Topical tacrolimus for high-risk corneal transplantation: a randomized, clinical trial.

BACKGROUND: The prevalence of rejection is 10-30% in penetrating keratoplasty (PKP) case, and the rate is higher in cases of high-risk patients. Although using topical corticosteroids is a standard method for management the rejection of post-PKP patients, it may not be sufficiently potent in high-risk patients. Topical administration of tacrolimus (TAC) may be effective in suppression rejection after corneal transplantation. This study aimed to investigate the efficacy and safety of topical TAC in high-risk PKP patients in Japan. METHODS: This study was a single centre, single-blinded, randomized controlled trial. Patients with a history of PKP, graft rejection, atopic dermatitis, or deep corneal neovascularisation who underwent PKP were enrolled. They were randomly assigned to receive 0.1% TAC ophthalmic suspension or artificial tear (AT) up to week 52 after surgery. All participants received 0.1% betamethasone up to week 13 after surgery then they received 0.1% fluorometholone up to week 52. The incidence of immunological rejection during the observation period was the main outcome measure in this study. RESULTS: Thirty patients were enrolled in this study, and 12 eyes in the TAC group and 13 eyes in the AT group completed the study, respectively. Five out of 30 patients discontinued participation after providing informed consent. No serious adverse effects were developed in patients who received 0.1% TAC ophthalmic suspension. No rejection episodes occurred in the TAC group, while one eye in the AT group had rejection. Graft clarity, best spectacle-corrected visual acuity, intraocular pressure, and corneal endothelial cell density were not significantly different between the TAC and AT groups. CONCLUSION: Our results demonstrated that good tolerability of 0.1% TAC ophthalmic suspension. However, we failed to demonstrate its efficacy in preventing immunological rejection in high-risk patients undergoing PKP. TRIAL REGISTRATION: This study was first registered in the University Hospital Medical Information Network (UMIN000029669, Date of registration: November 1, 2017). With the enforcement of the Clinical Trial Act in Japan, the study re-registered in the Japan Registry of Clinical Trials (jRCTs031180342, Date of registration: March 18, 2019).

Three-Dimensional Assessment of Descemet Membrane Reflectivity by Optical Coherence Tomography in Fuchs Endothelial Corneal Dystrophy.

PURPOSE: This study aimed to evaluate Descemet membrane reflectivity using anterior segment optical coherence tomography (AS-OCT) in eyes with Fuchs endothelial corneal dystrophy (FECD). METHODS: We retrospectively assessed 144 eyes of 88 consecutive participants (41 FECD, 15 pseudophakic bullous keratopathies [BKs], and 32 healthy controls, 63.5 ± 16.5 years). FECD was graded 0 to 3 based on the guttae areas using specular microscopy. The sum of AS-OCT reflectivity of the 3-dimensional volume from 10 µm thickness from the endothelial surface of the cornea and residual stromal area was calculated as D sum (endo) and D sum (stroma) in the central area of 3- and 6-mm diameters, respectively. The D ES ratio was defined as the ratio of D sum (endo) to D sum (stroma). The percentage of the guttae area in the specular images was calculated using MATLAB. D sum (endo) and D ES ratio were compared among FECD, BK, and healthy controls. RESULTS: D sum (endo) in FECD grade 3 was significantly higher than that in healthy control eyes, FECD patients with mild and moderate guttae, and BK (all P ≤ 0.040). The D ES ratio in FECD patients with mild to severe guttae (grade 1-3) was significantly higher than that in healthy control eyes and BK (all P ≤ 0.035). The percentage of the guttae area was significantly correlated with D sum (endo) (R = 0.488, P < 0.001 for 3 mm, R = 0.512, P < 0.001 for 6 mm) and D ES ratio (R = 0.450, P < 0.001 for 3 mm, R = 0.588, P < 0.001 for 6 mm). CONCLUSIONS: Descemet membrane reflectivity in AS-OCT can be objective biomarkers for assessing guttae and FECD severity from early to end-stage FECD.

Incidence and Clinical Features of Immunologic Rejection After Deep Anterior Lamellar Keratoplasty.

