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Purpose: This study aimed to investigate the effects of subconjunctival injection of aflibercept, a soluble protein decoy for VEGFR-1 and VEGFR-2, on corneal angiogenesis and VEGFR-expressing CD11b+ cells in a mouse model of suture-induced corneal neovascularization. Methods: Corneal neovascularization was induced in BALB/c mice by placing three sutures on the cornea. Immediately after surgery, either 200 µg aflibercept (5 µL) or an equal volume of phosphate-buffered saline (PBS) was administered into the subconjunctival space. Seven days after later, corneal new vessels were quantified through clinical examination and measurement of the CD31-stained area in corneal flat mounts. The levels of pro-angiogenic and inflammatory markers in the cornea were evaluated using RT-qPCR. The percentages of VEGFR-2+CD11b+ cells and VEGFR-3+CD11b+ cells were analyzed in the cornea, blood, and draining cervical lymph nodes (DLNs) using flow cytometry. Results: Subconjunctival injection of aflibercept significantly reduced the growth of corneal new vessels compared to subconjunctival PBS injection. The mRNA levels of Cd31, vascular growth factors (Vegfc and Angpt1), and pro-angiogenic/inflammatory markers (Tek/Tie2, Mrc1, Mrc2, and Il6) in the cornea were downregulated by subconjunctival aflibercept. Also, the percentage of VEGFR-3+CD11b+ cells in the cornea, blood, and DLNs was decreased by aflibercept, whereas that of VEGFR-2+CD11b+ cells was unaffected. Conclusion: Subconjunctival aflibercept administration inhibits inflammatory angiogenesis in the cornea and reduces the numbers of cornea-infiltrating and circulating VEGFR-3+CD11b+ cells. Key messages: What is known: • Aflibercept inhibits hemangiogenesis in the eye by interfering with the VEGF-A/VEGFR-2 signaling. What is new: • Subconjunctival aflibercept downregulates the VEGF-C and angiopoietin signaling in the cornea. • Subconjunctival aflibercept reduces both circulating and cornea-infiltrating VEGFR-3+CD11b+ myeloid cells. [ABSTRACT FROM AUTHOR]

Pterygium is an abnormal growth of fibrous conjunctival tissue that invades the cornea, resulting in corneal distortion, astigmatism, and increased higher-order aberrations (HOAs). However, few studies have compared eyes with pterygium to normal fellow eyes when interpreting HOAs and there is no study that revealed the effect of the thickness or grading of the pterygium on the change of HOAs. Therefore, we evaluated the effects of nasal pterygium by comparing the normal fellow eye of 59 patients. The pterygium significantly increased with-the-rule corneal astigmatism and corneal irregularity. Trefoils, horizontal coma, and quatrefoils were significantly induced by the pterygium. The grading of the pterygium was not correlated with its characteristics except for the thickness. In multiple linear regression analysis, pterygium-induced corneal astigmatic/irregularity values and horizontal trefoil/quatrefoil were associated with the area of the pterygium. The length of the pterygium was an independent inducer of oblique trefoil/quatrefoil, while horizontal coma was independently associated with both its length and width. The thickness was not correlated with any optical parameters. Together, the results demonstrate that nasal pterygium significantly induces corneal astigmatism, irregularity and some HOAs. These pterygium-associated changes in optical parameters could be predicted by the length, width and area of the pterygium. [ABSTRACT FROM AUTHOR]

Background: Reported bacteraemia outcomes following inactive empirical antibiotics (based on in vitro testing) are conflicting, potentially reflecting heterogeneity in causative species, MIC breakpoints defining resistance/susceptibility, and times to rescue therapy.Methods: We investigated adult inpatients with Escherichia coli bacteraemia at Oxford University Hospitals, UK, from 4 February 2014 to 30 June 2021 who were receiving empirical amoxicillin/clavulanate with/without other antibiotics. We used Cox regression to analyse 30 day all-cause mortality by in vitro amoxicillin/clavulanate susceptibility (activity) using the EUCAST resistance breakpoint (>8/2 mg/L), categorical MIC, and a higher resistance breakpoint (>32/2 mg/L), adjusting for other antibiotic activity and confounders including comorbidities, vital signs and blood tests.Results: A total of 1720 E. coli bacteraemias (1626 patients) were treated with empirical amoxicillin/clavulanate. Thirty-day mortality was 193/1400 (14%) for any active baseline therapy and 52/320 (16%) for inactive baseline therapy (P = 0.17). With EUCAST breakpoints, there was no evidence that mortality differed for inactive versus active amoxicillin/clavulanate [adjusted HR (aHR) = 1.27 (95% CI 0.83-1.93); P = 0.28], nor of an association with active aminoglycoside (P = 0.93) or other active antibiotics (P = 0.18). Considering categorical amoxicillin/clavulanate MIC, MICs > 32/2 mg/L were associated with mortality [aHR = 1.85 versus MIC = 2/2 mg/L (95% CI 0.99-3.73); P = 0.054]. A higher resistance breakpoint (>32/2 mg/L) was independently associated with higher mortality [aHR = 1.82 (95% CI 1.07-3.10); P = 0.027], as were MICs > 32/2 mg/L with active empirical aminoglycosides [aHR = 2.34 (95% CI 1.40-3.89); P = 0.001], but not MICs > 32/2 mg/L with active non-aminoglycoside antibiotic(s) [aHR = 0.87 (95% CI 0.40-1.89); P = 0.72].Conclusions: We found no evidence that EUCAST-defined amoxicillin/clavulanate resistance was associated with increased mortality, but a higher resistance breakpoint (MIC > 32/2 mg/L) was. Additional active baseline non-aminoglycoside antibiotics attenuated amoxicillin/clavulanate resistance-associated mortality, but aminoglycosides did not. Granular phenotyping and comparison with clinical outcomes may improve AMR breakpoints. [ABSTRACT FROM AUTHOR]

