Diseased Corneas Research Articles

Replace or Regenerate? Diverse Approaches to Biomaterials for Treating Corneal Lesions.

The inner structures of the eye are protected by the cornea, which is a transparent membrane exposed to the external environment and subjected to the risk of lesions and diseases, sometimes resulting in impaired vision and blindness. Several eye pathologies can be treated with a keratoplasty, a surgical procedure aimed at replacing the cornea with tissues from human donors. Even though the success rate is high (up to 90% for the first graft in low-risk patients at 5-year follow-up), this approach is limited by the insufficient number of donors and several clinically relevant drawbacks. Alternatively, keratoprosthesis can be applied in an attempt to restore minimal functions of the cornea: For this reason, it is used only for high-risk patients. Recently, many biomaterials of both natural and synthetic origin have been developed as corneal substitutes to restore and replace diseased or injured corneas in low-risk patients. After illustrating the traditional clinical approaches, the present paper aims to review the most innovative solutions that have been recently proposed to regenerate the cornea, avoiding the use of donor tissues. Finally, innovative approaches to biological tissue 3D printing and xenotransplantation will be mentioned.

Pearls And Pitfalls of Keratoplasty to Achieve and Optimal Visual Function: A Case Report

Introduction : Keratoplasty, also known as corneal transplant, is a surgical procedure in which a damaged or diseased cornea is replaced with a healthy donor cornea. One of the common reasons for performing this procedure is to restore vision in people with a leukoma eye. Leukoma, also known as corneal opacification, is a condition in which the cornea becomes cloudy or opaque, leading to impaired vision or even blindness. This case will explain keratoplasty procedures for treating leukoma, the benefits and risks of the surgery, and the postoperative care required for a successful recovery.
 Case Illustration : A 49 years old Female diagnosed with Leukoma due to her symptoms, signs, and examination with VOD: 1/60 ph (-) and VOS : 6/7.5. The patient then underwent keratoplasty surgery. 7th day post operation, Corneal Graft had 16 interrupted sutures with minimal edema. VOD 6/60 and Intra ocular pressure on the right eye was 13.1 mmHg. Oral and topical corticosteroids Continued and planned to taper off gradually.
 Discussion : The success of the procedure depends on several factors, including the cell count of donor, determining high/low risk patients, Intraoperative, and the postoperative care provided. Topical corticosteroids remain the mainstay to prevent immunological graft reactions. Regular evaluation of the graft is important as the risk of rejection occur up to years.
 Conclusion : Keratoplasty has proven to be an effective treatment option for individuals with a leukoma eye. The procedure can significantly improve visual acuity and quality of life for these individuals.

Effect of antiglaucomatous eye drops on corneal endothelium

First choice therapy for reducing the intraocular pressure in context of glaucoma remains the applications of eye drops. Longterm exposure to topical therapy can clearly have an impact on the ocular surface, but as the medications penetrate through the cornea and are present in humour aqueous, also on all other layers of cornea, including corneal endothelium. In general, none of the medications from the standard pharmacological groups influences significantly an otherwise healthy corneal endothelium in an eye with glaucoma or ocular hypertension – be it in terms of central corneal thickness, be it in terms of endothelial cell density and morphology, be it for beta blockers, carbonic anhydrase inhibitors, pilocarpine, alpha2 agonists or prostaglandin analogues. The situation changes in diseased corneas, such as in Fuchs endothelial dystrophy, where topically applied carbonic anhydrase inhibitors can lead to increase in corneal thickness. Benzalkonium chloride has been proven toxic for corneal endothelial cells in vitro. However, in the daily practice and under real life circumstances, it is from the specific point of view on the corneal endothelium still not clear whether using non‐preserved topical glaucoma medications is an absolute imperative. One separate topic here is also a group of Rho‐kinase inhibiting topical medications. Apart from new mechanisms of action for reducing the intraocular pressure, this group of medications has also a direct influence on the corneal structures – from cornea verticillata on the epithelium corneal level, to mobilizing peripheral endothelial corneal cells as a possible therapeutic path for Fuchs endothelial dystrophy. One part of the lecture will address also these issues.

"Partial Open Sky Method" - A novel technique to avoid the open sky condition during Triple procedure or Penetrating keratoplasty.