PURPOSE: The aim of this study was to investigate the incidence and clinical features of immunologic rejection after deep anterior lamellar keratoplasty (DALK). METHODS: This study included 411 patients (464 eyes, median age [interquartile range; IQR] 55.8 years [36.1-69.5]) who underwent DALK at Tokyo Dental College between June 1997 and 2021. Of 411 patients, 24 (24 eyes [5.2%], 51.9 years [IQR 31.6-65.4]) developed immunologic rejection. We characterized the clinical features, risk factors associated with immunologic rejection, and prognosis. RESULTS: The interval between DALK and immunologic rejection was 14.5 (range, 5-78) months. Immunologic rejection occurred after cessation/reduction of topical steroid in 9 (47.4%) and suture removal in 4 eyes (21.1%). The postoperative duration of topical steroid use in eyes with immunologic rejection was significantly shorter (10.0 months, [IQR 6.0-14.0]) than those without immunologic rejection (28.3 [IQR 15.8-42.7], P = 0.001). Immunologic rejection manifested as stromal edema in 19 (100.0%), ciliary hyperemia in 17 (89.5%), keratic precipitates in 13 (68.4%), epithelial edema in 13 (68.4%), infiltration in 9 (47.4%), corneal opacity in 4 (21.1%), and Descemet membrane detachment in 2 eyes (10.5%). After treatment, corneal clarity was restored in 17 eyes (89.5%); however, immunologic rejection led to corneal endothelial decompensation in 2 eyes (10.5%). Endothelial cell density decreased from 1795.7 ± 722.6 to 1651.6 ± 655.6 cells/mm2 after immunologic rejection (P = 0.074). CONCLUSIONS: Post-DALK immunologic rejection was associated with specific clinical triggers such as reduction/cessation of topical steroids or suture removal.

Temperature Field, Flow Field, and Temporal Fluctuations Thereof in Ammonothermal Growth of Bulk GaN-Transition from Dissolution Stage to Growth Stage Conditions.

With the ammonothermal method, one of the most promising technologies for scalable, cost-effective production of bulk single crystals of the wide bandgap semiconductor GaN is investigated. Specifically, etch-back and growth conditions, as well as the transition from the former to the latter, are studied using a 2D axis symmetrical numerical model. In addition, experimental crystal growth results are analyzed in terms of etch-back and crystal growth rates as a function of vertical seed position. The numerical results of internal process conditions are discussed. Variations along the vertical axis of the autoclave are analyzed using both numerical and experimental data. During the transition from quasi-stable conditions of the dissolution stage (etch-back process) to quasi-stable conditions of the growth stage, significant temperature differences of 20 K to 70 K (depending on vertical position) occur temporarily between the crystals and the surrounding fluid. These lead to maximum rates of seed temperature change of 2.5 K/min to 1.2 K/min depending on vertical position. Based on temperature differences between seeds, fluid, and autoclave wall upon the end of the set temperature inversion process, deposition of GaN is expected to be favored on the bottom seed. The temporarily observed differences between the mean temperature of each crystal and its fluid surrounding diminish about 2 h after reaching constant set temperatures imposed at the outer autoclave wall, whereas approximately quasi-stable conditions are reached about 3 h after reaching constant set temperatures. Short-term fluctuations in temperature are mostly due to fluctuations in velocity magnitude, usually with only minor variations in the flow direction.

Diagnostic Ability of a Smartphone App for Dry Eye Disease: Protocol for a Multicenter, Open-Label, Prospective, and Cross-sectional Study.