To investigate the effect of fucosyltransferase (FUT) 1-mediated fucosylation on meibomian glands (MG), we first confirmed that FUT1 and its fucosylated products were expressed in the eyelid, conjunctiva and skin in wild-type (WT) mice, whereas their mRNA and protein levels were downregulated in Fut1 knock-out (KO) mice. We then evaluated age-dependent changes in the total and acinar areas of MG, meibocyte differentiation, lipid synthesis, and eyelid inflammation and oxidative stress in Fut1 KO and WT mice. Results show that both the total and acinar areas of MG were smaller in Fut1 KO mice than in WT mice in all evaluated age groups. Meibocyte differentiation, lipid-producing capacities and the enzyme levels responsible for lipid synthesis were reduced in Fut1 KO mice, compared to WT controls. The levels of pro-inflammatory cytokines and oxidative-stress-related markers were elevated in the eyelids and MG of FUT1 KO mice. These findings demonstrate the physiologic function of FUT1-mediated fucosylation in MG development and function, and indicate its potential role in ocular surface homeostasis. [ABSTRACT FROM AUTHOR]

Objective: We investigated whether (1) imported pre-cut tissue is feasible for Descemet membrane endothelial keratoplasty (DMEK) in eyes of Asian patients, (2) the clinical outcome is comparable between the endothelium‐in and endothelium‐out methods, and (3) the corneal edema-induced anterior curvature changes may have an effect on the refractive error. Methods: The medical records of 32 DMEK patients who underwent either the endothelium-out or endothelium-in method using imported pre-cut grafts with a 3-day pre-cut-to-use time were retrospectively analyzed. Fuchs' endothelial dystrophy (37.5%) and bullous keratopathy (62.5%) cases were included. The main clinical outcome measures were graft survival, best corrected visual acuity (BCVA), endothelial cell density (ECD), corneal thickness (CT), and complications. Correlation of the anterior curvature changes with refractive error was analyzed in the DMEK with cataract surgery group. Results: The overall survival rate was 71.9%. Final graft failures were caused by rejection, glaucoma, and infection. Visual acuities improved by 89.3%. BCVA better than 20/40 and 20/20 was found in 75% and 28.6% of patients, respectively. The ECDs at 3 months and 1 year were 1400 and 1083 cells/mm2, respectively. The mean survival time, ECD, BCVA, CT, and complication rates were not different between the endothelium-in and endothelium-out methods. A hyperopic shift by +0.42 D was not related to the anterior curvature changes. Conclusion: Imported pre-cut tissues with a ≤ 3-day pre-cut-to-use time are feasible for DMEK in the treatment of corneal endothelial edema in eyes of Asian patients, and both endothelium-in and endothelium-out methods appear to be comparatively effective. Edema-induced anterior curvature change may not affect the refractive shift. [ABSTRACT FROM AUTHOR]

Background: While aging is a potent risk factor of dry eye disease, age-related gut dysbiosis is associated with inflammation and chronic geriatric diseases. Emerging evidence have demonstrated that gut dysbiosis contributes to the pathophysiology or exacerbation of ocular diseases including dry eye disease. However, the relationship between aging-related changes in gut microbiota and dry eye disease has not been elucidated. In this pilot study, we investigated the association between aging-dependent microbiome changes and dry eye severity in C57BL/6 male mice. Results: Eight-week-old (8 W, n = 15), one-year-old (1Y, n = 10), and two-year-old (2Y, n = 8) C57BL/6 male mice were used. Dry eye severity was assessed by corneal staining scores and tear secretion. Bacterial genomic 16 s rRNA from feces was analyzed. Main outcomes were microbiome compositional differences among the groups and their correlation to dry eye severity. In aged mice (1Y and 2Y), corneal staining increased and tear secretion decreased with statistical significance. Gut microbiome α-diversity was not different among the groups. However, β-diversity was significantly different among the groups. In univariate analysis, phylum Firmicutes, Proteobacteria, and Cyanobacteria, Firmicutes/Bacteroidetes ratio, and genus Alistipes, Bacteroides, Prevotella, Paraprevotella, and Helicobacter were significantly related to dry eye severity. After adjustment of age, multivariate analysis revealed phylum Proteobacteria, Firmicutes/Bacteroidetes ratio, and genus Lactobacillus, Alistipes, Prevotella, Paraprevotella, and Helicobacter to be significantly associated with dry eye severity. Conclusions: Our pilot study suggests that aging-dependent changes in microbiome composition are related to severity of dry eye signs in C57BL/6 male mice. [ABSTRACT FROM AUTHOR]

In this report we use a case study of risk of sudden unexpected death in epilepsy (SUDEP) to illustrate the contribution of systematic literature reviews of disease-specific ethical issues (DSEI). In particular, we show how ethically-relevant empirical data from such reviews can be used in the examination of the reasons for and against a particular normative approach to our DSEI. That is, we have attempted to offer a normative recommendation in response to the question of whether or not the risk of SUDEP should be disclosed to all patients. This case study functions as a form of empirical bioethics by providing a means of assessing empirical claims underlying reasons. As a result of this process, we are then able to provide clear and transparent, if not definitive, justification for a normative recommendation in response to a question of interest. [ABSTRACT FROM AUTHOR]

Purpose: To determine the incidence of spontaneous regression of congenital corneal opacity (CCO) and identify clinical factors associated with the regression. Methods: Medical records and anterior segment photographs were reviewed of 57 eyes in 35 patients with CCO that were not related to congenital glaucoma, tumors, infection, trauma, or metabolic disorders and were followed up without corneal transplantation for longer than one year at Seoul National University Hospital. Spontaneous regression of corneal opacity was defined as a decrease in corneal opacity significant enough for visual axis clearance. Data on demographics, systemic, and ocular characteristics were collected and compared between patients who had spontaneous regression of CCO and those who did not. Results: Spontaneous regression of corneal opacity developed in 32 eyes (22 patients, 56.1%) out of 57 CCO eyes (35 patients) at the mean 8.2 ± 5.4 months of age (the median 6.7 months). Absence of combined ocular anomalies such as iris anomaly, lens opacity, and peripheral corneal vascularization was significantly associated with the regression of opacity. Conclusions: Corneal opacity can spontaneously regress in 56.1% of eyes with CCO during the first year of life. Careful follow-up with amblyopia management can be one of treatment options for CCO. [ABSTRACT FROM AUTHOR]