Penetrating keratoplasty is referred to as an "open-sky" procedure because the intraocular contents are entirely exposed to atmospheric pressure after the diseased cornea has been trephined off and before the donor button is sutured. Suprachoroidal hemorrhage (SCH) is a major vision-threatening complication, associated with this open-sky procedure. While numerous factors may predispose an eye to SCH, like hypertension, myopia, trauma, glaucoma, etc., it is better to be prepared for the worst eventuality. We described a novel technical modification, denoted as the "partial open sky technique", that we used during the surgical steps of trephining and excision of host corneal tissue in seven cases of triple procedure and penetrating keratoplasty in our center over two months. We propose that the technique would be additionally helpful in managing the inadvertent suprachoroidal hemorrhage associated with keratoplasty over the available existing methods. Abbreviations: SCH = Suprachoroidal hemorrhage, ICCE = Intracapsular cataract surgery, ECCE = Extracapsular cataract surgery, WTW = White to White.

3D Bioprinting of Acellular Corneal Stromal Scaffolds with a Low Cost Modified 3D Printer: A Feasibility Study

Purpose Loss of corneal transparency is one of the major causes of visual loss, generating a considerable health and economic burden globally. Corneal transplantation is the leading treatment procedure, where the diseased cornea is replaced by donated corneal tissue. Despite the rise of cornea donations in the past decade, there is still a huge gap between cornea supply and demand worldwide. 3D bioprinting is an emerging technology that can be used to fabricate tissue equivalents that resemble the native tissue, which holds great potential for corneal tissue engineering application. This study evaluates the manufacturability of 3D bioprinted acellular corneal grafts using low-cost equipment and software, not necessarily designed for bioprinting applications. This approach allows access to 3D printed structures where commercial 3D bioprinters are cost prohibitive and not readily accessible to researchers and clinicians. Methods Two extrusion-based methods were used to 3D print acellular corneal stromal scaffolds with collagen, alginate, and alginate-gelatin composite bioinks from a digital corneal model. Compression testing was used to determine moduli. Results The printed model was visually transparent with tunable mechanical properties. The model had central radius of curvature of 7.4 mm, diameter of 13.2 mm, and central thickness of 0.4 mm. The compressive secant modulus of the material was 23.7 ± 1.7 kPa at 20% strain. 3D printing into a concave mold had reliability advantages over printing into a convex mold. Conclusions The printed corneal models exhibited visible transparency and a dome shape, demonstrating the potential of this process for the preparation of acellular partial thickness corneal replacements. The modified printing process presented a low-cost option for corneal bioprinting.

A novel technique of penetrating keratoplasty to prevent intraocular contents extrusion for infectious keratitis

PurposeTo evaluate the safety and the effectiveness of our novel penetrating keratoplasty for infectious keratitis.MethodsRetrospective, noncomparative, interventional case series of patients with infectious keratitis who received the novel penetrating keratoplasty technique were analyzed. A prepared plastic sheet was located between the diseased cornea and iris-lens diaphragm. After the diseased lesions were removed, the graft was positioned on the plastic sheet and sutured to the recipient bed. The plastic sheet was pulled out from the anterior chamber before the all interrupted sutures were placed. The intra- and post-operative complications, the outcome of the graft and the number of corneal endothelial cells were analyzed.ResultsA total of 82 eyes of 82 patients was included. The mean follow-up period was 29 ± 16 months (range from 13 to 45 months). No intraocular content extrusion, simultaneous cataract extraction and suprachoroidal hemorrhage occurred. Direct contact between the infectious cornea and the graft was successfully avoided. Greater than expected endothelial cell reduction or complications were not found.ConclusionsThis modified technique effectively prevents the extrusion of intraocular contents while avoiding the direct contact with donor endothelium during the procedure. The occurrence rate of complications such as endothelial cell loss is not higher than the conventional methods.

Case Series: Transient Corneal Subepithelial Macrocysts with Scleral Contact Lens Wear

Scleral lens wear is indicated in cases of corneal irregularity and ocular surface disease to improve vision and ocular surface condition. The purpose of this case series is to discuss transitory corneal subepithelial macrocysts associated with scleral lens wear in various conditions such as dry eye, post-radial keratotomy, and post-superficial keratectomy. Such diseased or damaged corneas have weakened epithelial attachments which can lead to macrocyst formation. Three cases documented with spectral-domain anterior segment optical coherence tomography highlight the clinical presentation of corneal subepithelial macrocysts. CE Notification: This article is available as a COPE accredited CE course. You may take this course for 1-hour credit. Read the article and take the qualifying test to earn your credit. Please check COPE course expiry date prior to enrollment. The COPE course test must be taken before the course expiry date.

