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1.
Strategies to Increase the Production of Biosynthetic Riboflavin.
Zhao, G, Dong, F, Lao, X, Zheng, H
Molecular biotechnology. 2021;(10):909-918
Abstract
Riboflavin is widely regarded as an essential nutrient that is involved in biological oxidation in vivo. In addition to preventing and treating acyl-CoA dehydrogenase deficiency in patients with keratitis, stomatitis, and glossitis, riboflavin is also closely related to the treatment of radiation mucositis and cardiovascular disease. Chemical synthesis has been the dominant method for producing riboflavin for approximately 50 years. Nevertheless, due to the intricate synthesis process, relatively high cost, and high risk of pollution, alternative methods of chemical syntheses, such as the fermentation method, began to develop and eventually became the main methods for producing riboflavin. At present, there are three types of strains used in industrial riboflavin production: Ashbya gossypii, Candida famata, and Bacillus subtilis. Additionally, many recent studies have been conducted on Escherichia coli and Lactobacillus. Fermentation increases the yield of riboflavin using genetic engineering technology to modify and induce riboflavin production in the strain, as well as to regulate the metabolic flux of the purine pathway and pentose phosphate pathway (PP pathway), thereby optimizing the culture process. This article briefly introduces recent progress in the fermentation of riboflavin.
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2.
Cool Crosslinking: Riboflavin at 4°C for Pain Management After Crosslinking for Keratoconus Patients, A Randomized Clinical Trial.
Toro-Giraldo, L, Morales Flores, N, Santana-Cruz, O, Ramirez-Miranda, A, Navas, A, Olivo-Payne, A, Lichtinger, A, Jimenez-Corona, A, Graue-Hernández, EO
Cornea. 2021;(1):1-4
Abstract
PURPOSE To explore corneal cooling as a method of pain management in corneal-accelerated collagen cross-linking. METHODS This was a prospective and interventional randomized clinical trial registered in the National Institutes of Health Clinical Trials through the identifier NCT030760770. The research was conducted at the Institute of Ophthalmology "Conde de Valenciana." A total of 98 patients were randomly assigned to one of the following 2 groups: cold riboflavin (4°C) group or control group (riboflavin at room temperature). The inclusion criteria were patients of any sex, older than 18 years of age with keratoconus diagnosis who needed management with cross-linking in both eyes because of the evidence of progression. The exclusion criteria were patients who had cross-linking without epithelial debridement, unilateral cross-linking, or any other ocular pathologies besides keratoconus and any cognitive incapacity that would make the understanding of the pain test difficult. The main outcome measures were pain, tearing, photophobia, foreign body sensation, and irritation. RESULTS At 2 hours post-op, pain in the case and control groups was 3.80 ± 3.00 and 8.08 ± 2.21 (P < 0.05), tearing was 1.56 ± 1.96 and 8.29 ± 2.42 (P < 0.05), photophobia was 5.44 ± 3.57 and 7.83 ± 2.64 (P < 0.05), foreign body sensation was 2.20 ± 2.78 and 6.54 ± 2.73 (P < 0.05), and irritation was 3.48 ± 2.98 and 6.79 ± 3.00 (P < 0.05), respectively. A statistical significant difference was maintained in pain values on day 1 (2.79 ± 3.09 and 4.91 ± 3.27 [P < 0.05]), 2 (2.54 ± 2.41 and 4.00 ± 2.43 [P < 0.05]), and 4 (0.45 ± 0.76 and 1.22 ± 1.67 [P < 0.05]). CONCLUSIONS This study demonstrated that pain and associated symptoms decreased significantly in the riboflavin 4°C group.
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3.
Alteration of Flavin Cofactor Homeostasis in Human Neuromuscular Pathologies.
Tolomeo, M, Nisco, A, Barile, M
Methods in molecular biology (Clifton, N.J.). 2021;:275-295
Abstract
The aim of this short review chapter is to provide a brief summary of the relevance of riboflavin (Rf or vitamin B2) and its derived cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) for human neuromuscular bioenergetics.Therefore, as a completion of this book we would like to summarize what kind of human pathologies could derive from genetic disturbances of Rf transport, flavin cofactor synthesis and delivery to nascent apoflavoproteins, as well as by alteration of vitamin recycling during protein turnover.
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4.
Accelerated Pulsed High-Fluence Corneal Cross-Linking for Progressive Keratoconus.