Background: Mobile phone apps have been shown to enhance guideline adherence by prescribers, but have not been widely evaluated for their impact on guideline adherence by prescribers caring for inpatients with infections. Objectives: To determine whether providing the Auckland City Hospital (ACH) antibiotic guidelines in a mobile phone app increased guideline adherence by prescribers caring for inpatients with community acquired pneumonia (CAP) or urinary tract infections (UTIs). Methods: We audited antibiotic prescribing during the first 24 hours after hospital admission in adults admitted during a baseline and an intervention period to determine whether provision of the app increased the level of guideline adherence. To control for changes in prescriber adherence arising from other factors, we performed similar audits of adherence to antibiotic guidelines in two adjacent hospitals. Results: The app was downloaded by 145 healthcare workers and accessed a total of 3985 times during the three month intervention period. There was an increase in adherence to the ACH antibiotic guidelines by prescribers caring for patients with CAP from 19% (37/199) to 27% (64/237) in the intervention period (p = 0.04); but no change in guideline adherence at an adjacent hospital. There was no change in adherence to the antibiotic guidelines by prescribers caring for patients with UTI at ACH or at the two adjacent hospitals. Conclusions: Provision of antibiotic guidelines in a mobile phone app can significantly increase guideline adherence by prescribers. However, providing an app which allows easy access to antibiotic guidelines is not sufficient to achieve high levels of prescriber adherence. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effect of tacrolimus ointment on corneal epithelium. Methods: Eight-week-old male BALB/c mice were divided into 3 groups. In group 1, no injury was made. In group 2, the central 2-mm corneal epithelium was scraped off. In group 3, the whole corneal and limbal epithelium was removed after absolute ethanol application. In each group, the corneas were observed and treated daily with 0.03% or 0.1% tacrolimus ointment (Protopic®). The viability of cultivated human corneal epithelial cells was also examined after 24-h incubation with various concentrations of tacrolimus. Results: Tacrolimus ointment significantly delayed the epithelial healing in corneas with epithelial injuries (groups 2 and 3) in dose- and frequency-dependent manners, whereas it did not have any effects on uninjured corneas (group 1). The proportion of terminal deoxynucleotidyl transferase-mediated nick end labeling-positive cells and mRNA levels of inflammatory cytokines were higher in tacrolimus-treated corneas, compared with controls. Tacrolimus did not directly reduce the viability of corneal epithelial cells in culture. Conclusions: Topical application of tacrolimus ointment onto the ocular surface induced toxicity in the cornea with epithelial defects through the impairment of epithelial healing and induction of apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: Background: Safety concerns exist for corneal recipients under immunosuppression. We report long‐term safety results of porcine corneal xenotransplantation under immunosuppression in nonhuman primates. Methods: Systemic monitoring data from 49 Chinese rhesus macaques that received pig corneal transplant between 2009 and 2018 were retrospectively reviewed. The recipients were divided into 4 groups depending on the systemic immunosuppressants used: (a) conventional steroid group; costimulation blockade groups ([b] anti‐CD154 antibody, [c] anti‐CD40 antibody); and (d) commercially available immunosuppressants (anti‐CD20 antibody, tacrolimus, basiliximab) group. We compared results of general condition monitoring; hematologic, biochemical, and electrolyte tests; and Rhesus Cytomegalovirus infection monitoring. Results: All recipients recovered from early weight loss. White blood cell counts significantly decreased at 6 months in the steroid and anti‐CD154 groups. Abnormal liver and kidney function and electrolyte imbalance were not observed in all groups. The mean value of Rhesus Cytomegalovirus DNA copies was consistently lower than 200 copies/mL, and antibody titers did not change over time in all groups. Tacrolimus‐associated thrombotic microangiopathy was developed in one case, which resolved after discontinuation of tacrolimus. In 2017, a simian varicella virus outbreak led to clinical signs in 5 that received immunosuppressive therapies, of which 3 died. Conclusion: Costimulatory blockade‐based and anti‐CD20 antibody/tacrolimus‐based immunosuppressive therapies seem to be comparably safe with steroid therapy in nonhuman primates receiving corneal xenotransplantation, as they did not reactivate Rhesus Cytomegalovirus and maintained manageable systemic status. Although reactivation is rare, antiviral prophylaxis for simian varicella virus should be considered in immunocompromised hosts. [ABSTRACT FROM AUTHOR]

To improve the strain properties of Bi-based lead-free ceramics at lower electric fields, ferroelectric 0.82(Bi1/2Na1/2)TiO3-0.18(Bi1/2K1/2)TiO3(BNKT) seed particles were embedded in Bi0.5(Na0.385K0.09Li0.025)(Ti0.975Ta0.025)O3(BNKLTT) ceramics exhibiting relaxor behaviour using a conventional solid-state reaction. The unipolar strain versus electric field hysteresis loops of the BNKT-BNKLTT composites resulted in a maximum Smax/Emaxof 761 pm/V at 4 kV/mm when 30 wt.% BNKT particles were added, which was higher than that of the single ferroelectric or relaxor phase. [ABSTRACT FROM AUTHOR]

Abstract: Guidelines for the multiple sleep latency test (MSLT) were published in 1986 and updated in 2005. Individual interpretation of instructions may lead to variability in conducting and reporting the test with implications for diagnosis. Objective: To assess variability in conducting MSLT among sleep laboratories in Europe. Methods: A questionnaire based on the clinical MSLT guidelines was posted or emailed to 283 sleep centres in Europe. Results: Ninety adult laboratories performing MSLT returned the questionnaire. Indications for MSLT were: narcolepsy, excessive daytime somnolence, driving issues and assessment of wakefulness. Routinely, only 17% of laboratories performed urinary drug screening and 68.2% asked patients to complete sleep diaries. Overnight polysomnography before MSLT was ran in 87.5% of laboratories. There was variation in setup and instructions among countries. Sleep onset was scored as one epoch of any stage sleep by 65.9% of labs. REM latency was calculated and reported according to the 2005 guidelines in 73.7% of cases. Abnormal daytime sleepiness was considered to be a sleep latency⩽5min in 33% laboratories. Conclusion: There is marked variability in the practice and interpretation of the MSLT in Europe. [Copyright &y& Elsevier]

Abstract: A counter electrode was prepared for a dye-sensitized solar cell (DSSC) through electrochemical deposition of mesoporous platinum on fluorine-doped tin oxide glass in the presence of a structure-directing nonionic surfactant, octaethylene glycol monohexadecyl ether (C16EO8). The DSSC fabricated with the electrochemically deposited Pt (ED-Pt) counter electrode rendered a higher solar-to-electricity conversion efficiency of 7.6%, compared with approximately 6.4% of the cells fabricated with the sputter-deposited or most commonly-employed thermal deposited Pt counter electrodes. This enhanced efficiency is attributed to the higher short-circuit photocurrent arising from the increases in the active surface area and light reflection as well as the decrease in the sheet resistance of the ED-Pt film, relative to those of the Pt films prepared by the other two deposition methods. The sputter-deposited Pt film yielded almost the same photovoltaic characteristics as the thermal deposited Pt film. The Pt films were characterized by FE-SEM, AFM, cyclic voltammetry, chronoamperometry, electrochemical impedance spectroscopy, sheet resistance measurements, adhesion tests, and light reflection tests. [Copyright &y& Elsevier]

