructure was preserved better after R-UVA crosslinking compared to a glutaraldehyde-crosslinked DHV. In addition, we found that the R-UV-DHV exhibited excellent human umbilical vein endothelial cell adhesion and cells could readily grow on its surface. In an in vitro anti-calcification experiment, the R-UV-DHV demonstrated non-calcifying properties in a simulated body fluid. Furthermore, the R-UV-DHV showed characteristics of slow degradation, non-calcification, and reduced pro-inflammatory response through a rat subcutaneous implantation model. As a result, R-UVA can effectively crosslink the DHV and the R-UV-DHV possessed satisfactory biocompatibility. R-UVA crosslinking can be a new approach for improving the performance of the DHV to prepare a better scaffold for tissue-engineered valves.

Background: Detoxification of inorganic arsenic (iAs) occurs when it methylates to form monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). Lower proportions of urinary iAs and MMA, and higher proportions of DMA indicate efficient methylation. The role of B-vitamins in iAs methylation in children with low-level arsenic exposure is understudied., Objectives: Our study objective was to assess the association between B-vitamin intake and iAs methylation in children with low-level arsenic exposure (<50 µg/L in water; urinary arsenic 5-50 µg/L)., Methods: We conducted a cross-sectional study in 290 ∼7-y-old children in Montevideo. Intake of thiamin, riboflavin, niacin, vitamin B-6, and vitamin B-12 was calculated by averaging 2 nonconsecutive 24-h recalls. Total urinary arsenic concentration was measured as the sum of urinary iAs, MMA, and DMA, and adjusted for urinary specific gravity; iAs methylation was measured as urinary percentage As, percentage MMA, and percentage DMA. Arsenic concentrations from household water sources were assessed. Linear regressions tested the relationships between individual energy-adjusted B-vitamins and iAs methylation., Results: Median (range) arsenic concentrations in urine and water were 9.9 (2.2-48.7) and 0.45 (0.1-18.9) µg/L, respectively. The median (range) of urinary percentage iAs, percentage MMA, and percentage DMA was 10.6% (0.0-33.8), 9.7% (2.6-24.8), and 79.1% (58.5-95.4), respectively. The median (range) intake levels of thiamin, riboflavin, niacin, and vitamin B-6 were 0.81 (0.19-2.56), 1.0 (0.30-2.24), 8.6 (3.5-23.3), and 0.67 (0.25-1.73) mg/1000 kcal, respectively, whereas those of folate and vitamin B-12 were 216 (75-466) and 1.7 (0.34-8.3) µg/1000 kcal, respectively. Vitamin B-6 intake was inversely associated with urinary percentage MMA (β = -1.60; 95% CI: -3.07, -0.15). No other statistically significant associations were observed., Conclusions: Although vitamin B-6 intake was inversely associated with urinary percentage MMA, our findings suggest limited support for a relation between B-vitamin intake and iAs methylation in children exposed to low-level arsenic., (Copyright © The Author(s) 2020.)

Purpose: To compare the efficacy, safety and stability of standard epithelium-off cross-linking (SCXL) versus accelerated epithelium-off cross-linking (ACXL) and transepithelial epithelium-on cross-linking (TCXL) in the treatment of progressive keratoconus (KC) in children., Methods: This prospective multicentre controlled trial included 271 eyes (136 children) with grade 1-3 progressive KC who were randomized to undergo SCXL (n = 91, as a control group), ACXL (n = 92) or TCXL (n = 88). Uncorrected and corrected distance visual acuity, subjective refraction, pachymetry, keratometry and corneal topography measurements were recorded preoperatively and 6, 12 and 24 months postoperatively., Results: At 1 year, there was no significant difference in uncorrected distance visual acuity, refractive sphere, cylinder, spherical equivalent or Kmax between the ACXL and SCXL groups; however, during year 2, ACXL regressed while SCXL continued to improve. After 2 years, there were significant differences in all visual, refractive and keratometric components between SCXL and both ACXL and TCXL (p < 0.0001) and between ACXL and TCXL (p < 0.0001). KC progressed in 5.4% of patients who had ACXL and 28.4% of those who had TCXL but in none of those who had SCXL. Vernal keratoconjunctivitis was documented in 43.3% of eyes that progressed postoperatively., Conclusion: SCXL was more effective for paediatric KC and achieved greater stability than either ACXL or TCXL, and ACXL was