Gore, DM, Leucci, MT, Koay, SY, Kopsachilis, N, Nicolae, MN, Malandrakis, MI, Anand, V, Allan, BD
American journal of ophthalmology. 2021;:9-16
Abstract
PURPOSE To report on 2-year results of accelerated corneal collagen cross-linking (CXL) in progressive ectasia using the Avedro KXL system. DESIGN Prospective interventional case series. METHODS A total of 870 patients (1,192 eyes) attending Moorfields Eye Hospital after CXL were included. All patients undergoing CXL had progressive keratoconus. Corneas with a minimum stromal thickness <375 μm were excluded. Riboflavin 0.1% soak duration was 10 minutes. High-fluence pulsed UVA was delivered at 30 mW/cm2 for 4 minutes, with a 1.5-second on/off cycle (total energy 7.2 J/cm2). Subjective refractive, corneal tomography, and specular microscopy were performed at baseline, 6, 12, and 24 months postoperatively. The primary outcome measure was a change in maximum keratometry (Kmax) at 24 months. RESULTS Twelve- and 24-month follow-up data were available on 543 and 213 patients, respectively (mean age 25.4 ± 6.6 years). In mild cones (Kmax < 55 diopter [D]), mean keratometry remained unchanged at 24 months. In more advanced disease, we observed modest corneal flattening compared to baseline (Kmax 63.2 ± 6.5 D vs 61.9 ± 8.1 D, P = .02), but no significant changes in central keratometry (K1 or K2). Keratometric stabilization was confirmed in 98.3% of eyes. Mean CDVA, manifest refraction and endothelial cell density did not change. Overall, 2.7% of eyes lost more than 2 lines of CDVA. CONCLUSION Accelerated pulsed CXL is a safe, effective, and refractively neutral intervention (at 2 years) to halt disease progression in keratoconus.
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5.
Biomechanical effect of ultraviolet-A-riboflavin cross-linking on simulated human corneal stroma model and its correlation with changes in corneal stromal microstructure.
Li, H, Liu, T, Mu, B, Zhao, X, Xue, C, Shen, M, Jhanji, V, Wang, Y
Experimental eye research. 2020;:108109
Abstract
In this study, we established an experimental human corneal stroma model of simulated cornea tissue composed of thin anterior cornea strips layers obtained from small incision lenticular extraction (SMILE) surgery. We investigated the biomechanical effect of ultraviolet-A- riboflavin cross-linking at different depths of corneal stroma model and correlated it with stromal microstructural changes examined by transmission electron microscopy (TEM). Corneal strips were harvested from fresh human corneal lenticules obtained after SMILE surgery. Experimental models (n = 34) were established by superimposing the corneal lenticule strips until their thickness reached close to 500 μm. Corneal cross-linking (CXL) was performed subsequently using standard or accelerated protocol. Elasticity and viscosity were quantified using stress-strain extensometer. TEM was used to visualize the collagen fiber diameter and interfibrillar spacing. The relative change in Young's modulus (rel. ΔE) decreased nonlinearly with increasing stromal depth both in the standard and accelerated groups. Compared to the sham controls, the rel. ΔE in standard and accelerated CXL groups increased significantly in the anterior 400 μm and 275 μm depth, respectively. Also, the relative change in stress (rel. ΔS) was significantly lower after standard and accelerated CXL compared to sham controls. Depth analysis showed similar results for the elastic effect. TEM images showed a small, non-significant increase in fibril diameter. The interfibrillar spacing decreased significantly after standard and accelerated CXL in the anterior-mid stromal region. We noted that the increase of corneal stiffness correlated with decrease in interfibrillar spacing after CXL. The stiffening effect was depth dependent. The effect of accelerated CXL was less in the deep corneal stromal regions compared to standard CXL.
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6.
Randomized Control Trial on the Effectiveness of Collagen Cross-linking on Bullous Keratopathy.