Fucosylation is involved in a wide range of biological processes from cellular adhesion to immune regulation. Although the upregulation of fucosylated glycans was reported in diseased corneas, its implication in ocular surface disorders remains largely unknown. In this study, we analyzed the expression of a fucosylated glycan on the ocular surface in two mouse models of dry eye disease (DED), the NOD.B10.H2b mouse model and the environmental desiccating stress model. We furthermore investigated the effects of aberrant fucosylation inhibition on the ocular surface and DED. Results demonstrated that the level of type 2 H antigen, an α(1,2)-fucosylated glycan, was highly increased in the cornea and conjunctiva both in NOD.B10.H2b mice and in BALB/c mice subjected to desiccating stress. Inhibition of α(1,2)-fucosylation by 2-deoxy-D-galactose (2-D-gal) reduced corneal epithelial defects and increased tear production in both DED models. Moreover, 2-D-gal treatment suppressed the levels of inflammatory cytokines in the ocular surface and the percentages of IFN-γ+CD4+ cells in draining lymph nodes, whereas it did not affect the number of conjunctival goblet cells, the MUC5AC level or the meibomian gland area. Together, the findings indicate that aberrant fucosylation underlies the pathogenesis of DED and may be a novel target for DED therapy. [ABSTRACT FROM AUTHOR]

Purpose: To describe a case of macular hole (MH) formation secondary to bacterial septic embolism and demonstrate the changing thereof using serial spectral-domain optical coherence tomography (SD-OCT) images. Methods: A single case report. Results: A 69-year-old woman who had been diagnosed with Klebsiella pneumonia septicemia was referred for decreased vision in her left eye. Impending MH was detected by SD-OCT and retinitis with multiple retinal hemorrhages by funduscopy. One week after the initial visit, a full-thickness MH had formed, and 13 weeks after the initial visit, we were able to close the MH following vitrectomy and gas tamponade. The MH was formed by retinal thinning due to outer retinal disruption without vitreomacular traction. Conclusion: Metastatic retinal septic embolism and consequent outer retinal disruption can cause MH. Ophthalmologists must be aware of the possibility of MH in cases of retinal metastatic bacterial septic embolism, especially if the lesion infiltrates the fovea. [ABSTRACT FROM AUTHOR]

The search for alternatives to allotransplants is driven by the shortage of corneal donors and is demanding because of the limitations of the alternatives. Indeed, current progress in genetically engineered (GE) pigs, the introduction of gene-editing technology by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9, and advanced immunosuppressants have made xenotransplantation a possible option for a human trial. Porcine corneal xenotransplantation is considered applicable because the eye is regarded as an immune-privileged site. Furthermore, recent non-human primate studies have shown long-term survival of porcine xenotransplants in keratoplasty. Herein, corneal immune privilege is briefly introduced, and xenogeneic reactions are compared with allogeneic reactions in corneal transplantation. This review describes the current knowledge on special issues of xenotransplantation, xenogeneic rejection mechanisms, current immunosuppressive regimens of corneal xenotransplantation, preclinical efficacy and safety data of corneal xenotransplantation, and updates of the regulatory framework to conduct a clinical trial on corneal xenotransplantation. We also discuss barriers that might prevent xenotransplantation from becoming common practice, such as ethical dilemmas, public concerns on xenotransplantation, and the possible risk of xenozoonosis. Given that the legal definition of decellularized porcine cornea (DPC) lies somewhere between a medical device and a xenotransplant, the preclinical efficacy and clinical trial data using DPC are included. The review finally provides perspectives on the current standpoint of corneal xenotransplantation in the fields of regenerative medicine. [ABSTRACT FROM AUTHOR]

Using metagenomics, continuing evidence has elicited how intestinal microbiota trigger distant autoimmunity. Sjögren's syndrome (SS) is an autoimmune disease that affects the ocular surface, with frequently unmet therapeutic needs requiring new interventions for dry eye management. Current studies also suggest the possible relation of autoimmune dry eye with gut microbiota. Herein, we review the current knowledge of how the gut microbiota interact with the immune system in homeostasis as well as its influence on rheumatic and ocular autoimmune diseases, and compare their characteristics with SS. Both rodent and human studies regarding gut microbiota in SS and environmental dry eye are explored, and the effects of prebiotics and probiotics on dry eye are discussed. Recent clinical studies have commonly observed a correlation between gut dysbiosis and clinical manifestations of SS, while environmental dry eye portrays characteristics in between normal and autoimmune. Moreover, a decrease in both the Firmicutes/Bacteroidetes ratio and genus Faecalibacterium have most commonly been observed in SS subjects. The presumable pathways forming the "gut dysbiosis–ocular surface–lacrimal gland axis" are introduced. This review may provide perspectives into the link between the gut microbiome and dry eye, enhance our understanding of the pathogenesis in autoimmune dry eye, and be useful in the development of future interventions. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the outcome of therapeutic penetrating keratoplasty (TPK) for medically-uncontrolled infectious keratitis, and to determine the factors associated with the recurrence of infection after TPK. Methods: A 10-year retrospective study of medically-uncontrolled infectious keratitis with positive culture results, who received TPK at a tertiary referral center in Korea was performed. Data collection included patient demographics, medical history, pre- and post-operative findings, surgical procedures, causative microorganisms, and visual acuities (VA). The primary outcome measure was the recurrence of infection after TPK, and the factors were compared between patients with and without recurrence. Results: A total of 19 patients (19 eyes) were analyzed, of which 6 eyes (31.6%) had infection recurrence at 21.6 ± 22.84 months after TPK. Recurrence occurred more frequently in the female sex (vs. male, p = 0.013) and in longer duration (>30 days) from infection onset to TPK (vs. ≤30 days, p = 0.025). Final best-corrected-VA was poorer in patients with recurrence than those without (LogMAR 1.60 ± 0.97 vs. 2.40 ± 0.46, p = 0.026). Evisceration was performed in 2 out of 6 patients with recurrence (33.3%), while none was performed in those without recurrence (p = 0.028). Conclusion: Infection recurrence after TPK was 31.6%. Given the poor outcome of TPK in eyes with recurrence, close monitoring and intensive treatment are required post-TPK. [ABSTRACT FROM AUTHOR]