Birefringence analysis of collagen supraorganization in cat corneas with tropical keratopathy.

To evaluate the birefringent properties of the cornea and examine the supraorganizational aspects of collagen fibers in cats with tropical keratopathy. In this study, 10-micrometer-thick sections of corneal tissue from cats with tropical keratopathy were examined, both in the opaque and transparent areas of the anterior stroma. Control samples were obtained from healthy cat corneas. Polarized light microscopy was employed to evaluate the birefringent properties using two distinct methods. The first method involved measuring the optical retardation associated with corneal birefringence, while the second method assessed the alignment/waviness of the birefringent collagen fibers. Differences were significant when p < .05. Tropical keratopathy resulted in a significant rise (p < .05) in optical retardation in both opaque and transparent regions of the cat cornea. In the anterior stroma, both the opaque zones and transparent tissue exhibited a higher degree of collagen fiber packing than the control corneas. However, no significant differences (p > .05) in alignment were observed between the transparent tissue of the diseased cornea and the healthy corneas. Supraorganizational changes in collagen fiber packing are not restricted to lesion zones in cat corneas affected by tropical keratopathy. Such alterations also occur in the corneal tissue of the anterior stroma adjoining the lesions. Therefore, it is plausible that the transparent tissue of the anterior stroma in corneas affected by the disease may have functional abnormalities, despite its macroscopic healthy appearance. Additional investigations are required to clarify the implications of these potential defects and their conceivable contribution to tropical keratopathy.

Histopathology of the Host Cornea Following Penetrating Keratoplasty.

To study the ultra-structural changes in the diseased corneal cells by histopathology, electron microscopy, and immunohistochemistry using conventional antisera and monoclonal antibodies with the ultimate goal of justifying pre-treatment and post-treatment advice and, if necessary, modifying the post-operative treatment for improved graft survival. Thirty cases registered for penetrating keratoplasty were worked up for routine systemic and ophthalmic criteria. A full-thickness diseased cornea was subjected to histopathology after suitable staining and fixation, including electron microscopic and immunohistochemical studies where possible. The ages ranged from four to 60 years. The majority (26%) were in the age group of 31-40 years. The most frequent causes of corneal pathology that underwent keratoplasty include post-traumatic corneal scarring (40%), followed by pseudophakic bullous keratopathy (16.7%). In almost all cases, the histopathology confirmed the existing clinical diagnosis. Histopathology helped to confirm one doubtful case of Fuchs' dystrophy and to contradict one clinical diagnosis of pseudophakic bullous keratopathy, which turned out to be epithelization of the anterior chamber. The results underline the significance of the histopathological study of these corneal conditions to increase the post-surgical survival of the corneal graft.

Patterns of Corneal Disorders in Corneal Button Specimens: Descriptive Study in a Tertiary Referral Hospital in Bahrain

Introduction: Corneal injuries and disorders are among the commonest clinical scenarios that are encountered in the ophthalmology clinical practice. Penetrating Keratoplasty (PKP) surgeries count for the most frequent efficient surgical management of diseased corneas. The latter are usually sent as button specimens for histopathology examination for further describing the pattern of the corneal disorders. Aims and Objectives: The aims of this study are to discuss the rate of Penetrating Keratoplasty (PKP) surgeries in SMC in 6 years interval (2016-2022) along with to determine the most common histopathological and microbiological diagnosis of corneal specimens from Penetrating Keratoplasty (PKP) and to study the clinical spectrum with age and sex distribution of corneal disorders in Bahrain alongside correlation with the comorbidities and the pathological diagnosis. Patients and Methods: It is a retrospective analysis of one-hundred and one histopathology reports of corneal button specimens at Salmaniya medical complex during the last 6 years (1-1-2016 till 31-3-2022). Medical records, surgical notes and histopathology reports of patients were retrieved from ISEHA system. Statistical analysis was done using Microsoft Excel 2019. Results: Corneal scarring (44%) was the most common pathological diagnosis, followed by Keratoconus (KC) (15%), acute keratitis (14%), degeneration (9%), chronic keratitis with fibrosis (5%), decompensated cornea and failed graft (5%), pseudophakic bullous keratopathy (3%) and herpetic keratitis (3%). There was Bahraini nationality (98%) and male preponderance (66%). The most common age group affected was 70–79 years with the median age of 51.5 year. Conclusion: Our study shows the importance of determining the most common histological diagnoses of corneal button specimens along with the correlation of the latter with the age, gender, surgical complications and systemic comorbidities. Knowing the exact pathology of the diseased cornea would assist in providing the proper post-operative management and to avoid possible elements that could promote complications.