Choy, BNK, Ng, ALK, Zhu, MM, Liu, CC, Xu, S, Lai, JSM
Cornea. 2020;(11):1341-1347
Abstract
PURPOSE To investigate the long-term effect and safety of collagen cross-linking (CXL) on patients with bullous keratopathy (BK) in a randomized control manner. It is, to our knowledge, the first randomized control study on the effect of CXL on BK. METHODS Subjects were randomized to receive CXL as in the standard protocol for treating keratoconus or a placebo treatment. Subjects were assessed at baseline and up to 12 months after treatment. Primary outcomes were central corneal thickness (CCT) and pain scores. RESULTS Forty-two patients with BK participated in the study treatment, 26 subjects were randomized to the CXL group and 16 subjects to the control group. The reduction of CCT in the CXL group was 37.6 and 63.8 μm at 2 and 4 weeks, respectively, which were significantly higher than that in the control group. However, there was no statistical difference in CCT reduction between the 2 groups at 12 weeks and after. There were no consistent advantages in pain score, corneal clarity, and visual acuity over the controls throughout the 1-year follow-up. However, CXL was associated with more recurrent epithelial defect (12%), and 2 of the 3 subjects with epithelial defect required amniotic membrane transplant. CONCLUSIONS CXL reduced corneal thickness in the patients with BK, at least for the initial period. However, there were no improvement in pain, corneal clarity, and vision that were of more clinical relevance to the patients. Its short-term benefit was unlikely to outweigh its potential risk of recurrent epithelial defect.
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7.
Accelerated Versus Standard Corneal Cross-Linking for Progressive Keratoconus: A Meta-Analysis of Randomized Controlled Trials.
Kobashi, H, Tsubota, K
Cornea. 2020;(2):172-180
Abstract
PURPOSE To compare the clinical results of accelerated corneal collagen cross-linking (ACXL) to standard corneal collagen cross-linking (SCXL) in progressive keratoconus by summarizing randomized controlled trials using a meta-analysis. METHODS Trials meeting the selection criteria were quality appraised, and data were extracted by 2 independent authors. A comprehensive search was performed using the Cochrane methodology to evaluate the clinical outcomes of ACXL and SCXL for treating progressive keratoconus. Estimates were evaluated by weighted mean difference (WMD) and 95% confidence interval (CI) for absolute changes of the outcomes during 12-month observation periods. Postoperative demarcation line depth was also compared. RESULTS We identified 6 randomized controlled trials that met the eligibility criteria for this meta-analysis. SCXL resulted in a significantly better outcome in postoperative changes in best spectacle-corrected visual acuity (WMD = -0.02; 95% CI, -0.03 to -0.01; P < 0.0001); however, the small differences may not be clinically significant. ACXL provided a significantly better improvement of cylindrical refraction after the 1-year follow-up (WMD = 0.15; 95% CI, 0.05-0.26; P = 0.005). Demarcation line depth at 1 month after SCXL was deeper than that after ACXL (WMD = -102.25; 95% CI, -157.16 to -47.35; P = 0.0003). No differences in the changes in maximum keratometry, central corneal thickness, uncorrected visual acuity, spherical equivalent refraction, corneal biomechanical properties, and corneal endothelial cell density were found among both groups. CONCLUSIONS An ACXL shows a comparable efficacy and safety profile at the 1-year follow-up, but it has less impact on improving best spectacle-corrected visual acuity when compared with the Dresden protocol. Overall, both methods similarly stop the disease progression.
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8.
Corneal collagen cross-linking for bacterial infectious keratitis.
Davis, SA, Bovelle, R, Han, G, Kwagyan, J
The Cochrane database of systematic reviews. 2020;(6):CD013001
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Abstract
BACKGROUND Infectious keratitis is an infection of the cornea that can be caused by bacteria, viruses, fungi, protozoa, or parasites. It may be associated with ocular surgery, trauma, contact lens wear, or conditions that cause deficiency or loss of corneal sensation, or suppression of the immune system, such as diabetes, chronic use of topical steroids, or immunomodulatory therapies. Photoactivated chromophore for collagen cross-linking (PACK-CXL) of the cornea is a therapy that has been successful in treating eye conditions such as keratoconus and corneal ectasia. More recently, PACK-CXL has been explored as a treatment option for infectious keratitis. OBJECTIVES To determine the comparative effectiveness and safety of PACK-CXL with standard therapy versus standard therapy alone for the treatment of bacterial keratitis. