Ocular repercussions in COVID-19 patients: structural changes of the retina and choroid.

BACKGROUND: Neurotropic capabilities of SARS-COVs allow viruses to reach the central nervous system by hematogenous neuronal dissemination. The human retina, as an extension of the Central Nervous System, may have some neurodegenerative and/or vascular modifications related to COVID-19. OBJECTIVES: To evaluate choroidal and inner neural layers in participants previously recovered from COVID-19 compared to the control group using optical coherence tomography. METHODS: With a cross-sectional approach, the sample (n = 96), constituted by patients who have recovered from COVID-19 (n = 56) and healthy participants control group (n = 40) were ophthalmologically characterized. The neurodegenerative and vascular histological assessment was performed using SD-OCT and the mean thickness was measured in Early Treatment Diabetic Retinopathy Study (ETDRS) subfields. Retinal nerve fiber layer, Ganglion cell layer and subfoveal choroidal thickness were obtained through semi-automatic measurement. RESULTS: A total of 40 controls (27 women [67.5%]) and 56 COVID-19 participants (34 women [60.8%]) were included in this first report. There were retinal thickness significant differences in nearly all inner ETDRS subfields: nasal 3 mm (p = .025), I3 (p = .049), and temporal 3 mm (p = .009). Also, a decrease in neural layers was found in the nasal 3 mm (p = .049) and temporal 3 mm (p = .029) during ganglion cell layer assessment. The peripapillary retinal nerve fiber layer thickness was thinner in the COVID-19 group in superior temporal (p = .019), nasal (p = .002), inferior temporal (p = .046) and global (p = .014). Concerning the subfoveal choroidal measurement, an increase was observed in the COVID-19 group (p = .002). CONCLUSION: Participants who had recovered from COVID-19 showed a non-glaucomatous neuropathy trend pattern. We found differences closer to the classic description of the "bow-tie" observed in other neurological as compressive neuropathies at the chiasma location. OCT assessment also showed an increase in choroidal thickness as a result of vascular changes.

Correction: The Efficacy, Safety, and Efficiency of the Off-Label Use of Bevacizumab in Patients Diagnosed With Age-Related Macular Degeneration: Protocol for a Systematic Review and Meta-Analysis.

[This corrects the article DOI: 10.2196/38658.].

The Efficacy, Safety, and Efficiency of the Off-Label Use of Bevacizumab in Patients Diagnosed With Age-Related Macular Degeneration: Protocol for a Systematic Review and Meta-Analysis.

BACKGROUND: Age-related macular degeneration (AMD) is recognized as the leading cause of vision loss in older people. Considering the phenomenon of aging societies worldwide, the prevalence of AMD is expected to increase gradually in the future. AMD can be divided into early, intermediate, and late stages, with the early and intermediate stages being mainly asymptomatic, and the late stage being classified as geographic atrophy, neovascular AMD, or both. Current pharmacological treatments for neovascular AMD include anti-vascular endothelial growth factor agents, such as ranibizumab, pegaptanib, and aflibercept. Additionally, it has been reported that the off-label use of intravitreally administered bevacizumab is effective. It is also lower cost than other agents, which makes it an interesting pharmacological approach. OBJECTIVE: This review aims to evaluate the efficacy, safety, and efficiency of bevacizumab for the treatment of neovascular AMD. METHODS: This review will only consider randomized controlled clinical trials that compare the use of bevacizumab with another pharmacological agent or a placebo in patients aged 50 years and older who are diagnosed with vascular AMD. It will exclude studies that include participants diagnosed with polypoidal choroidal vasculopathy or retinal angiomatous proliferation. To identify and select relevant articles, we will develop a highly sensitive search strategy and apply it in MEDLINE via the PubMed platform. Upon selection of the studies and analysis of the titles, abstracts, and full texts, the results will be presented according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The analysis and extraction of the data will be performed by 2 independent reviewers. Risk of bias will be evaluated with the Critical Appraisal Skills Programme (CASP) checklist. Finally, the same reviewers will also perform a quality assessment of the included studies with the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool. RESULTS: The search strategy, after the application of the inclusion and exclusion criteria, identified 15 randomized clinical trials, which are currently being analyzed. This project has no funding and it has been developed by a multidisciplinary research team of pharmacologists and orthoptists. The study was initiated in May 2021 and it is expected to conclude by the end of 2023. CONCLUSIONS: This review will provide a synthesis of current information and underlying evidence about the off-label use of bevacizumab in neovascular AMD. It will provide a clearer vision of a possible new pharmacological approach, as well as the most suitable treatment designs, for the treatment of neovascular AMD. TRIAL REGISTRATION: PROSPERO CRD42021244931; https://tinyurl.com/p6m5ycpk. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/38658.