Corneal “re-shaping” by lenticule implantation in keratoconus: The role of tissue addition

Prof. Leonardo Mastropasqua is Director at the National High-Tech Eye Center, Ophthalmology Clinic, Department of Medicine and Aging Science, University G. D’Annunzio of Chieti-Pescara, Chieti, Italy. In the following editorial, talk about the prospects for corneal lenticule implantation. Mario Nubile is Associate Professor of the same faculty. Both are specialized in corneal, cataract and refractive surgery and focus on imaging technologies of the anterior eye segment. In the following editorial, they talk about the prospects for corneal lenticule implantation and tissue-addition techniques for reshaping the diseased cornea.

Probing mechanisms and improving management of glaucoma following Boston keratoprosthesis surgery.

Corneal blindness is a leading cause of visual impairment worldwide. The most common treatment is to replace the diseased cornea with standard corneal transplantation. In eyes at high risk of graft failure, the Boston keratoprosthesis type 1 (KPro) can be used to restore vision and is currently the most frequently used artificial cornea in the world. However, glaucoma is a well-known complication of KPro surgery and is the most important threat to vision in KPro-implanted eyes. This chronic disease is influenced by elevated intraocular pressure (IOP) and damages the optic nerve, leading to progressive vision loss. In KPro patients, glaucoma is highly prevalent and extremely challenging to manage, yet its exact cause remains unknown.

Thrombospondin-1 induction and VEGF reduction by proteasome inhibition

The present study focuses on investigating the expression of thrombospondin-1 (TSP-1), a natural inhibitor of neovascularization. Immunofluorescent staining was used to detect the expression of TSP-1 in rabbit corneal tissue with vascularization induced by limbectomy. TSP-1 was detected in healthy and Cultured Autologous Oral Mucosal Epithelial Cell Sheet (CAOMECS) grafted rabbit corneas. TSP-1 was not detected in diseased corneas. Rabbit and human primary oral mucosal and corneal epithelial cells were cultured and treated with proteasome inhibitor (PI) in vitro. Changes in the expression of TSP-1, HIF-1 alpha and 2 alpha, VEGF-A, and VEGF receptor were analyzed by Western blotting. Neovascularization developed in rabbits’ corneas as early as 1 month after limbectomy and was stable for at least 3 months. HIF-1 alpha and VEGF-A expression was reduced in CAOMECS grafted corneas, as compared to sham corneas. While TSP-1 expression was decreased in injured corneas, it was expressed in CAOMECS grafted corneas, but still less expressed compared to healthy corneas. PI treatment, of human oral mucosal and corneal epithelial cells increased TSP-1 expression and reduced VEGF-A expression. The results showed that TSP-1 expression was lost in injured corneal surface and that CAOMECS grafting restored TSP-1 expression to certain extent. Proteasome inhibition treatment increased TSP-1 and decreased VEGF-A expression in human oral mucosal and corneal epithelial cells. The result suggests that corneal neovascularization could be managed with the inhibition of the proteasome after CAOMECS grafting and increase corneal transparency.