BACKGROUND: Dry eye disease (DED) is one of the most common ocular surface diseases. Numerous patients with DED remain undiagnosed and inadequately treated, experiencing various subjective symptoms and a decrease in quality of life and work productivity. A mobile health smartphone app, namely, the DEA01, has been developed as a noninvasive, noncontact, and remote screening device, in the context of an ongoing paradigm shift in the health care system, to facilitate a diagnosis of DED. OBJECTIVE: This study aimed to evaluate the capabilities of the DEA01 smartphone app to facilitate a DED diagnosis. METHODS: In this multicenter, open-label, prospective, and cross-sectional study, the test method will involve using the DEA01 smartphone app to collect and evaluate DED symptoms, based on the Japanese version of the Ocular Surface Disease Index (J-OSDI), and to measure the maximum blink interval (MBI). The standard method will then involve a paper-based J-OSDI evaluation of subjective symptoms of DED and tear film breakup time (TFBUT) measurement in an in-person encounter. We will allocate 220 patients to DED and non-DED groups, based on the standard method. The primary outcome will be the sensitivity and specificity of the DED diagnosis according to the test method. Secondary outcomes will be the validity and reliability of the test method. The concordance rate, positive and negative predictive values, and the likelihood ratio between the test and standard methods will be assessed. The area under the curve of the test method will be evaluated using a receiver operating characteristic curve. The internal consistency of the app-based J-OSDI and the correlation between the app-based J-OSDI and paper-based J-OSDI will be assessed. A DED diagnosis cutoff value for the app-based MBI will be determined using a receiver operating characteristic curve. The app-based MBI will be assessed to determine a correlation between a slit lamp-based MBI and TFBUT. Adverse events and DEA01 failure data will be collected. Operability and usability will be assessed using a 5-point Likert scale questionnaire. RESULTS: Patient enrollment will start in February 2023 and end in July 2023. The findings will be analyzed in August 2023, and the results will be reported from March 2024 onward. CONCLUSIONS: This study may have implications in identifying a noninvasive, noncontact route to facilitate a diagnosis of DED. The DEA01 may enable a comprehensive diagnostic evaluation within a telemedicine setting and facilitate early intervention for undiagnosed patients with DED confronting health care access barriers. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs032220524; https://jrct.niph.go.jp/latest-detail/jRCTs032220524. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/45218.

Clinical Trial of Autologous Cultivated Limbal Epithelial Cell Sheet Transplantation for Patients with Limbal Stem Cell Deficiency.

PURPOSE: To confirm the efficacy and safety of Good Manufacturing Practice (GMP)-compliant autologous cultivated limbal epithelial cell sheets in government-controlled clinical trials that adhered to Good Clinical Practice stipulations for patients with unilateral limbal stem cell deficiency (LSCD). DESIGN: A prospective, multicenter, open-label, uncontrolled, single-arm clinical trial. PARTICIPANTS: Ten consecutive eyes of 10 patients with unilateral LSCD were followed for 2 years after surgery. Preoperative LSCD stage was IIB in 4 eyes and III in 6 eyes. METHODS: A limbal tissue biopsy was obtained from the healthy eye, after which limbal stem cells were dissociated and cultivated on temperature-responsive culture surfaces. All cell sheets were fabricated in a GMP-grade facility under established standard operating procedures. Cell sheets were evaluated using defined shipment criteria before transplantation, and only those that met the criteria were used. The cell sheet was transplanted onto each of the patients' diseased eye after removing the conjunctival scar tissue that covered the corneal surface. The severity of LSCD was determined according to a staging method agreed on by global consensus, with eyes evaluated as being in stages IA-C representing successful corneal epithelial reconstruction. Diagnosis and staging of LSCD were determined by the trial's Eligibility Judgment Committee and Effect Assessment Committee using slit-lamp photographs including fluorescein staining. Both committees comprised 2 or 3 third-party cornea specialists, who were provided with information anonymously and randomly. MAIN OUTCOME MEASURE: Corneal epithelial reconstruction rate was the primary end point. RESULTS: Corneal epithelial reconstruction was successful in 6 of 10 eyes (60%) 1 year postoperatively and was significantly higher than the 15% clinically significant efficacy rate achieved by allogeneic limbal transplantation. The reconstruction rate was 70% of eyes 2 years postoperatively. Additionally, improvements in visual acuity were noted in 50% and 60% of eyes at 1 and 2 years, respectively. No clinically significant transplantation-related adverse events were observed. CONCLUSIONS: The efficacy and safety of cultivated limbal epithelial cell sheet transplantation were thus confirmed, and the cell sheet, named "Nepic," is now approved as a cellular and tissue-based product in Japan. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

High-Energy Computed Tomography as a Prospective Tool for In Situ Monitoring of Mass Transfer Processes inside High-Pressure Reactors-A Case Study on Ammonothermal Bulk Crystal Growth of Nitrides including GaN.

For the fundamental understanding and the technological development of the ammonothermal method for the synthesis and crystal growth of nitrides, an in situ monitoring technique for tracking mass transport of the nitride throughout the entire autoclave volume is desirable. The feasibility of using high-energy computed tomography for this purpose was therefore evaluated using ex situ measurements. Acceleration voltages of 600 kV were estimated to yield suitable transparency in a lab-scale ammonothermal setup for GaN crystal growth designed for up to 300 MPa operating pressure. The total scan duration was estimated to be in the order of 20 to 40 min, which was sufficient given the comparatively slow crystal growth speed in ammonothermal growth. Even shorter scan durations or, alternatively, lower acceleration voltages for improved contrast or reduced X-ray shielding requirements, were estimated to be feasible in the case of ammonoacidic growth, as the lower pressure requirements for this process variant allow for thinned autoclave walls in an adapted setup designed for improved X-ray transparency. Promising nickel-base and cobalt-base alloys for applications in ammonothermal reactors with reduced X-ray absorption in relation to the maximum operating pressure were identified. The applicability for the validation of numerical simulations of the growth process of GaN, in addition to the applicability of the technique to further nitride materials, as well as larger reactors and bulk crystals, were evaluated.