superior to TCXL. SCXL also achieved marked improvement in both myopia and spherical equivalent; however, these refractive outcomes were unpredictable and uncontrollable. TCXL had a 28.4% failure rate within 2 years. SCXL is preferable for management of paediatric KC., (© 2019 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Background: Zinc is a vital micronutrient for humans and is essential for protein synthesis, cell growth, and differentiation. Severe zinc deficiency can lead to slower physical, cognitive and sexual growth, cause skin disorders, decrease immunity, increase incidence of acute illnesses in infants and children and contribute to childhood stunting. By estimation, 17.3% of the world population is at risk of inadequate zinc intake. Such nutritional impairment increases the risk of diarrhoea and pneumonia by 20%, as well as leads to a global loss of more than 16 million disability-adjusted life years in children less than five years of age. Not only does zinc deficiency affect lives, it adds to the considerable financial burden on depleted resources in countries that are most affected. By preventing or curing this deficiency, we can improve childhood mortality, morbidity and growth., Objectives: To assess the effectiveness of zinc supplementation for the promotion of growth, reduction in mortality, and the prevention of infections in infants less than six months of age., Search Methods: We used the standard search strategy of the Cochrane Neonatal Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 4), MEDLINE via PubMed (1966 to 18 May 2018), Embase (1980 to 18 May 2018), and CINAHL (1982 to 18 May 2018). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. An updated search from 1 January 2018 to 29 January 2020 was run in the following databases: CENTRAL via CRS Web, MEDLINE via Ovid, and CINAHL via EBSCOhost., Selection Criteria: All randomised controlled (individual and cluster randomised) and quasi-randomised trials of zinc supplementation in healthy, term infants, less than six months of age comparing infant mortality, incidence of diarrhoea or respiratory illnesses, growth and/or serum zinc levels were eligible., Data Collection and Analysis: Two review authors screened search results (title and abstracts) and relevant full texts. Studies fulfilling prespecified inclusion criteria were included with any disagreements resolved by consensus. Extraction and analysis were then conducted. We used the GRADE approach to assess the quality of evidence as indicated by certainty in effect estimates., Main Results: Eight studies (with 85,629 infants) were included and five studies were meta-analysed, out of which four studies compared zinc with placebo, and one compared zinc plus riboflavin versus riboflavin. Certain growth outcomes after six months of intervention (Weight for Age Z-scores (WAZ) (standardised mean difference) (SMD) 0.16, 95% CI 0.03 to 0.29; three studies, n = 955; fixed-effect; heterogeneity Chi² P = 0.96); I² = 0%); change in WAZ (SMD 0.16, 95% CI 0.07 to 0.25; one study, n = 386; fixed-effect); (Weight-for-Length Z-score (WLZ) (SMD 0.15, 95% CI 0.02 to 0.28; three studies, n = 955; fixed-effect; heterogeneity: Chi² P = 0.81); I² = 0%); (change in WLZ (SMD 0.17, 95% CI 0.06 to 0.28; one study, n = 386; fixed-effect)) were positively affected by zinc supplementation compared to placebo. A single study reported no difference in the incidence of diarrhoea and lower respiratory tract infection with zinc supplementation. Zinc had no effect on mortality in children younger than 12 months. When zinc plus riboflavin was compared to riboflavin only, significant improvement was observed in the incidence of wasting at 24 months (risk ratio (RR) 0.59, 95% CI 0.37 to 0.96; one study, n = 296; fixed-effect), but significant worsening of incidence of stunting was present at 21 months (RR 1.53, 95% CI 1.09 to 2.16; one study, n = 298; fixed-effect)., Authors' Conclusions: There was a significant positive impact of zinc supplementation on WAZ and WLZ after six months of intervention in infants compared to placebo. When a combined supplement of zinc and riboflavin was compared to riboflavin, there was a significant reduction in wasting at 24 months, but stunting at 21 months was negatively affected. Although included trials were of good-to-moderate quality, evidence that could be meta-analysed was based on a few studies which affected the overall quality of results. Regardless, there is a need for strong trials conducted in infants younger than six months before a strong recommendation can be made supporting zinc supplementation in this age group., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