DNA methyltransferase expression (DNMT1, DNMT3a and DNMT3b) as a potential biomarker for anti-VEGF diabetic macular edema response.

PURPOSE: DNA methylation is involved in Diabetic Retinopathy progression showing a metabolic memory mechanism. However, the association of DNA methyltransferase with diabetic macular edema is still unknown. We aimed to describe the differences in DNA methyltransferase gene expression in patients with different diabetic macular edema responses. METHODS: A total of 27 diabetic patients, aged 59-90 years, were prospectively enrolled in this cross-sectional study. The participants were classified into control group (CG, n = 11), diabetic macular edema responders (rDME, n = 9) and non-responder diabetic macular edema (nrDME, n = 7) after anti-vascular endothelial growth factor (anti-VEGF) treatment. Only cases with a complete ophthalmological examination, digital 133° color fundus, and SD-OCT assessments were used. After RNA extraction and first-strand cDNA synthesis, quantitative real-time PCR was performed with specific primers on the CFX Connect™ Real-Time PCR Detection System to assess differential transcriptional expression patterns. RESULTS: The DNMT1 gene showed a positive correlation (r = 0.617; p = 0.043) with Best Corrected Visual Acuity (BCVA) in CG, a positive correlation (r = 0.917; p = 0.010) with HbA1c in nrDME and a negative correlation (r = -0.659; p = 0.049) with GCL-IPL thickness in rDME. DNMT3A gene showed a positive correlation (r = -0.890; p = 0.001) with Sub-foveal Choroidal thickness in rDME whereas DNMT3b gene showed a negative correlation (r = -0.815; p = 0.007) with HbA1c and RNFL (r = -0.664; p = 0.026) in CG. CONCLUSIONS: Patients with similar metabolic profile risk factors showed associated DNA methyltransferase transcriptional expression patterns differences fitting with the anti-VEGF diabetic macular edema response. Further studies are needed to clarify if these results (1) reflect disease evolution, (2) translate the therapeutic impact, (3) or can help to predict the therapeutic resistance profile.

Initial medication adherence in newly diagnosed glaucoma patients: three adherence measures.

AIM: To determine initial medication adherence in newly diagnosed glaucoma patients treated with anti-glaucoma drugs. METHODS: This retrospective and observational study included all patients diagnosed with glaucoma in the Primary Health Care units in Portugal during the years 2012 and 2013, which in consequence received a first prescription for anti-glaucoma drugs. Data was collected from electronic prescribing records of the primary care units and from pharmacy claims records. Initiation of glaucoma treatment and early discontinuation were measured, and the combination of (non)-initiation and early discontinuation accounted for initial medication (non)-adherence. RESULTS: A total of 3548 new glaucoma patients (40.1% male; 59.9% female) were included. The 1133 (31.9%) patients were initially classified as non-users, since there was no pharmacy claim found for their first prescription for glaucoma treatment. Additionally, 277 (11.5%) patients early discontinued their treatment, acquiring only their first prescription. Overall, the initial medication non-adherence rate was 39.7% since 1410 patients either didn't initiate treatment or discontinued it early. CONCLUSION: This study, reveals a major opportunity to improve glaucoma treatment and its control, since a large proportion of patients fail to engage with their prescribed therapy, which implies that implementation of individual or group strategies that enable patients with glaucoma to correctly perform their treatment is still needed.

Determination of permeability data and 3-D modelling of the host rock and sinters from a geothermal field: Los Geysers, northern Trans-Mexican Volcanic Field.

This data article describes the connected pore cluster data from segmented nano-images of rocks related to a geothermal system. The collected samples include two (2) vesicle-amygdaloidal basalt (host rock) and four (4) horizons collected from a siliceous sinter mound (rock precipitated from hot waters). All the samples have undergone computed tomography scanning using a SkyScan 2211 multiscale X-ray nano-CT system (Bruker®), and the slices were analyzed using the Digital Rock Physics (DRP) approach. Pore volume and fluid permeability in the three directions were calculated with scripts of Python (v.3.9) and the visualizations of the 3D models were run with Paraview (v.5.10) software. The petrophysical properties, diagrams, and figures were produced by stacking the 2D projections (8-bit grayscale *.png images format) from the scanning. Raw data (images) were deposited in a repository, which has granted a persistent identifier (Mendeley Data: https://data.mendeley.com/datasets/srpxhpd37p/2). This article provides a study case to handle the data that test the interconnectivity and ability to transport fluids and/or exogenous matter carried during high-flow events in rocks outcropping at the surface level of a geothermal system.