Outcome of Lamellar Graft Patching for the Treatment of Noninfectious Corneal Perforations.

PURPOSE: The aims of this study were to evaluate the clinical outcome of lamellar graft patching used for treating noninfectious corneal perforations and to determine the clinical factors affecting tectonic integrity. METHODS: This retrospective study includes a total of 71 eyes of 67 patients who underwent lamellar graft patching for the treatment of corneal perforations due to persistent epithelial defects secondary to limbal stem cell deficiency (LSCD, 21 eyes; 29.6%), peripheral ulcerative keratitis (17 eyes; 23.9%), neurotrophic keratitis due to herpes simplex keratitis (HSK, 14 eyes; 19.7%), and other causes (19 eyes; 26.8%). We evaluated the tectonic integrity of the globe, visual outcomes, and postoperative complications. RESULTS: Tectonic integrity was achieved in 53 eyes (74.6%). The survival proportions of eyes that achieved clear grafts were 77.8% and 65.2% at 12 and 24 months, respectively. Graft failure was observed in 19 eyes (26.8%). The survival rate of tectonic integrity and eyes that finally achieved a clear graft was significantly worse in eyes with LSCD compared with those without ( P < 0.001). The logarithm of minimal angle resolution improved significantly from 1.79 ± 0.98 to 1.22 ± 0.87 at 12 months and 1.08 ± 0.81 at 24 months. Postoperative complications included cataract formation (32 eyes, 45.1%), intraocular pressure rise (23 eyes, 32.4%), recurrent perforations (15 eyes, 21.1%), infectious keratitis (14 eyes, 19.7%), recurrence of herpes simplex keratitis (7 eyes, 9.9%), and traumatic graft dehiscence (1 eye, 1.4%). CONCLUSIONS: Lamellar graft patching is an effective and safe surgical treatment for noninfectious corneal perforations; however, careful attention to severe complications is necessary, especially in eyes with LSCD.

Trends in surgical procedures and indications for corneal transplantation over 27 years in a tertiary hospital in Japan.

PURPOSE: To characterize trends in procedures, and indications for corneal transplantation over 27 years in a single referral center in Japan. STUDY DESIGN: Retrospective study. METHODS: Data from a consecutive series of corneal transplant surgery cases performed from 1991 to 2017at Ichikawa General Hospital were collected. The surgical procedures, indications, and causes of corneal endothelial dysfunction were evaluated. RESULTS: Among 6,025 transplantations, a total of 3,991 cases underwent penetrating keratoplasty (PKP), 1009 underwent (deep) anterior lamellar keratoplasty, 746 underwent endothelial keratoplasty, and 309 underwent epithelial transplantation. Over that period the frequency of PKP decreased, whereas the frequency of lamellar keratoplasty increased. The four major surgical indications were bullous keratoplasty (BK 30.0%), regraft (24.2%), post-keratitis scars (17.1%), and keratoconus (11.4%). After dividing the study period into four time periods, we found that BK and regraft increased (from 20.3% to 34.5% and 18.2% to 31.1%, respectively), whereas post-keratitis scars and keratoconus decreased (from 26.0% to 9.5% and 14.1% to 7.2%, respectively) between the first and last period. Pseudophakic or aphakic BK were the major causes of corneal endothelial dysfunction until 2010. Cases of laser-iridotomy-induced BK peaked in 35 eyes (34.3% of BK) in 2000 and declined after 2013. Cases of Fuchs endothelial corneal dystrophy increased from 0 in 1991, to 15 eyes (18.5% of BK) in 2017. CONCLUSION: Lamellar keratoplasty has replaced PKP in our hospital. BK and regraft have increased, whereas post-keratitis scars and keratoconus have decreased. Laser-iridotomy-induced BK has decreased during the past decade, whereas Fuchs endothelial corneal dystrophy has increased.