An experiment was conducted to investigate the effects of dietary riboflavin levels on reproductive performance, riboflavin status, and antioxidant status of laying duck breeders, to estimate the requirement of this vitamin for duck breeders. Different levels crystalline riboflavin (0, 2.5, 5, 10, and 15 mg/kg) were supplemented to a corn-soybean-corn gluten meal basal diet to produce 5 dietary treatments with different analyzed total riboflavin levels (1.48, 3.20, 6.30, 11.71, and 16.83 mg/kg). A total of 80 White Pekin duck breeders aged 40 wk were allotted to 5 dietary treatments of 16 birds each (8 replicates per treatment and 2 breeders per replicate), and all birds were raised individually for 9 wk. At the end of the experiment, reproductive performance, tissue riboflavin concentrations, and antioxidant status of White Pekin duck breeders were measured. The results showed that body weight, egg weight, egg production, and egg fertility were not affected by dietary riboflavin levels. However, among all of the laying duck breeders, the birds fed the basal diet without riboflavin supplementation had the lowest egg hatchability, plasma riboflavin, egg yolk riboflavin, and egg albumen riboflavin (P < 0.001). In addition, the duck breeders fed the basal diet without riboflavin supplementation showed the lowest antioxidant capacity indicated by greatest plasma malondialdehyde (MDA) content and lowest reduced glutathione content, total superoxide dismutase (T-SOD) activities, and total antioxidant capacity in both plasma (P < 0.001) and egg yolk (P < 0.001). These results revealed that dietary riboflavin supplementation improved the reproductive performance and antioxidant status of the duck breeders. According to the broken-line model, the riboflavin requirements (based on dietary total riboflavin) of laying duck breeders in terms of the egg hatchability, plasma riboflavin, egg yolk riboflavin, egg albumen riboflavin, plasma T-SOD activity, and plasma MDA content were 3.19, 7.42, 3.88, 7.44, 6.45, and 8.84 mg/kg, respectively., (Copyright © 2019. Published by Elsevier Inc.)

Riboflavin transporter deficiency (RTD) was recently characterized as a cause of genetic recessive childhood-onset motor neuron disease (MND) with hearing loss, formerly described as Brown-Vialetto-Van-Lear syndrome. We describe a 18-year-old woman with probable RTD mimicking juvenile Amyotrophic Lateral Sclerosis (ALS) who presented with an inaugural respiratory failure and moderate distal four limbs weakness. Only one heterozygous SLC52A3 mutation was detected, but presence of a sub-clinical auditory neuropathy and dramatic improvement under high dose riboflavin argued for a RTD. As RTD probably has a larger phenotypic spectrum than expected, a high dose riboflavin trial should be discussed in young-onset MND., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Objectives: Adequate intake of vitamin B complex could be prerequisite to health. However, few studies have been reported on the association of thiamine (vit B 1 ), riboflavin (vit B 2 ) and niacin (vit B 3 ) with periodontal health. This study described the association between periodontal health and dietary vit B 1 , vit B 2 and vit B 3 intake in the Korean population., Methods: A total of 12 750 adults aged over 19 years were selected for this study as a sub-sample of the national data set from Korean National Health and Nutrition Examination Survey (IV and V). Periodontitis and gingivitis were defined as Community Periodontal Index (CPI) scores of 3-4 and 1-2, respectively. Information on dietary vit B 1 , vit B 2 and vit B 3 intake was from 24-hour dietary recall method. Multivariable complex logistic regression analyses estimated association between vit B 1 , vit B 2 and vit B 3 intakes and periodontal health after adjusting for various potential confounders. Stratified analyses by age, sex, dyslipidemia and total energy intake were also undertaken., Results: The overall estimated prevalence of periodontitis (CPI 3-4) and gingivitis (CPI 1-2) was 29.9% and 46.6%, respectively. Our data showed none of the inadequate intake of vit B 1 , vit B 2 and B 3 showed significant association with gingivitis after adjusting for potential