Indications and Visual Outcome in Patients Undergoing Penetrating Keratoplasty

Background: Penetrating keratoplasty is commonly performed surgery in patients suffering from corneal blindness and visual impairment, where full thickness diseased cornea is replaced with healthy cornea. This study aims to outline indications of Penetrating keratoplasty and visual outcomes following the procedure.&#x0D; Materials and Methods: This retrospective, hospital-based study included 48 eyes of 48 subjects fulfilling inclusion criteria and underwent Penetrating keratoplasty from January 2017-2020 at Bharatpur Eye Hospital. General ophthalmologic examination was done preoperatively and postoperatively. Indication of the surgery along with demographic outline and requisite investigations were performed.&#x0D; Results: Mean age of the subjects was 47±1.83 years (13-74 years) where most of them were in 61-70years (23%) age group. Male subjects were more (62.5%) compared to females. Triple procedure was performed in 6.25 percent of patients. The most common indication was infective keratitis (52%) followed by corneal opacity/ scarring, regrafts, keratoconus and bullous keratopathy. Penetrating keratoplasty was performed slightly more for therapeutic purpose (52%) than optical. Intraoperative complications were observed in 16.7% of patients, positive vitreous pressure being the sole cause. Ameliorated visual acuity was observed in 71% of patients with43.75% of patients having VA of ≥3/60&#x0D; Conclusion: Infective keratitis was the predominant indication followed by corneal opacity/ scarring. Penetrating keratoplasty helps in maintaining integrity of the globe along with restoration of vision

Autophagy in the normal and diseased cornea.

The cornea and covering tear film are together the 'objective lens' of the eye through which 80% of light is refracted. Despite exposure to a physically harsh and at times infectious or toxic environment, transparency essential for sight is in most cases maintained. Such resiliency makes the avascular cornea a superb model for the exploration of autophagy in the regulation of homeostasis with relevancy to all organs. Nonetheless, missense mutations and inflammation respectively clog or apparently overwhelm autophagic flux to create dystrophies much like in neurodegenerative diseases or further exacerbate inflammation. Here there is opportunity to generate novel topical therapies towards the restoration of homeostasis with potential broad application.

Corneal Epithelial Regeneration: Old and New Perspectives.

Corneal blindness is the fifth leading cause of blindness worldwide, and therapeutic options are still often limited to corneal transplantation. The corneal epithelium has a strong barrier function, and regeneration is highly dependent on limbal stem cell proliferation and basement membrane remodeling. As a result of the lack of corneal donor tissues, regenerative medicine for corneal diseases affecting the epithelium is an area with quite advanced basic and clinical research. Surgery still plays a prominent role in the treatment of epithelial diseases; indeed, innovative surgical techniques have been developed to transplant corneal and non-corneal stem cells onto diseased corneas for epithelial regeneration applications. The main goal of applying regenerative medicine to clinical practice is to restore function by providing viable cells based on the use of a novel therapeutic approach to generate biological substitutes and improve tissue functions. Interest in corneal epithelium rehabilitation medicine is rapidly growing, given the exposure of the corneal outer layers to external insults. Here, we performed a review of basic, clinical and surgical research reports on regenerative medicine for corneal epithelial disorders, classifying therapeutic approaches according to their macro- or microscopic target, i.e., into cellular or subcellular therapies, respectively.

Immunomodulatory Role of Neuropeptides in the Cornea.

The transparency of the cornea along with its dense sensory innervation and resident leukocyte populations make it an ideal tissue to study interactions between the nervous and immune systems. The cornea is the most densely innervated tissue of the body and possesses both immune and vascular privilege, in part due to its unique repertoire of resident immune cells. Corneal nerves produce various neuropeptides that have a wide range of functions on immune cells. As research in this area expands, further insights are made into the role of neuropeptides and their immunomodulatory functions in the healthy and diseased cornea. Much remains to be known regarding the details of neuropeptide signaling and how it contributes to pathophysiology, which is likely due to complex interactions among neuropeptides, receptor isoform-specific signaling events, and the inflammatory microenvironment in disease. However, progress in this area has led to an increase in studies that have begun modulating neuropeptide activity for the treatment of corneal diseases with promising results, necessitating the need for a comprehensive review of the literature. This review focuses on the role of neuropeptides in maintaining the homeostasis of the ocular surface, alterations in disease settings, and the possible therapeutic potential of targeting these systems.