Correlations between tear fluid and aqueous humor cytokine levels in bullous keratopathy.

PURPOSE: To evaluate the correlation between tear fluid and aqueous humor (AqH) cytokine levels in eyes with bullous keratopathy (BK) and with normal endothelium. METHODS: This prospective consecutive case-series study included 71 eyes of 71 patients: 31 eyes with BK, 18 eyes with non-BK corneal diseases, and 22 eyes with uncomplicated cataract (healthy controls). Total protein and cytokine (interleukin [IL]-1α, IL-1ß, IL-4, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, monocyte chemotactic protein [MCP]-1, E-selectin, P-selectin, soluble intercellular adhesion molecule [sICAM]-1, and IP-10) levels in the tear fluid and AqH were measured using multiplex beads immunoassay. The correlations between tear and AqH cytokine levels were assessed. RESULTS: The AqH protein level was significantly higher in BK eyes (1.09 ± 0.08 mg/mL) than in non-BK (0.63 ± 0.11, P = 0.0004) and healthy control (0.62 ± 0.06, P = 0.0002) eyes. The tear total protein and IL-4 levels were significantly higher in the BK group compared to healthy controls (P = 0.0374 and 0.0032, respectively). The AqH IL-8 and sICAM-1 levels were significantly higher in the BK group compared to controls (P = 0.0001 and 0.0083, respectively). In BK eyes, the tear IL-4 level was significantly correlated with the MCP-1(r = 0.563, P = 0.001) and total protein (r = 0.589, P = 0.001) AqH levels. The tear IL-8 level was significantly correlated with the MCP-1(r = 0.598, p = 0.001) and IL-4 (r = 0.781, p < 0.0001) AqH levels in BK eyes. However, no significant correlations were found between tear and AqH cytokine levels in non-BK and healthy controls eyes. CONCLUSIONS: The tear cytokine levels are correlated with those of AqH only in BK, but not in non-BK and healthy controls.

Pathological processes in aqueous humor due to iris atrophy predispose to early corneal graft failure in humans and mice.

Corneal endothelial cell (CEnC) loss after corneal transplantation is the major cause of graft failure and remains a clinically relevant challenge to overcome. Accumulated knowledge derived from long-term clinical outcomes suggested that elevated protein levels in the aqueous humor are associated with CEnC loss. However, the full spectrum of driver proteins and molecular processes remains to be determined. Here, we defined the somatic microenvironmental landscape and cellular response across human aqueous humor in samples with poor corneal transplantation clinical outcomes using multiomics analyses and clarified specific driver alterations, including complement activation and disturbed energy homeostasis. These driver alterations were also confirmed in aqueous humor from a novel murine model that spontaneously develops iris atrophy, leading to CEnC loss. The application of the integrative multiomics performed in human samples to the novel murine model will help the development of therapeutic modalities for patients with CEnC loss after corneal transplantation.

Effects of Amniotic Membrane-Derived Fibroblast Supernatant on Corneal Epithelium.

Purpose: To evaluate the effects of human amniotic membrane-derived fibroblast (AMF) cell supernatant (AMF-sup) on corneal epithelium. Methods: The phenotype of AMF cells was analyzed by flow cytometry using cell-surface markers. AMF cells were also induced to form osteoblasts and neural cells, and cell phenotypes were observed by staining and RT-PCR. Cultivated human corneal limbal epithelial sheets generated using AMF-sup were analyzed using immunohistochemistry and colony-forming efficiency, and the wound healing of epithelial defects was observed using a tissue-punch method. The effects of instillation of each supernatant in a rabbit corneal epithelial wound healing model were compared. Results: Mesenchymal stem cell (CD29, CD44, CD73, and CD90) and neural crest (CD49d and CD56) markers were expressed on the AMF cell surface. Following induction of differentiation, isolated AMF cells showed characteristics of osteoblasts and neural cells. Application of AMF-sup resulted in maintenance of the limbal epithelial phenotype and immature state, and significantly promoted wound healing in cultivated human corneal limbal epithelial sheets (P < 0.05) and rabbit corneal epithelium (P < 0.05) compared with the control. Conclusions: These data suggest that AMF cells have multi-differentiation potential, and that AMF-sup is effective in maintaining the limbal epithelial phenotype and promoting corneal epithelial wound healing, which may be of value in ocular surface reconstruction.