confounders. Inadequate intake of vit B 3 showed higher prevalence odds of periodontitis by 1.25 times (adjusted odds ratio = 1.25, 95% CI = 1.07-1.46). The association of vit B 3 with periodontitis was stronger in females and participants aged 40-59 years., Conclusions: Inadequate dietary intake of vit B 3 was associated with periodontitis., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To determine if there is a benefit to adjuvant corneal crosslinking (CXL) and to compare natamycin versus amphotericin B for filamentous fungal keratitis., Design: Outcome-masked, 2×2 factorial design, randomized controlled clinical trial., Participants: Consecutive patients presenting with moderate vision loss from a smear-positive fungal ulcer at Aravind Eye Hospital, Madurai, India., Methods: Study eyes were randomized to 1 of 4 treatment combinations using an adaptive randomization protocol. The treatment arms included (1) topical natamycin 5% alone, (2) topical natamycin 5% plus CXL, (3) topical amphotericin B 0.15% alone, and (4) topical amphotericin 0.15% plus CXL., Main Outcome Measures: The primary outcome of the trial was microbiological cure at 24 hours on repeat culture. Secondary outcomes included best spectacle-corrected visual acuity (BSCVA) at 3 weeks and 3 months, percentage of study participants with epithelial healing at 3 days, 3 weeks, and 3 months, infiltrate or scar size at 3 weeks and 3 months, 3-day smear and culture, and adverse events., Results: Those randomized to CXL regardless of medication (topical natamycin or amphotericin) had 1.32-fold increased odds of 24-hour culture positivity, although this was not statistically significant (95% confidence interval [CI], 0.57-3.06; P = 0.51). We were also unable to find a difference in 24-hour culture positivity between those randomized to amphotericin and those randomized to natamycin when evaluating as a group regardless of whether or not they received CXL (coefficient 1.10; 95% CI, 0.47-2.54; P = 0.84). The BSCVA was approximately 0.22 logarithm of the minimum angle of resolution (logMAR) (2.2 Snellen lines) worse on average at 3 weeks among those receiving CXL regardless of medication (95% CI, -0.04 to 0.40; P = 0.04) and 0.32 logMAR (3.2 Snellen lines) worse visual acuity at 3 months after controlling for baseline visual acuity (95% CI, 0.03-0.54; P = 0.02). There was no difference in infiltrate or scar size, percentage of epithelialized or adverse events when comparing CXL with no CXL or the 2 topical medications., Conclusions: There appears to be no benefit of adjuvant CXL in the primary treatment of moderate filamentous fungal ulcers, and it may result in decreased visual acuity., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Hyperviscosity agents are commonly used in ophthalmic formulations for improving corneal drug penetration by increasing tissue contact time. One such viscosity agent is hydroxypropyl methylcellulose (HPMC). HPMC has been used in riboflavin solutions for photochemical UVA cross-linking (CXL). Sodium hydroxymethylglycinate (SMG) is a small molecule formaldehyde releaser that can function as a therapeutic tissue cross-linker for corneal and scleral applications. The present study was undertaken in order to study formulation factors using HPMC and SMG that could positively influence the cross-linking effect in these ocular tissues. Formulations containing 10 mM SMG and 100 mM sodium bicarbonate were prepared with varying HPMC concentrations from 0 to 4.4%. Their cross-linking effects on porcine and rabbit eyes were measured using differential scanning calorimetry (DSC), expressed as the change/difference in melting temperature (ΔTm) compared with the control. SMG in 4.4% HPMC solution resulted in ΔTm of 6.3 ± 1.21, while other concentration showed no differences in Tm shift on porcine cornea. In ex vivo rabbit cornea, there was a trend toward an increasing cross-linking effect with higher viscosity albeit mild differences. While a significant Tm shift was observed in porcine and rabbit sclera, there was no difference in effect of cross-linking between four HPMC concentrations. Increasing the HPMC concentration does not negatively affect the cross-linking efficacy attributed by SMG and could still be a positive cross-linking enhancer by virtue of increasing tissue contact time in a dynamic biological system. This information will be useful for planning further animal and human studies., (© 2020 The Author(s).)