It is not known how biological changes in the lacrimal (LGs) and meibomian (MGs) glands contribute to dry eye disease (DED) in a time-dependent manner. In this study, we investigated time-sequenced changes in the inflammation, oxidative stress, and senescence of stem cells in both glands of an aging-related DED mouse model. Eight-week (8W)-, one-year (1Y)-, and two-year (2Y)-old C57BL/6 male mice were used. MG areas of the upper and lower eyelids were analyzed by transillumination meibography imaging. The number of CD45+, 8-OHdG+, Ki-67+, and BrdU+ cells was compared in both glands. Increased corneal staining and decreased tear secretion were observed in aged mice. The MG dropout area increased with aging, and the age-adjusted MG area in lower lids was negatively correlated with the National Eye Institute (NEI) score. Increased CD4+ interferon (IFN)-γ+ cells in LGs were found in both aged mice. An increase in 8-OHdG+ cells in both glands was evident in 2Y-old mice. Reduced Ki-67+ cells, but no change in CD45+ cells, was observed in the MGs of 1Y-old mice. Increased BrdU+ cells were observed in the LGs of aged mice. This suggests that age-dependent DED in C57BL/6 mice is related to inflammation of the LGs, the development of MG atrophy, and oxidative stress in both glands. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the agreement of ocular biometry measured using a swept-source optical coherence (Casia 2) and a dual Scheimpflug (Galilei G6) tomography in keratoconus. Methods: This retrospective study included 102 eyes from 102 keratoconus patient examined using both devices. Parameters compared included flat (Kf) and steep (Ks) keratometry, astigmatism of anterior, posterior, and total keratometry, central (CCT) and thinnest (TCT) corneal thickness. To assess the agreement, intraclass coefficient (ICC) and Bland-Altman analysis with 95% limits of agreement (LoA) were used. Results: Anterior and total Ks and Kf showed moderate or good agreement with 95% limits of agreement (LoA) range over 9.75 D. Posterior Ks and Kf were lower in the Galilei G6 (all p < 0.001). Astigmatism showed moderate, poor, and moderate agreement for anterior, posterior, and total keratometry, respectively. CCT and TCT showed excellent agreement; however, the 95% LoA range was over 60 μm. Conclusion: The agreement between the two devices was not excellent for most parameters used to diagnose keratoconus and assess disease progression, and the differences were clinically significant. Therefore, the measurements from these two devices are not interchangeable for patients with keratoconus. [ABSTRACT FROM AUTHOR]

Background: We aimed to investigate (a) the long‐term survival of corneal grafts from α1,3‐galactosyltransferase gene‐knockout miniature (GTKOm) pigs in non‐human primates as a primary outcome and (b) the effect of anti‐CD20 antibody on the survival of corneal grafts from GTKOm pigs as a secondary outcome. Methods: Nine rhesus macaques undergoing full‐thickness corneal xenotransplantation using GTKOm pigs were systemically administered steroid, basiliximab, intravenous immunoglobulin, and tacrolimus with (CD20 group) or without (control group) anti‐CD20 antibody. Results: Graft survival was significantly longer (P =.008) in the CD20 group (>375, >187, >187, >83 days) than control group (165, 91, 72, 55, 37 days). When we compared the graft survival time between older (>7‐ month‐old) and younger (≤7‐month‐old) aged donor recipients, there was no significant difference. Activated B cells were lower in the CD20 group than control group (P =.026). Aqueous humor complement C3a was increased in the control group at last examination (P =.043) and was higher than that in the CD20 group (P =.014). Anti‐αGal IgG/M levels were unchanged in both groups. At last examination, anti‐non‐Gal IgG was increased in the control group alone (P =.013). Conclusions: The GTKOm pig corneal graft achieved long‐term survival when combined with anti‐CD20 antibody treatment. Inhibition of activated B cells and complement is imperative even when using GTKO pig corneas. [ABSTRACT FROM AUTHOR]

We investigated the predictive biomarkers for graft rejection in pig‐to‐non‐human primate (NHP) full‐thickness corneal xenotransplantation (n = 34). The graft score (0‐12) was calculated based on opacity, edema, and vascularization. Scores ≥ 6 were defined as rejection. NHPs were divided into two groups: (a) graft rejection within 6 months; and (b) graft survival until 6 months. In the evaluation of 2‐week biomarkers, none of the NHPs showed rejection within 2 weeks and the 34 NHPs were divided into two groups: (a) entire rejection group (n = 16); and (b) survival group (n = 18). In the evaluation of 4‐week biomarkers, four NHPs showing rejection within 4 weeks were excluded and the remaining 30 NHPs were divided into two groups: (a) late rejection group (n = 12); and (b) survival group (n = 18). Analysis of biomarker candidates included T/B‐cell subsets, levels of anti‐αGal IgG/M, donor‐specific IgG/M from blood, and C3a from plasma and aqueous humor (AH). CD8+IFNγ+ cells at week 2 and AH C3a at week 4 were significantly elevated in the rejection group. Receiver operating characteristic areas under the curve was highest for AH C3a (0.847) followed by CD8+IFNγ+ cells (both the concentration and percentage: 0.715), indicating excellent or acceptable discrimination ability, which suggests that CD8+IFNγ+ cells at week 2 and AH C3a at week 4 are reliable biomarkers for predicting rejection in pig‐to‐NHP corneal xenotransplantation. [ABSTRACT FROM AUTHOR]