Descemet stripping automated endothelial keratoplasty performed by trainees.

PURPOSE: To assess the surgical outcomes of Descemet stripping automated endothelial keratoplasty (DSAEK) performed by trainees. STUDY DESIGN: Retrospective, case control comparative study. METHODS: This study compared cases performed by trainees with those performed by an experienced surgeon. First 10 cases of DSAEK performed by trainees with more than 6 months follow-up periods were recruited. The surgical outcomes of DSAEK performed by the trainees (Trainee group) were compared with disease-matched pairs of cases performed by an experienced surgeon (Experienced group). Graft clarity, best spectacle-corrected visual acuity, corneal endothelial cell density, and incidence of intra- or post-operative complications were studied. RESULTS: Forty-one pairs were recruited. The graft clarity rate was not different between the Trainee and Experienced groups, with 95.1% and 97.6%, respectively, maintaining clear grafts at 12 months postoperatively. Trainee best spectacle corrected visual acuity was significantly worse at 6 and 12 months postoperatively compared with the Experienced group, and percent decreases in corneal endothelial density was more in the Trainee group at 3 months following surgery (P = 0.0029). While intra- or late post-operative complication rates were similar in both groups, incidences of early post-operative complications such as double chamber formation or pupillary block were observed more frequently in the Trainee group than in the Experienced group (P = 0.049). CONCLUSION: DSAEK can be performed relatively safely by training physicians with careful preparation and supervision by attending physicians. However, careful case selection and education on management of air injected in the anterior chamber seemed to be a key to long-term success.

Impact of Corneal Higher-Order Aberrations on Visual Acuity After Deep Anterior Lamellar Keratoplasty in Treating Keratoconus.

PURPOSE: To evaluate the incidence of the Descemet membrane (DM) folds after deep anterior lamellar keratoplasty (DALK) in treating keratoconus. We also evaluated the influence of DM folds and corneal higher-order aberrations (HOAs) on visual acuity after DALK. METHODS: This retrospective study included 89 consecutive eyes of 87 patients who underwent DALK for the treatment of keratoconus at Tokyo Dental College Ichikawa General Hospital from April 2002 to June 2017. The presence or absence of DM folds was determined by slitlamp microscopy. Visual acuity after DALK was compared between the eyes with and without DM folds. Corneal HOAs of the anterior and posterior surfaces and the total cornea were measured by anterior segment optical coherence tomography. Correlations among the presence of DM folds, corneal HOAs, and visual acuity were analyzed. RESULTS: The Descemet membrane folds developed in 28.1% (25/89) eyes after DALK for the treatment of keratoconus. However, there were no significant differences in postoperative visual acuity between the eyes with and without DM folds at 1, 3, 6, and 12 months (P=0.739, P=0.106, P=0.223, and P=0.186, respectively). The visual acuity at 12 months was significantly correlated with corneal HOAs within a 4-mm diameter (anterior surface: R=0.546, P=0.003; total cornea: R=0.506, P=0.007). CONCLUSIONS: Larger corneal HOAs, but not the presence of DM folds, were associated with poor visual acuity after DALK. In treating advanced keratoconus with DALK, it is important to minimize postoperative corneal HOAs, although DALK improves visual acuity by reducing HOAs due to keratoconus.

Temperature dependent control of the solubility of gallium nitride in supercritical ammonia using mixed mineralizer.

Using a mass-loss method, we investigated the solubility change of gallium nitride (GaN) in supercritical ammonia with mixed mineralizers [ammonium chloride (NH4Cl) + ammonium bromide (NH4Br) and NH4Cl + ammonium iodide (NH4I)]. The solubilities were measured over the temperature range 450-550 °C, at 100 MPa. The solubility increased with NH4Cl mole fraction at 450 °C and 100 MPa. The temperature dependence of the solubility curve was then measured at an equal mole ratio of the two mineralizers. The slope of the solubility-temperature relationship in the mixed mineralizer was between those of the individual mineralizers. These results show that the temperature dependence of the solubility of GaN can be controlled by the mineralizer mixture ratio. The results of the van't Hoff plot suggest that the solubility species were unchanged over the investigated temperature range. Our approach might pave the way to realizing large, high-quality GaN crystals for future gallium-nitride electronic devices, which are increasingly on demand in the information-based age.

A Novel Entity of Corneal Diseases with Irregular Posterior Corneal Surfaces: Concept and Clinical Relevance.