In recent years, quinoa (Chenopodium quinoa Willd), an ancestral crop of the Andean region of South America, has gained worldwide attention due to its high nutritional value. This grain is a good source of several vitamins and minerals; however, their bioavailability is decreased by the presence of antinutritional factors such as phytic acid. These compounds can be reduced using lactic acid bacteria (LAB), that have a GRAS (Generally Recognized as Safe) status and have traditionally been associated with food fermentation due to their biosynthetic capacity and metabolic versatility. The objective of this study was to evaluate the effectiveness of a pasta made with quinoa sourdough fermented by L. plantarum strains producing vitamins B 2 and B 9 and phytase to prevent vitamins and minerals deficiency using an in vivo mouse model. The results showed that the pasta fermented with the mixed culture containing L. plantarum CRL 2107 + L. plantarum CRL 1964 present increased B 2 and B 9 levels in mice blood. Likewise, higher concentrations of P, Ca +2 , Fe +2 , Mg +2 (18.75, 10.70, 0.37, 4.85 mg/dL, respectively) were determined with respect to the deficient group (DG) (9.85, 9.90, 0.26, 3.34 mg/dL, respectively). Hematological studies showed an increase in hemoglobin (14.4 ± 0.6 g/dL), and hematocrit (Htc, 47.0 ± 0.6%) values, compared to the DG (Hb: 12.6 ± 0.5 g/dL, Hto: 39.9 ± 1.1%). Furthermore, histological evaluations of the intestines showed an increase of the small intestine villi length in this latter group. The results allow us to conclude that bio-enrichment of quinoa pasta using LAB could be a novel strategy to increase vitamin and minerals bioavailability in cereal/pseudocereal - derived foods., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To assess the intake of thiamine, riboflavin and niacin and estimate the association between the adequacy of intake of those three B-vitamins and risk factors among older Chinese adults., Methods: A total of 3222 adults aged 65 and above with completed dietary data were derived from the 2015 survey of China Nutritional Transition Cohort Study 2015. The total subjects. Dietary data was recorded by three consecutive days with 24-hour recalls. The intake of those three B-vitamins were assessed by comparing with Chinese dietary thiamine, riboflavin and niacin reference intakes. The food sources of three vitamins were analyzed. Multivariate Logistic regression was used to estimate adjusted odds ratios for factors associated with the inadequacy of intake of those three vitamins., Results: The median daily intake of thiamine, riboflavin and niacin was 0. 8, 0. 7 and 12. 8 mg in males, and 0. 7, 0. 6 and 10. 9 mg in females, respectively. Adults aged 80 and above and living in the southern regions were more likely to have inadequate thiamine intake than adults aged 65-79 and living in northern regions, respectively. Adults had inadequate intake of riboflavin were more likely to be living in a village and adults with lower education levels than adults living in a city and adults with higher education levels. In males, adults had inadequate intake of niacin were more likely to be 80 years and above, with lower education levels, living in the northern regions, living in a village and with the lowest income. In females, adults had inadequate intake of niacin were more likely to be with lower education, living in northern regions and living in a village., Conclusion: About 80% adults were at the risk of the inadequate intake of thiamine and riboflavin in China. Age, education, income, regions and areas of residence were associated with the intake of thiamine, riboflavin and niacin.

Muscle weakness is a nonspecific finding of myopathy of any etiology that include iatrogenic, toxic, endocrinological, infectious, immunologic, and metabolic disorders. Among the metabolic myopathies glutaric aciduria type II (GAII) is an autosomal recessively inherited rare disorder of fatty acid and amino acid metabolisms. The late onset form is heterogeneous in terms of symptomatology and severity and for the cases that chronic manifestations of lipid storage myopathy are the only clues for the disease, differential diagnosis can be challenging. Here we report two cases of GAII: the first one was 18-year old boy who presented with proximal muscle weakness and in another center, he was diagnosed as polymyositis and treated with immunosuppressive therapies. He admitted to our clinic with ongoing muscle weakness and symptoms that were related to the side effects of immunosuppressive therapies. The second case was also presented with muscle weakness. For both cases, muscle biopsies and urinary organic acid analyses were consistent with the diagnosis of GAII. To differentiate inflammatory myositis from non-inflammatory myopathies; rheumatic symptoms, accompanying complaints of the patient and autoantibody positivity can be helpful. To our knowledge this is the first report to underline the differential diagnosis of inflammatory myopathies from metabolic myopathies.