Background: The collection and analysis of alert logs are necessary for hospital administrators to understand the types and distribution of alert categories within the organization and reduce alert fatigue. However, this is not readily available in most homegrown Computerized Physician Order Entry (CPOE) systems. Objective: To present a novel method that can collect alert information from a homegrown CPOE system (at an academic medical center in Taiwan) and conduct a comprehensive analysis of the number of alerts triggered and alert characteristics. Methods: An alert log collector was developed using the Golang programming language and was implemented to collect all triggered interruptive alerts from a homegrown CPOE system of a 726-bed academic medical center from November 2017 to June 2018. Two physicians categorized the alerts from the log collector as either clinical or non-clinical (administrative). Results: Overall, 1,625,341 interruptive alerts were collected and classified into 1,474 different categories based on message content. The sum of the top 20, 50, and 100 categories of most frequently triggered alerts accounted for approximately 80, 90 and 97 percent of the total triggered alerts, respectively. Among alerts from the 100 most frequently triggered categories, 1,266,818 (80.2%) were administrative and 312,593 (19.8%) were clinical alerts. Conclusion: We have successfully developed an alert log collector that can serve as an extended function to retrieve alerts from a homegrown CPOE system. The insight generated from the present study could also potentially bring value to hospital system designers and hospital administrators when redesigning their CPOE system. [ABSTRACT FROM AUTHOR]

Background: Xenotransplantation using fresh porcine corneas has been suggested as a feasible alternative to overcome the shortage of human donor corneas. Successful long‐term survival of grafts without evidence of xenozoonosis in clinically applicable pig‐to‐non‐human primate corneal transplantation model has brought researchers close to human clinical trials. Accordingly, we aimed to prepare a clinical trial protocol to conduct the first corneal xenotransplantation. Methods: We developed the clinical trial protocol based on international consensus statement on conditions for undertaking clinical trials of corneal xenotransplantation developed by the International Xenotransplantation Society. Detailed contents of the protocol have been modified with reference to comments provided by ophthalmologists and multidisciplinary experts, including an infectionist, an organ transplantation specialist, a clinical pharmacologist, a neuropsychiatrist, a laboratory medicine doctor, and a microbiologist. Results: Two patients with bilateral legal corneal blindness (best‐corrected visual acuity ≤20/200 in the better eye and ≤20/1000 in the candidate eye) or with (impending) corneal perforation will be enrolled. During the screening period, participants and their family members will have two separate deep consideration periods before signing informed consent forms. Each patient will undergo corneal xenotransplantation using fresh corneas from Seoul National University miniature pigs. Commercially available immunosuppressants will be administered and systemic infection prophylaxis will be performed according to the program schedule. After transplantation, each patient will be monitored at a specialized clinic to investigate safety up to 2 years and efficacy up to 1 year. Conclusions: A detailed clinical trial protocol for the first corneal xenotransplantation reflecting the global guidelines is provided. [ABSTRACT FROM AUTHOR]

Objective: To investigate gut dysbiosis in patients with Sjögren's syndrome (SS) or dry eye syndrome (DES) compared to normal subjects and to evaluate the association of dysbiosis with dry eye severity. Methods: 10 subjects with SS, 14 subjects with DES and 12 controls were enrolled. Corneal staining, tear break up time (TBUT) and tear secretion were evaluated. Bacterial genomic 16s rRNA from stool samples were analyzed. Main outcomes were microbiome compositional differences among groups and their correlation to dry eye signs. Results: Gut microbiome analysis revealed significant compositional differences in SS compared to controls and DES. In phylum, Bacteriodetes increased, while Firmicutes/Bacteroidetes ratio and Actinobacteria decreased (p<0.05). In genus, Bifidobacterium was reduced (vs controls; p = 0.025, vs DES; p = 0.026). Beta diversity of SS also showed significant distances from controls and DES (p = 0.007 and 0.019, respectively). SS showed decreased genus of Blautia (p = 0.041), Dorea (p = 0.025) and Agathobacter (p = 0.035) compared to controls and increased genus of Prevotella (p = 0.026), Odoribacter (p = 0.028) and Alistipes (p = 0.46) compared to DES. On the other hand, DES only had increased genus Veillonella (p = 0.045) and reduced Subdoligranulum (p = 0.035) compared to controls. Bacteroidetes, Actinobacteria and Bifidobacterium were significantly related with dry eye signs (p<0.05). After adjustment of age, gender and group classification, multivariate linear regression analysis revealed tear secretion was strongly affected by Prevotella (p = 0.025). With additional adjustment of hydroxychloroquine use, TBUT was markedly affected by Prevotella (p = 0.037) and Actinobacteria (p = 0.001). Conclusions: Sjögren's syndrome showed significant gut dysbiosis compared to controls and environmental dry eye syndrome, while dry eye patients showed compositional changes of gut microbiome somewhere in between Sjögren's syndrome and controls. Dysbiosis of the gut microbiota was partly correlated to dry eye severity. [ABSTRACT FROM AUTHOR]

There is an increasing need for an objective grading system to evaluate the severity of dry eye disease (DED). In this study, a fully automated deep learning-based system for the assessment of DED severity was developed. Corneal fluorescein staining (CFS) images of DED patients from one hospital for system development (n = 1400) and from another hospital for external validation (n = 94) were collected. Three experts graded the CFS images using NEI scale, and the median value was used as ground truth. The system was developed in three steps: (1) corneal segmentation, (2) CFS candidate region classification, and (3) estimation of NEI grades by CFS density map generation. Also, two images taken on different days in 50 eyes (100 images) were compared to evaluate the probability of improvement or deterioration. The Dice coefficient of the segmentation model was 0.962. The correlation between the system and the ground truth data was 0.868 (p<0.001) and 0.863 (p<0.001) for the internal and external validation datasets, respectively. The agreement rate for improvement or deterioration was 88% (44/50). The fully automated deep learning-based grading system for DED severity can evaluate the CFS score with high accuracy and thus may have potential for clinical application. [ABSTRACT FROM AUTHOR]

Purpose. To investigate visual performances after a unilateral or bilateral implantation of enlarged depth-of-focus intraocular lens in patients with cataract. Methods. In this prospective study, uneventful phacoemulsification and TECNIS® Symfony intraocular lens implantation were performed in 20 eyes of 17 patients. At postoperative 1, 4, and 12 weeks, the logarithm of the minimal angle of resolution visual acuity at far, intermediate, and near distances and the spherical equivalent in manifest refraction and automated refraction were measured. A questionnaire was used to investigate glare, spectacle dependency, and satisfaction at 12 weeks. The mean numerical error and mean absolute error were compared between intraocular lens formulas to assess the best-fit formula. Results. The logarithm of the minimal angle of resolution visual acuity significantly improved to 0.02 at far, 0.02 at intermediate, and 0.27 at near distances at 12 weeks (p<0.05). Spherical equivalent was −0.79 D on automated refraction and was significantly lower than −0.26 D measured on manifest refraction. Patients' satisfaction score was 9.06, 8.94, and 6.65 for far, intermediate, and near distances, respectively. Near glasses were required in 5 patients and 2 patients complained of photic phenomenon. Visual performances were not significantly different between bilateral and unilateral implanted patients. No patients reported bilateral imbalance due to unilateral surgery. The mean numerical error was closest to 0 D using the Barrett Universal II formula. The mean absolute error was not significantly different between these formulas. Conclusion. Unilateral or bilateral implantation of the enlarged depth-of-focus intraocular lens seems to be equally effective in improving visual performances in patients with cataract. [ABSTRACT FROM AUTHOR]