Exome Sequencing Data Analysis and a Case-Control Study in Mexican Population Reveals Lipid Trait Associations of New and Known Genetic Variants in Dyslipidemia-Associated Loci.

Background: Plasma lipid levels are a major risk factor for cardiovascular diseases. Although international efforts have identified a group of loci associated with the risk of dyslipidemia, Latin American populations have been underrepresented in these studies. Objective: To know the genetic variation occurring in lipid-related loci in the Mexican population and its association with dyslipidemia. Methods: We searched for single-nucleotide variants in 177 lipid candidate genes using previously published exome sequencing data from 2838 Mexican individuals belonging to three different cohorts. With the extracted variants, we performed a case-control study. Logistic regression and quantitative trait analyses were implemented in PLINK software. We used an LD pruning using a 50-kb sliding window size, a 5-kb window step size and a r2 threshold of 0.1. Results: Among the 34251 biallelic variants identified in our sample population, 33% showed low frequency. For case-control study, we selected 2521 variants based on a minor allele frequency ≥1% in all datasets. We found 19 variants in 9 genes significantly associated with at least one lipid trait, with the most significant associations found in the APOA1/C3/A4/A5-ZPR1-BUD13 gene cluster on chromosome 11. Notably, all 11 variants associated with hypertriglyceridemia were within this cluster; whereas variants associated with hypercholesterolemia were located at chromosome 2 and 19, and for low high density lipoprotein cholesterol were in chromosomes 9, 11, and 19. No significant associated variants were found for low density lipoprotein. We found several novel variants associated with different lipemic traits: rs3825041 in BUD13 with hypertriglyceridemia, rs7252453 in CILP2 with decreased risk to hypercholesterolemia and rs11076176 in CETP with increased risk to low high density lipoprotein cholesterol. Conclusions: We identified novel variants in lipid-regulation candidate genes in the Mexican population, an underrepresented population in genomic studies, demonstrating the necessity of more genomic studies on multi-ethnic populations to gain a deeper understanding of the genetic structure of the lipemic traits.

The role of Optical Coherence Tomography Angiography to detect early microvascular changes in Diabetic Retinopathy: a systematic review.

PURPOSE: To evaluate quantitative parafoveal microvascular changes using Optical Coherence Tomography Angiography (OCTA) by comparing the area of foveal avascular zone (FAZ) and vessel density (VD) between nondiabetic controls and patients with different levels of Diabetic Retinopathy (DR). METHODS: A systematic review was performed according to the recommendations of the "Cochrane Handbook for Systematic Reviews of Interventions" and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Three electronic databases including PubMed, Web of Science and Cochrane Library were systematically retrieved by using key terms with Boolean operators. The data extracted from each study included: first author, year of publication, study design, sample size and participant characteristics (mean age, type of diabetes mellitus and mean duration of diabetic disease). Outcome variables included: VD and area of FAZ, in superficial and deep capillary plexuses of parafovea. RESULTS: 355 articles were identified from our search of databases and 10 studies were included in this systematic review. Patients with diabetes with or without clinical signs of DR have a significantly enlarged area of FAZ and decreased parafoveal VD compared to healthy controls, as well as an association between these microvascular changes and worsening DR. CONCLUSION: OCTA can provide valuable information about early and subtle microvascular changes of parafoveal capillary plexuses in patients with diabetes and can identify preclinical DR before the manifestation of clinically apparent retinopathy. The non-invasive nature of OCTA allows routine imaging of the retinal vasculature, so this approach may be a promising tool for screening programmes of DR.

Manual Segmentation of 12 Layers of the Retina and Choroid through SD-OCT in Intermediate AMD: Repeatability and Reproducibility.