Various corneal diseases, such as hereditary corneal dystrophies, corneal infection, and bullous keratopathy, cause corneal opacity, scarring, and edema, leading to severely decreased visual acuity and loss of vision. These diseases were regarded as corneal opacity diseases, and the decreased visual acuity was considered to be predominantly caused by corneal opacity. The influence of corneal irregular astigmatism on vision has been poorly understood to date, mainly because accurate quantification of irregular astigmatism has been technically challenging. We have performed detailed analyses of the corneal higher-order aberrations (HOAs) of the anterior and posterior surfaces and total cornea in corneal diseases, using an anterior segment imaging system combined with a ray-tracing method. Subsequently, we conducted correlation analyses between corneal HOAs and visual acuities and characterized the typical HOA patterns in the corneal diseases. Our recent studies demonstrated that corneal HOAs directly degrade visual acuity in eyes with mild-to-moderate corneal opacities, such as corneal dystrophies, corneal scarring, and bullous keratopathy. The findings also suggested that correction of corneal HOAs using rigid gas-permeable contact lenses is effective in eyes with a smooth posterior surface and useful in certain patients with corneal scarring to some extent. Our data will be useful for decision making regarding surgical interventions, based on the amount of corneal HOAs. Our results further indicate the clinical relevance of irregular astigmatism in the posterior surfaces in assessing the visual function of eyes with various corneal diseases.

Corneal Higher-order Aberrations and Visual Improvement Following Corneal Transplantation in Treating Herpes Simplex Keratitis.

PURPOSE: To examine corneal higher-order aberrations (HOAs) and visual improvement following corneal transplantation in treating corneal scar caused by herpes simplex keratitis (HSK). DESIGN: Retrospective consecutive case series. METHODS: This study included a total of 52 eyes: 18 eyes of normal subjects, and 34 eyes of consecutive patients with corneal scar owing to HSK who underwent penetrating keratoplasty (PKP, 17 eyes) or deep anterior lamellar keratoplasty (DALK, 17 eyes). HOAs of the anterior, posterior surfaces and the total cornea were analyzed by anterior segment optical coherence tomography. The correlations between corneal HOAs and visual improvement were also analyzed. RESULTS: Mean logarithm of the minimal angle of resolution (logMAR) visual acuity significantly improved from 1.40 ± 0.70 to 0.46 ± 0.45 after corneal transplantation (P < .0001). Mean corneal HOAs of the anterior surface significantly decreased after corneal transplantation (PKP: from 1.16 ± 0.59 µm to 0.58 ± 0.35 µm, P = .035, DALK: from 0.94 ± 0.57 µm to 0.37 ± 0.18 µm, P = .004). Visual acuity following corneal transplantation was correlated with the corneal HOAs at 12 months (r = 0.53, P = .01). Visual improvement at 3, 6, and 12 months was positively correlated with preoperative HOAs of the total cornea and posterior surface (all P < .01). CONCLUSIONS: Preoperative corneal HOAs were associated with the visual improvement in treating corneal scar caused by HSK. Thus, the preoperative assessment of corneal HOAs, especially of the posterior surface, is important in the decision to perform corneal transplantation in eyes with HSK.

Aetiology-specific comparison of long-term outcome of deep anterior lamellar keratoplasty for corneal diseases.

AIMS: To evaluate the long-term outcome of deep anterior lamellar keratoplasty (DALK) for the treatment of herpetic keratitis, keratoconus, stromal scars and corneal dystrophies. METHODS: This retrospective consecutive case study includes 275 consecutive eyes of 254 patients who underwent DALK; 35 eyes with herpetic keratitis, 114 eyes with stromal scar, 93 eyes with keratoconus and 67 eyes with corneal dystrophy. Exclusion criteria included therapeutic DALK for the treatment of descemetocele or infectious keratitis, and eyes with limbal stem cell deficiency. Patients were examined at 1, 3 and 6 months, and 1, 3 and 5 years after DALK. Graft survival rate, best corrected visual acuity (BCVA), endothelial cell density (ECD) and postoperative complications were evaluated. RESULTS: The mean postoperative follow-up duration was 51±41 months. The graft survival rate of all subjects was 96.8% at 1 year, 89.9% at 3 years, 83.5% at 5 years and 74.1% at 10 years. At 6 months, BCVA significantly improved from 1.14±0.54 to 0.22±0.21 in the keratoconus group, from 1.13±0.60 to 0.44±0.54 in the herpes group, from 1.00±0.59 to 0.49±0.38 in the stromal scar group and from 1.04±0.52 to 0.32±0.29 in the corneal dystrophy group (all, p<0.0001). BCVA stabilised after 6 months thereafter up to 5 years. ECD decreased just after DALK and maintained >1000 cell/mm(2) at 5 years in all groups. CONCLUSIONS: DALK provides good visual acuity with slight ECD decrease over long term in all groups.