Goblet cells (GCs) in the conjunctiva are specialized epithelial cells secreting mucins for the mucus layer of protective tear film and playing immune tolerance functions for ocular surface health. Because GC loss is observed in various ocular surface diseases, GC examination is important for precision diagnosis. Moxifloxacin-based fluorescence microscopy (MBFM) was recently developed for non-invasive high-contrast GC visualization. MBFM showed promise for GC examination by high-speed large-area imaging and a robust analysis method is needed to provide GC information. In this study, we developed a deep learning framework for GC image analysis, named dual-channel attention U-Net (DCAU-Net). Dual-channel convolution was used both to extract the overall image texture and to acquire the GC morphological characteristics. A global channel attention module was adopted by combining attention algorithms and channel-wise pooling. DCAU-Net showed 93.1% GC segmentation accuracy and 94.3% GC density estimation accuracy. Further application to both normal and ocular surface damage rabbit models revealed the spatial variations of both GC density and size in normal rabbits and the decreases of both GC density and size in damage rabbit models during recovery after acute damage. The GC analysis results were consistent with histology. Together with the non-invasive high-contrast imaging method, DCAU-Net would provide GC information for the diagnosis of ocular surface diseases. [ABSTRACT FROM AUTHOR]

We compared the accuracy of three intraocular lens (IOL) calculation formulas in eyes with a shallow anterior chamber depth (ACD) and normal axial length (AXL) and control eyes. We retrospectively reviewed eyes with a shallow ACD (<2.5 mm from the corneal epithelium) with normal AXL (22.5≤AXL<24.0 mm) and controls (3.0≤ACD<3.5 mm and normal AXL). Prediction error (PE) and median absolute error (MedAE) were evaluated with SRK/T, Barrett Universal II (BUII), and Kane formulas after adjusting the mean PE to zero for all patients. Percentages of eyes achieving a PE within 0.25 to 1.00 D, and correlations between ACD, lens thickness (LT), and PE were analyzed. Thirty-five shallow ACD and 63 control eyes were included. PE in the shallow ACD group showed more hyperopic results with BUII and Kane but not with SRK/T compared to controls. Within the shallow ACD group, PE showed more hyperopic results in BUII and Kane compared to SRK/T. However, the standard deviation (SD) of PE among formulas was not different. In the shallow ACD group, SRK/T showed a higher percentage of PE within 0.25 D than BUII and Kane, but the percentages within 0.50 to 1.00 D were similar. PE was negatively correlated with ACD in BUII and Kane, and positively correlated with LT in all formulas. BUII and Kane may induce slight hyperopic shift in eyes with a shallow ACD and normal AXL. However, the performance of the three formulas was comparable in the shallow ACD group in terms of MedAE, the SD of PE, and the percentage of eyes achieving PE within 0.50 D. [ABSTRACT FROM AUTHOR]

Age and ocular biometric values were correlated with each other. With age, anterior and total corneal astigmatism changed toward ATR. Posterior corneal astigmatism maintained ATR regardless of age. Purpose: To evaluate the characteristics of ocular biometric parameters in adult Korean patients with cataract. Setting: Department of Ophthalmology, Seoul National University Hospital, Seoul, South Korea. Design: Retrospective case series. Methods: Ocular biometric values of 5273 eyes of 5273 Korean patients undergoing cataract surgery measured with the IOLMaster 700 at the Seoul National University Hospital between November 2019 and December 2021 were reviewed. Results: A total of 5273 eyes of 5273 Korean patients were analyzed. The mean ± SD age was 66.1 ± 12.8 years, and 62% were female. Overall, age and ocular biometric parameters were correlated with each other. Particularly, age showed a negative correlation with anterior chamber depth (ACD; r = −0.357), axial length (AL; r = −0.344), and posterior keratometry (PK; r = −0.054) and a positive correlation with lens thickness (LT; r = 0.484), angle α (r = 0.194), total keratometry (TK; r = 0.137), anterior keratometry (AK; r = 0.129), and angle κ (r = 0.071). AL showed a positive correlation with ACD (r = 0.503) and PK (r = 0.339) and a negative correlation with AK (r = −0.342), TK (r = −0.334), LT (r = −0.288), angle α (r = −0.220), and angle κ (r = −0.040). With age, anterior and total corneal astigmatism changed from with-the-rule (WTR) to against-the-rule (ATR) astigmatism. Posterior corneal astigmatism was ATR regardless of age; however, the magnitude decreased with age. Conclusions: Age showed a significant correlation in the order of LT, ACD, and AL. With age, angle α and κ increased, and total corneal astigmatism changes from WTR to ATR, which is mainly affected by changes in anterior corneal astigmatism. AL showed a significant correlation in the order of ACD, AK, PK, and TK. These data are pertinent for improving the result after cataract surgery, especially when using premium intraocular lenses. [ABSTRACT FROM AUTHOR]

Conjunctival goblet cells (CGCs) are specialized epithelial cells playing key roles for ocular surface homeostasis, and their examination is important for diagnosing ocular surface diseases. Despite recent advancements in high-contrast CGC imaging for non-invasive examination, significant challenges remain for human applications. High-speed large-area imaging over the curved ocular surface is needed to assess statistically meaningful CGCs in the extensive human conjunctiva. To address this challenge, we developed a novel surface detection method and an integrated microscopy system for human use. With both a long detection range of 2 mm and a high update rate of 50 Hz, the surface detection method enabled real-time surface tracking during large-area imaging. The integrated microscopy could complete 5 × 2 patch imaging in approximately 10 s. CGC density analysis showed significantly reduced uncertainties with large-area imaging. This is the first demonstration of non-contact large-area cellular examination in humans, and this new development holds promise for non-invasive CGC examination and accurate diagnosis of ocular surface diseases. [ABSTRACT FROM AUTHOR]