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2019, Issue 7); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Science Information database (LILACS); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 8 July 2019. SELECTION CRITERIA We included randomized controlled trials (RCTs), quasi-RCTs, and controlled clinical trials (CCTs) of PACK-CXL for bacterial keratitis. We included quasi-RCTs and CCTs as we anticipated that there would not be many RCTs eligible for inclusion. DATA COLLECTION AND ANALYSIS Two review authors working independently selected studies for inclusion in the review, assessed trials for risk of bias, and extracted data. The primary outcome was proportion of participants with complete healing at four to eight weeks. Secondary outcomes included visual acuity, morphology, adverse events, and treatment failure at four to eight weeks. MAIN RESULTS We included three trials (two RCTs and one quasi-RCT) in this review for a total of 59 participants (59 eyes) with bacterial keratitis. Trials were all single-center and were conducted in Egypt, Iran, and Thailand between 2010 and 2014. It is very uncertain whether PACK-CXL with standard antibiotic therapy is more effective than standard antibiotic therapy alone for re-epithelialization and complete healing (risk ratio (RR) 1.53, 95% confidence interval (CI) 0.88 to 2.66; participants = 15). We judged the certainty of the evidence to be very low due to the small sample size and high risk of selection and performance bias. The high risk of selection bias reflects the overall review. Masking of participants was not possible for the surgical arm. No participant had a best-corrected visual acuity of 20/100 or better at eight weeks (very low certainty evidence). There is also no evidence that use of PACK-CXL with standard therapy results in fewer instances of treatment failure than standard therapy alone (RR 0.50, 95% CI 0.05 to 4.98; participants = 32). We judged the certainty of evidence to be low due to the small sample size and high risk of selection bias. There were no adverse events reported at 14 days (low certainty evidence). Data on other outcomes, such as visual acuity and morphological characteristics, could not be compared because of variable time points and specific metrics. AUTHORS' CONCLUSIONS The current evidence on the effectiveness of PACK-CXL for bacterial keratitis is of low certainty and clinically heterogenous in regard to outcomes. There are five ongoing RCTs enrolling 1136 participants that may provide better answers in the next update of this review. Any future research should include subgroup analyses based on etiology. A core outcomes set would benefit healthcare decision-makers in comparing and understanding study data.
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Corneal refractive surgery combined with simultaneous corneal cross-linking: Indications, protocols and clinical outcomes-A review.
Ma, J, Wang, Y, Jhanji, V
Clinical & experimental ophthalmology. 2020;(1):78-88
Abstract
Corneal refractive surgery is one of the most common approaches for correction of refractive errors. Combined corneal refractive surgery and corneal cross-linking (CXL) has been proposed as a method to achieve better refractive stability and to prevent iatrogenic corneal ectasia. However, there are concerns regarding its indications, surgical safety, standardization of protocols and long-term effect on corneal tissue. This review article aims to discuss the current knowledge and recent updates on combination of CXL and refractive surgery.
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10.
Standard and accelerated corneal cross-linking long-term results: A randomized clinical trial.
Hashemi, H, Mohebbi, M, Asgari, S
European journal of ophthalmology. 2020;(4):650-657
Abstract
PURPOSE To compare long-term results between accelerated and standard corneal cross-linking protocols in the treatment of progressive keratoconus and compare their effectiveness between central (cone in the central 3 mm) and peripheral (cone beyond 3 mm) cases. METHODS In this randomized clinical trial, we compared 31 eyes treated with accelerated corneal cross-linking (18 mW/cm2, 5 min) and 31 eyes treated with standard corneal cross-linking (3 mW/cm2, 30 min), 16 central and 11 peripheral keratoconus in each group. In this report, 4-year changes in vision, refraction, topography, corneal biomechanics, and corneal cell count were evaluated. RESULTS Uncorrected distance visual acuity improvement was better with standard corneal cross-linking (0.19 ± 0.30 logMAR) than accelerated corneal cross-linking (0.08 ± 0.35 logMAR), but the intergroup difference was not statistically significant (p = 0.283). Cylinder and spherical equivalent significantly increased similarly in both groups. Among topographic indices, anterior Kmax-3 mm showed more reduction in standard corneal cross-linking than accelerated corneal cross-linking (1.35 ± 1.39 vs 0.36 ± 1.10 D, p = 0.011). Anterior Kmax-8 mm reduced by 1.50 ± 1.82 and 0.37 ± 1.58 D in the standard corneal cross-linking and accelerated corneal cross-linking groups, respectively (p = 0.029). Compared to 18-month results, none of the indices at 4 years showed any significant intergroup difference (all p > 0.05). In cases with peripheral keratoconus, changes in anterior Kmax-3 mm (+0.03 ± 0.66 vs -1.17 ± 1.15 D, p = 0.012) and anterior Kmax-8 mm (+0.43 ± 1.09 vs -1.57 ± 1.40 D, p = 0.003) were greater with standard corneal cross-linking. In central cases, no significant intergroup difference was observed. CONCLUSION At 4 years after the procedure, standard corneal cross-linking offered better anterior corneal flattening in the center and periphery. These differences concerned cases of peripheral keratoconus, and the two protocols were similarly effective in central cases. Beyond the 18th month, the two protocols appeared to be similarly effective.