Aims: To report 2-year outcomes of transepithelial, accelerated, pulsed, corneal crosslinking (t-ACXL) for patients with progressive keratoconus., Methods: Prospective, interventional case series at a university hospital tertiary referral centre. Forty eyes with progressive keratoconus undergoing t-ACXL were included. Treatment was performed with pulsed illumination (1 s on/1 s off) using 45 mW/cm 2 for 5 min and 20 s, for a surface dose of 7.2 J cm 2 . Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), manifest refraction spherical equivalent (MRSE), corneal tomography, anterior segment optical coherence tomography (OCT) and confocal microscopy were evaluated preoperatively and at 12 and 24 months postoperatively., Results: The mean patient age was 23.32 ± 5.18 years (SD) (range 14-42 years). The mean CDVA significantly improved from 0.38 ± 0.32 logMAR at baseline to 0.30 ± 0.21 logMAR at 24 months (P < 0.01). There was no significant difference in UDVA, MRSE, asymmetry indices, tomographic parameters and endothelial density. The improvement in visual acuity was inversely correlated with preoperative CDVA and preoperative K Max . No complications were encountered., Conclusions: In this prospective study, t-ACXL appeared safe and effective in halting progression of keratoconus within a follow-up period of 24 months.

Background: Alloimmunization to platelet-rich plasma (PRP) transfusions can cause adverse reactions such as platelet refractoriness or transplant rejection. Pathogen reduction treatment with ultraviolet light and riboflavin (UV + R) of allogeneic PRP was shown to reduce allogeneic antibody responses and confer partial antigen-specific immune tolerance to subsequent transfusions in mice. Studies have shown that UV + R was effective at both rapidly killing donor white blood cells (WBCs) and reducing their ability to stimulate an allogeneic response in vitro. However, the manner in which UV + R induces WBC death and its associated role in the immune response to treated PRP is unknown., Methods and Materials: This study evaluates whether UV + R causes WBC apoptosis by examining phosphatidylserine exposure on the plasma membrane, membrane asymmetry, caspase activity, and chromatin condensation by flow cytometry. The immunogenicity of WBCs killed with UV + R versus apoptotic or necrotic pathways was also examined in vivo., Results: WBCs after UV + R exhibited early apoptotic-like characteristics including phosphatidylserine exposure on the outer leaflet of the plasma membrane and loss of membrane asymmetry, but unlike canonical apoptotic cells, caspase activity and chromatin condensation were not apparent. However, in vivo studies demonstrated, unlike untreated or necrotic WBCs, both apoptotic WBCs and UV + R-treated WBCs failed to prime alloantibody responses to subsequent untreated transfusions., Conclusion: Overall, the mechanism of WBC death following UV + R treatment shares some membrane characteristics of early apoptosis but is distinct from classic apoptosis. Despite these differences, UV + R-treated and apoptotic WBCs both offer some protection from alloimmunization., (© 2019 AABB.)

An experiment was designed to delineate the efficacy of a dietary mixture of selenium nanoparticles (Se-NPs) and riboflavin (RF) on the thermal efficiency/tolerance of Pangasianodon hypophthalmus reared under arsenic (2.8 mg/L) and high-temperature (34 °C) stress. A green synthesis method was employed for the synthesis of Se-NPs using fish gills, which are normally discarded as by-products. Four isocaloric and iso-nitrogenous experimental diets were used, namely, a control diet (Se-NPs and RF @ 0 mg/kg diet) and diets containing RF @ 5, 10 or 15 mg/kg diet and Se-NPs @ 0.5 mg/kg diet, and feeding was performed for 95 days. At the end of the feeding trial, the thermal tolerance was evaluated by determination of the following parameters: critical thermal minimum (CTMin), lethal thermal minimum (LTMin), critical thermal maximum (CTMax), and lethal thermal maximum (LTMax). The anti-oxidative status in the form of catalase (CAT), glutathione-s-transferase (GST) and glutathione peroxidase (GPx) activities was significantly (p < 0.01) enhanced upon concurrent exposure to arsenic and high temperature at LTMin and LTMax, whereas a non-significant (p > 0.05) change in superoxide dismutase (SOD) activity was observed in the brain at LTMin and brain, gill and kidney at LTMax. Supplementation with Se-NPs @ 0.5 mg/kg diet and RF @ 5, 10 or 15 mg/kg diet significantly (p < 0.01) improved the anti-oxidative status with or without stressors. AChE activity in the brain was significantly (p < 0.01) inhibited upon concurrent exposure to arsenic and high temperature and improved in the treatment group supplemented with Se-NPs and RF. The arsenic concentration in muscle and experimental