Conjunctival goblet cells (CGCs) are mucin-secreting cells in the eye and play essential roles for ocular surface homeostasis. Since various ocular surface pathologies are related to CGC dysfunction, CGC examination is important for the evaluation of ocular surface conditions. Recently we introduced moxifloxacin-based fluorescence microscopy (MBFM) for non-invasive CGC imaging. However, the imaging speed was up to 1 frame per second (fps) and needed to be improved for clinical applications. In this study, we developed a high-speed moxifloxacin-based, extended depth-of-field (EDOF) microscopy system that operates at a maximum imaging speed of 15 fps. The system used a deformable mirror for the high-speed axial sweeping of focal plane during single-frame acquisitions. The acquired images contained both in-focus and out-of-focus information, and deconvolution was used to filter the in-focus information. The system had a DOF of 800 $\mu \text{m}$ , field-of-view of 1.2 mm $\times1.2$ mm, and resolution of $2.3~\mu \text{m}$. Its performance was demonstrated by real-time, breathing-motion-insensitive CGC imaging of mouse and rabbit models, in vivo. High-speed EDOF microscopy has potentials for non-invasive, real-time CGC examinations of human subjects. [ABSTRACT FROM AUTHOR]

Abstract: This paper investigates the hypothesis that technological convergence has been a major driving force for the recent productivity increase in Korea. Based on the dynamic panel data of Korean industries, the direct impact of information and communication technology (ICT) on labor productivity is assessed through growth accounting, and the indirect network effect of ICT on industrial total factor productivity (TFP) is estimated. The results confirm the essential role of broadband networks for successful convergence. The policy implications for the regulatory change are drawn from the empirical analysis. [Copyright &y& Elsevier]

We investigated whether aging-dependent changes in dendritic cell (DC) distributions are distinct in autoimmune dry eye compared with an aging-related murine model. Corneal staining and tear secretion were evaluated in young and aged C57BL/6 (B6) and NOD.B10.H2b mice (NOD). In the corneolimbus, lacrimal gland (LG), and mesenteric lymph node (MLN), CD11b− and CD11b+ DCs, CD103+ DCs and MHC-IIhi B cells were compared between young and aged B6 and NOD mice. With increased corneal staining, tear secretion decreased in both aged B6 and NOD mice (p < 0.001). In both aged B6 and NOD mice, the percentages of corneolimbal CD11b+ DCs were higher (p < 0.05) than those in young mice. While, the percentages of lymph nodal CD103+ DCs were higher in aged B6 and NOD mice (p < 0.05), the percentages of corneolimbal CD103+ DCs were only higher in aged NOD mice (p < 0.05). In aged NOD mice, the proportions of lacrimal glandial and lymph nodal MHC-IIhi B cells were also higher than those in young mice (p < 0.05). It indicates that corneolimbal or lacrimal glandial distribution of CD103+ DCs or MHC-IIhi B cells may be distinct in aged autoimmune dry eye models compared to those in aged immune competent murine models. [ABSTRACT FROM AUTHOR]

Abstract: Electric field-induced strain (EFIS) properties of Bi1/2(Na0.82K0.18)1/2TiO3 (BNKT) ceramics modified with Sr(K1/4Nb3/4)O3 (SKN) have been investigated as functions of composition and temperature. BNKT ceramics near a phase boundary revealed the coexistence of ferroelectric rhombohedral and tetragonal phases, resulting in a typical ferroelectric butterfly-shaped bipolar S–E loop at room temperature, whose normalized strain (S max/E max) showed a significant temperature coefficient of 0.38pm/V/K. However, 5mol% SKN-modified BNKT ceramics revealed a typical electrostrictive behaviour with a thermally stable electrostrictive coefficient, Q 33 =0.021m4/C2, which is almost comparable to that of Pb(Mg1/3Nb2/3)O3 (PMN) ceramics that have been dominantly used as Pb-based electrostrictive materials over the last decades. [Copyright &y& Elsevier]

Abstract: To investigate abnormal cerebral perfusion in narcoleptics with cataplexy, 25 narcoleptics with cataplexy and 25 normal controls were enrolled in this study. Cerebral perfusion was measured by brain single photon emission computed tomography (SPECT) using 99mTc-ethylcysteinate dimer. Patients and normal controls had not received any medication prior to the SPECT scan. Differences in cerebral perfusion between narcoleptics and normal controls were subjected to statistical parametric mapping (SPM) analysis. Overnight polysomnography and multiple sleep latency test (MSLT) were performed in all patients. Brain SPECT was carried out on all patients and normal controls during the waking state. Clinical symptoms and MSLT results of all patients are in accord with the International Classification of Sleep Disorders criteria for narcolepsy. MSLT showed a short mean sleep latency (1.69 ± 1.0 min) and 2–5 sleep onset REM periods in individual patient. SPM analysis of brain SPECT showed hypoperfusion of the bilateral anterior hypothalami, caudate nuclei, and pulvinar nuclei of thalami, parts of the dorsolateral/ventromedial prefrontal cortices, parahippocampal gyri, and cingulate gyri in narcoleptics [P < 0.05 by Student''s t test with false discovery rate (FDR) correction]. Significant hypoperfusion in the white matter of frontal and parietal lobes was also noted in narcoleptics. This study shows reduced cerebral perfusion in subcortical structures and cortical areas in narcoleptics. The distribution of abnormal cerebral perfusion is concordant with the pathway of the cerebral hypocretin system and may explain the characteristic features of narcolepsy, i.e., cataplexy, emotional lability, and attention deficit. [Copyright &y& Elsevier]

Abstract: This work attempted to reduce hysteresis in electric field-induced strain properties of lead-free Bi1/2(Na0.82K0.18)1/2TiO3ceramics by modification with a (Ba,Ca)ZrO3(BCZ) solid solution. It was found that BCZ induced a phase transition from a ferroelectric state to a relaxor, resulting in a large strain at the transition region like other previous reports on Bi-based ceramics. Although previous works on Bi-based ceramics reported the normalized strain over 600pm/V with large hysteresis over 50%, BCZ modified BNKT showed a much lower hysteresis of 25% while maintaining a large normalized strain of 549pm/V, which is believed to open a new road to further reduce the strain hysteresis in Bi-based lead-free relaxors. [Copyright &y& Elsevier]