PURPOSE: To evaluate the repeatability and reproducibility of the segmentation of 12 layers of the retina and the choroid, performed manually by SD-OCT, along the horizontal meridian at three different temporal moments, and to evaluate its concordance with the same measurements performed by two other operators in intermediate AMD. METHODS: A cross-sectional study of 40 eyes from 40 subjects with intermediate AMD was conducted. The segmentation was performed manually, using SD-OCT. The 169 measurements per eye were repeated at three time points to study the intra-operator variability. The same process was repeated a single time by two different trained operators for the inter-operator variability. RESULTS: Forty participants (28 women and 12 men) were enrolled in this study, with an average age of 76.4 ± 8.2 (range, 55-92 years). Overall, the maximum values of the various structures were found in the 3 mm of the macula. Intra-operator variability: the highest ICC values turned out to be discovered in thicker locations. Inter-operator variability: except correlation values of 0.826 (0.727; 0.898) obtained in the OPL (T2.5) and 0.634 (0.469; 0.771) obtained in the IPL (N2), all other correlation values were > 0.92, in most cases approaching higher values like 0.98. CONCLUSION: The measurements of several layers of the retina and the choroid achieved at 13 locations presented a good repeatability and reproducibility. Manual quantification is still an alternative for the weaknesses of automatic segmentation. Locations of greatest concordance should be those used for the clinical control and monitoring.

Mutations in ARL2BP, a protein required for ciliary microtubule structure, cause syndromic male infertility in humans and mice.

Cilia are evolutionarily conserved hair-like structures with a wide spectrum of key biological roles, and their dysfunction has been linked to a growing class of genetic disorders, known collectively as ciliopathies. Many strides have been made towards deciphering the molecular causes for these diseases, which have in turn expanded the understanding of cilia and their functional roles. One recently-identified ciliary gene is ARL2BP, encoding the ADP-Ribosylation Factor Like 2 Binding Protein. In this study, we have identified multiple ciliopathy phenotypes associated with mutations in ARL2BP in human patients and in a mouse knockout model. Our research demonstrates that spermiogenesis is impaired, resulting in abnormally shaped heads, shortened and mis-assembled sperm tails, as well as in loss of axonemal doublets. Additional phenotypes in the mouse included enlarged ventricles of the brain and situs inversus. Mouse embryonic fibroblasts derived from knockout animals revealed delayed depolymerization of primary cilia. Our results suggest that ARL2BP is required for the structural maintenance of cilia as well as of the sperm flagellum, and that its deficiency leads to syndromic ciliopathy.

Manufacturing of lightweight aggregates from biomass fly ash, beer bagasse, Zn-rich industrial sludge and clay by slow firing.

A 70:30 black-white clay mixture (C) has been blended with different proportions of three wastes: bagasse from beer production (BG), a flux sludge used in galvanization (FS) and fly ash enriched to 60% with K2O from a biomass plant (FA). A complete characterization of the raw materials was performed. Mixtures of C and FA for 15, 17.5 and 20 wt% of K2O were blended with water, shaped into prismatic specimens, oven-dried, muffle-sintered at 1000-1200 °C, and finally crushed into lightweight aggregates (LWAs). The amounts of FA corresponding to K2O = 20% for a temperature, T, of 1000 °C (LWA variety C20K-1000) yielded the best technological properties: oven-dry density of 1.22 g/cm3, water absorption of 39.8% and open porosity of 48.6%. Therefore, other specimens containing BG and FS were sintered according to the same protocol considering K2O = 20% and T = 1000 °C. White aggregates were also obtained at 1000 °C (C-1000 variety) from C-mixture (without FS, FA and BG). The addition of BG (5,7 and 10 wt%) did not mean any improvement with respect to C20K-1000, and in the case of FS (25-40%), the development of red color was fostered, which could be interesting for gardening or ornamental purposes. A leaching test conducted on the aggregate with 40 wt% FS showed that the concentration of heavy metals was below the permitted environmental thresholds. Although the leachable Zn concentration of the aggregate (205 ppm) was reduced by 85% with respect to the original residue, it is still high enough for crops that demand this metal. The outcome of this investigation proves the usefulness of recycling agricultural and industrial wastes to obtain high quality LWAs for agriculture or gardening.

Outer Retina and Choroidal Thickness in Intermediate Age-Related Macular Degeneration: Reticular Pseudodrusen Findings.

PURPOSE: To evaluate outer retina and choroidal thickness in subjects with intermediate age-related macular degeneration (iAMD) and to describe associations with the presence of reticular pseudodrusen (RPD). METHODS: This was a retrospective, cross-sectional analysis of 157 consecutive eyes (specifically: 62 eyes classified as having RPD and 95 eyes with drusen ≥125 µm). Only cases with digital color fundus photographs, red-free, and infrared, obtained and graded according to the Age-Related Eye Disease Study to define iAMD, were used for this study. Outer retina and choroidal thickness were manually segmented and quantified at 12 locations in the horizontal meridian. RESULTS: RPD appeared to be associated with thinning of the outer layers even after adjustment for gender and age. The presence of RPD in iAMD decreased with increase of choroidal thickness (total odds ratio [OR] 0.991, 95% confidence interval [CI] 0.985-0.996; nasal OR 0.992, 95% CI 0.986-0.997), with increased thickness of the myoid zone of the photoreceptors (total OR 0.812, 95% CI 0.688-0.958; nasal OR 0.863, 95% CI 0.755-0.987) and with increased thickness of the outer segment of the photoreceptors (total OR 0.850, 95% CI 0.731-0.989; nasal OR 0.857, 95% CI 0.736-0.989). CONCLUSIONS: The greatest differences between eyes with and without RPD are found at the level of the choroidal thickness and at the level of the photoreceptors.