Effects of corneal irregular astigmatism on visual acuity after conventional and femtosecond laser-assisted Descemet's stripping automated endothelial keratoplasty.

PURPOSE: To compare short-term outcomes of Descemet's stripping automated endothelial keratoplasty (DSAEK) using a graft prepared with either a femtosecond laser or a microkeratome. METHODS: Thirty-eight patients underwent DSAEK with grafts prepared with either a femtosecond laser (f-DSAEK; 21 eyes) or a microkeratome (m-DSAEK; 17 eyes). Visual acuity, endothelial cell density, regular astigmatism and irregular astigmatism were compared between the two groups preoperatively and at 1, 3, and 6 months post-operatively. Fourier analysis was conducted to calculate astigmatism of the anterior and posterior surfaces, and total cornea, using anterior segment optical coherence tomography (AS-OCT). RESULTS: Visual acuity (logMAR) improved from 1.20 ± 0.60 to 0.43 ± 0.25 after m-DSAEK (P < 0.001) and from 1.20 ± 0.57 to 0.77 ± 0.33 after f-DSAEK (P = 0.0028) at 6 months following DSAEK. Visual acuity after m-DSAEK was significantly better than after f-DSAEK at 1, 3, and 6 months (P < 0.05). AS-OCT corneal images revealed greater irregularities on the posterior surfaces of f-DSAEK grafts compared to m-DSAEK grafts. Irregular astigmatism of the total cornea and the posterior surface was significantly larger after f-DSAEK than after m-DSAEK, although there was no significant difference in irregular astigmatism of the anterior surface at 6 months. Postoperative visual acuity was significantly correlated with the postoperative irregular astigmatism of the total cornea (r = 0.6657 and P < 0.001) and the anterior (r = 0.416, P = 0.016) and posterior surfaces (r = 0.7046, P < 0.001). CONCLUSIONS: Visual outcomes after f-DSAEK were poor compared to conventional m-DSAEK due to an increase in irregular astigmatism caused by posterior surface irregularities.

Age-dependent alteration of intraocular soluble heparan sulfate levels and its implications for proliferative diabetic retinopathy.

PURPOSE: To assess the relationship between intraocular soluble heparan sulfate (HS) concentration and age in subjects with and without diabetic retinopathy. METHODS: Vitreous from subjects with idiopathic maculopathies (n=17), i.e., macula hole or epiretinal membrane, or nonproliferative diabetic retinopathy (non-PDR; n=5) and aqueous humor from subjects with PDR (n=16), non-PDR (n=7), or cataracts (n=15) was collected. The levels of HS and vascular endothelial growth factor (VEGF) were measured using enzyme-linked immunosorbent assay. Concentrations of sulfated glycosaminoglycan were determined through dimethylmethylene blue-based assay. The effect of the vitreal HS level on the binding of exogenous VEGF to surface-bound heparin was determined in vitro. RESULTS: The level of HS in vitreous samples from subjects with idiopathic maculopathies increased concomitantly with age (p=0.020, R²=0.327). Meanwhile, HS levels in aqueous humor were lower in PDR subjects than in non-PDR (p=0.003) and cataract subjects (p=0.007). However, the PDR subjects were significantly younger than the non-PDR subjects (p<0.001) or cataract subjects (p<0.001). When the three groups were controlled for age, the levels of HS glycosaminoglycans were no longer different between the three (p=0.247). The increasing level of HS or sulfated glycosaminoglycan in the vitreous was associated with its increased inhibitory effect on interaction between VEGF and surface heparin in vitro (p=0.014, R²=0.377). CONCLUSIONS: The HS level of the intraocular fluid increased with age. The possible link between low HS in intraocular fluid and increased localization of VEGF at the retinal surface may provide one explanation for the higher susceptibility of younger subjects with diabetes mellitus to developing PDR.