water and Se concentration in muscle and experimental feed were analysed. Overall, the results indicated that supplementation with RF @ 5 mg/kg diet and Se-NPs @ 0.5 mg/kg diet could confer protection to the fish against arsenic and thermal stress and led to enhanced thermal efficiency/tolerance of P. hypophthalmus., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric aciduria type II, is a mitochondrial fatty acid oxidation disorder caused by variants in ETFA, ETFB, and ETFDH. Recently, riboflavin transporter genes and the mitochondrial FAD transporter gene have also been associated with MADD-like phenotype., Methods: We present a case of MADD identified by newborn biochemical screening in a full-term infant suggestive of both medium-chain acyl-CoA dehydrogenase deficiency and MADD. Urine organic acid GC/MS analysis was also concerning for both disorders. However, panel sequencing of ETFA, ETFB, ETFDH, and ACADM was unrevealing. Ultimately, a variant in the FAD synthase gene, FLAD1 was found explaining the clinical presentation., Results: Exome sequencing identified compound heterozygous variants in FLAD1: NM&#95;025207.4: c.[442C>T];[1588C>T], p.[Arg148*];[Arg530Cys]. The protein damaging effects were confirmed by Western blot. The patient remained asymptomatic and there was no clinical decompensation during the first year of life. Plasma acylcarnitine and urinary organic acid analyses normalized without any treatment. Riboflavin supplementation was started at 15 months., Conclusion: Newborn screening, designed to screen for specific treatable congenital metabolic diseases, may also lead to the diagnosis of additional, very rare metabolic disorders such as FLAD1 deficiency. The case further illustrates that even milder forms of FLAD1 deficiency are detectable in the asymptomatic state by newborn screening., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Background: Infant DNA methylation profiles are associated with their mother's periconceptional nutritional status. DNA methylation relies on nutritional inputs for one-carbon metabolic pathways, including the efficient recycling of homocysteine. This randomised controlled trial in nonpregnant women in rural Gambia tests the efficacy of a novel nutritional supplement designed to improve one-carbon-related nutrient status by reducing plasma homocysteine, and assesses its potential future use in preconception trials., Methods and Findings: We designed a novel drink powder based on determinants of plasma homocysteine in the target population and tested it in a three-arm, randomised, controlled trial. Nonpregnant women aged between 18 and 45 from the West Kiang region of The Gambia were randomised in a 1:1:1 allocation to 12 weeks daily supplementation of either (a) a novel drink powder (4 g betaine, 800 μg folic acid, 5.2 μg vitamin B12, and 2.8 mg vitamin B2), (b) a widely used multiple micronutrient tablet (United Nations Multiple Micronutrient Preparation [UNIMMAP]) containing 15 micronutrients, or (c) no intervention. The trial was conducted between March and July 2018. Supplementation was observed daily. Fasted venepuncture samples were collected at baseline, midline (week 5), and endline (week 12) to measure plasma homocysteine. We used linear regression models to determine the difference in homocysteine between pairs of trial arms at midline and endline, adjusted for baseline homocysteine, age, and body mass index (BMI). Blood pressure and pulse were measured as secondary outcomes. Two hundred and ninety-eight eligible women were enrolled and randomised. Compliance was >97.8% for both interventions. At endline (our primary endpoint), the drink powder and UNIMMAP reduced mean plasma homocysteine by 23.6% (-29.5 to -17.1) and 15.5% (-21.2 to -9.4), respectively (both p < 0.001), compared with the controls. Compared with UNIMMAP, the drink powder reduced mean homocysteine by 8.8% (-15.8 to -1.2; p = 0.025). The effects were stronger at midline. There was no effect of either intervention on blood pressure or pulse compared with the control at endline. Self-reported adverse events (AEs) were similar in both intervention arms. There were two serious AEs reported over the trial duration, both in the drink powder arm, but judged to be unrelated to the intervention. Limitations of the study include the use of a single targeted metabolic outcome, homocysteine., Conclusions: The trial confirms that dietary supplements can influence metabolic pathways that we have shown in previous studies to predict offspring DNA methylation. Both supplements reduced homocysteine effectively and remain potential candidates for future epigenetic trials in pregnancy in rural Gambia., Trial Registration: Clinicaltrials.gov Reference NCT03431597., Competing Interests: The authors have declared that no competing interests exist.