Numerical estimation of stress and refractive power maps in healthy and keratoconus eyes

Keratoconus is an eye condition caused by localized thinning of the corneal tissue, which leads to a characteristic cone-shaped protrusion of the cornea. We investigate the mechanical behavior of keratoconus and suspect keratoconus corneas versus healthy corneas by using patient-specific finite element models. Patient-specific geometries of the corneas are obtained from diagnostic images provided by corneal topographer, transformed into solid models, and discretized in hexahedral elements. For the diseased corneas, a suitable reduction of the stiffness is applied within a limited region of the cornea around the conus. After the identification of the stress-free configuration, the models are used to simulate pressurization tests up to 40 mmHg. The material parameters have been estimated within the stress-free configuration identification procedure. As expected, numerical results reveal a more compliant behavior for the diseased corneas in terms of apex displacement plots as a function of the intraocular pressure, with diseased corneas experiencing up to 44% increase in apex displacement compared to healthy corneas. The maps of the stress confirm, for the diseased corneas, a marked increase of the maximum tensile stress, on both anterior and posterior surfaces, to be ascribed mainly to the reduction of the corneal thickness. Stress maps also show, for keratoconus corneas, a marked increase of the ratio between posterior and anterior tensile stress in the conus. Numerical analyses are used to construct the refractive power maps, revealing clearly that the maximum dioptric power in keratoconus corneas is at the center of the cone-shape rather than at the apex.

The systematization of nursing care to patients who are potential corneal donors: an integrative literature review

Introduction: Corneal transplantation is a surgery that consists of replacing a portion of the diseased cornea of a patient with a healthy cornea, in order to improve vision or correct ocular perforations. With the advancement of studies, resuscitation and life support techniques, brain activity came to define the life and death of the individual, thus linking death to neurological criteria. The care of patients with brain death, potential corneal donors, is characterized as a complex activity, implemented by the multidisciplinary team that works in an adult intensive care unit with the systematization of nursing care in the workplace the nurse ensures that the quality of care will be permanent. Objective: Application of the systematization of nursing care, according to the NANDA taxonomy, in a patient with brain death, for the preservation of the cornea of this potential donor. Method: This is an Integrative Literature Review. For data collection, three moments were used: checking the keywords, obtaining the sample and synthesizing the data. Results and discussion: 12 articles contributed positively to the research for the results and discussions, presenting subjects such as: Loss of the potential donor due to care maintenance and the need for systematization in nursing care; Strategy for early diagnosis of brain death and the importance of a commission for assistance support. After reading and identifying categories emerged in the research, the conditions that evidence organ and tissue donations were satisfactorily shown. Conclusion: It was possible to identify the absence of protocols for the systematization of nursing care in the Intensive Care Unit, and as a consequence the decrease in corneal transplants, evidenced by the absence of early strategies for the diagnosis of brain death.

Aldehyde Dehydrogenases Expression in Corneal Epithelial Cells with Limbal Stem Cell Deficiency.

Purpose: The purpose of the present study is to investigate the expression of aldehyde dehydrogenases (ALDHs) in rabbit corneas with limbal stem cell deficiency (LSCD) and corneas treated with cultured autologous oral mucosa epithelial cell sheet CAOMECS designed to reconstruct the ocular surface with LSCD. Methods: New Zealand white rabbit autologous oral mucosal epithelial cells were isolated from a buccal biopsy and cultured to be grafted back onto corneas of rabbit model of LSCD. Immunofluorescent staining and Western blot analysis were used to compare the expression of ALDH1A1 and ALDH1A3 in healthy, LSCD-diseased, CAOMECS treated corneas. Human oral mucosal and corneal epithelial cells (OMECS and CECs) were cultured and treated with retinoic acid (RA) to further investigate the expression of ALDHs. Results: In healthy corneas, ALDH1A1 and ALDH1A3 were markedly expressed in basal cells of corneal epithelium. In LSCD diseased corneas, ALDH1A1 and ALDH1A3 were markedly expressed in the conjunctivalized apical epithelial cells, the goblet cells, and the stroma. CAOMECS grafted corneas showed a decreased expression of ALDHs as compared to LSCD diseased corneas. Western blot analysis confirmed the up regulation of ALDH1A1 and ALDH1A3 expression in LSCD-diseased corneal epithelial cells. CAOMECS expressed low levels of ALDH1A1 and ALDH1A3, as compared to diseased CECs (D-CEC). When ALDH1A3 was up regulated by retinoic acid treatment in OMECS, Pax-6 expression was down regulated, suggesting a decrease in regenerative capacity when ALDH enzymes are up regulated. Conclusions: These findings report for the first time the up regulation of ALDH1A1 and ALDH1A3 in rabbit corneas with LSCD and document that CAOMECS grafting used to reconstruct corneal epithelium may reduce the expression levels of ALDH enzymes.