Ganglion Cell Complex in Early and Intermediate Age-Related Macular Degeneration: Evidence by SD-OCT Manual Segmentation.

PURPOSE: To evaluate ganglion cell layer (GCL) and ganglion cell complex (GCC) thickness manually by spectral-domain optical coherence tomography in subjects with early and intermediate age-related macular degeneration (AMD) in 12 locations on the horizontal meridian. METHODS: A total of 450 eyes (specifically, 246 eyes classified as having early/intermediate AMD plus 204 control eyes) were studied. Mann-Whitney U and Kruskal-Wallis tests were used to compare values between the healthy controls and the AMD group and also between the subgroups under study. Diagnostic performance was also compared calculating the areas under the receiver operating characteristic curve. RESULTS: The manual layer segmentation showed clear boundaries between the GCL and the GCC. It was in the temporal GCC that more changes were found. CONCLUSIONS: The GCC, especially in the temporal region, allowed the discrimination of differences between various subgroups that have faint variations as well as between early AMD and the first signs of aging.

Oxidative stress status in liver mitochondria and lymphocyte DNA damage of atherosclerotic rabbits supplemented with water soluble coenzyme Q10.

The effects of the administration of water soluble coenzyme Q10 (25 mg/kg per day) over 30 days, after 50 days feeding on a high-fat diet (3% lard + 1.3% cholesterol), were investigated in the plasma and liver mitochondria of rabbits. Results showed that this atherogenic diet enhanced lipid levels both in plasma and liver mitochondria, reduced plasma and mitochondrial concentrations of retinol and coenzyme Q10, led to higher DNA damage in peripheral blood lymphocytes and reactive oxygen species concentration in liver mitochondria. The treatment of animals with coenzyme Q10 reduced (to the healthy group levels) lipid concentration in liver mitochondria with no effect on plasma lipids, increased mitochondrial levels of alpha-tocopherol, restored mitochondrial coenzyme Q10 and improved alpha-tocopherol levels in plasma. Moreover, coenzyme Q10 supplementation reduced mitochondrial reactive oxygen species levels and decreased DNA damage in peripheral blood lymphocytes. The findings suggest that antioxidant therapy with coenzyme Q10 may be used in the treatment of liver pathologies associated to the intake of high-fat, atherogenic, diets.

Effects of a leukocyte depleting arterial line filter on perioperative morbidity in patients undergoing cardiac surgery: a controlled randomized trial.

BACKGROUND: Activated leukocytes may increase morbidity in cardiac surgery. The objective of this study is to investigate the influence on morbidity of leukocyte-depleting blood filters placed into the arterial line of cardiopulmonary bypass circuits. METHODS: Simple, blind, prospective, randomized and controlled clinical trial carried out in a cardiac surgery ICU at a university center. We included 159 consecutive low-risk patients (ie, Parsonnet score < 10) undergoing cardiac surgery who were initially stratified in three risk levels according to the Parsonnet score at admission into the hospital (ie, low, < 4; middle, 4 to 7; and high, 8 to 10). Once stratified, all patients were randomized to undergo cardiopulmonary bypass either with a conventional blood filter or with a leukocyte filter (randomization ratio, 2:1). The outcome variable was morbidity. Patients were considered to have a high morbidity if any of the following clinical situations were present (ie, pulmonary dysfunction, cardiac dysfunction, perioperative infections, postoperative hyperthermia, and hyperdynamic states). RESULTS: The leukocyte filter was used in 52 patients and the conventional filter in 107 patients. The morbidity rate was similar in both groups, but patients with leukocyte filter had a lower incidence of perioperative infections, fever, and hyperdynamic states as compared with patients with the conventional filter. CONCLUSIONS: Leukocyte filtration in patients undergoing cardiac surgery with extracorporeal perfusion showed no measurable effects on postoperative morbidity. However, although not statistically significant, a decrease was observed in the rates of perioperative infection, fever, and hyperdynamic states.