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Hyaluronic acid (HA) is a polysaccharide found in the extracellular matrix of the epithelial, nervous, and connective tissues of vertebrates. It is widely used in the treatment of ocular surface diseases (OSDs), including dry eye, due to its high water-retaining capacity, viscoelasticity, and role as a signaling molecule in inflammation and wound healing. This paper reviews the physicochemical and biological properties of HA related to the treatment of OSDs and the results of published preclinical studies, clinical trials, and meta-analyses on the effects of HA eye drops on the tear film, the mechanism of action of HA eye drops, and its clinical effects and adverse events in OSDs, such as corneal/conjunctival epithelial defects, dry eye, and postoperative dry eye. This review should help inform clinical judgments by providing clinical evidence and precautions on the use of HA eye drops in OSDs, including dry eye.

Purpose: To derive the optimized intraocular lens (IOL) constants from automated and manifest refraction after cataract surgery in Korean patients, and to evaluate whether there is a difference in optimized IOL constants according to the refraction method.Methods: This retrospective multicenter cohort study enrolled 4,103 eyes of 4,103 patients who underwent phacoemulsification and in-the-bag IOL implantation at 18 institutes. Optimized IOL constants for the SRK/T, Holladay, Hoffer Q, and Haigis formulas were calculated via autorefraction or manifest refraction of samples using the same biometry and IOL. The IOL constants derived from autorefraction and manifest refraction were compared.Results: Of the 4,103 eyes, the majority (62.9%) were measured with an IOLMaster 500 followed by an IOLMaster 700 (15.2%). A total of 33 types of IOLs were used, and the Tecnis ZCB00 was the most frequently used (53.0%). There was no statistically significant difference in IOL constants derived from autorefraction and manifest refraction when IOL constants were optimized with a large number of study subjects. On the other hand, optimized IOL constants derived from autorefraction were significantly smaller than those from manifest refraction when the number of subjects was small.Conclusions: It became possible to use the IOL constants optimized from Koreans to calculate the IOL power. However, if the IOL constant is optimized using autorefraction in a small sample group, the IOL constant tends to be small, which may lead to refractive error after surgery.

Recently, the role of the corneal nerve in the pathogenesis of dry eye disease (DED) has been highlighted. Considering that neuropeptides are known as important mediators between the nervous and immune systems, neurogenic inflammation induced and regulated by neuropeptides secreted from nerve terminals is expected to be involved in the pathogenesis of DED. And iatrogenic DED has been recently spotlighted as an important field with increasing interest in DED that occurs after ocular surgery or contact lens use. In this paper, recent studies on the role of neuropeptides in the pathogenesis of DED, in particular, the changes and possible roles of neuropeptides in iatrogenic DED were reviewed.

Transcranial focused ultrasound stimulation is a promising therapeutic modality for human brain disorders because of its noninvasiveness, long penetration depth, and versatile spatial control capability through beamforming and beam steering. However, the skull presents a major hurdle for successful applications of ultrasound stimulation. Specifically, skull-induced focal aberration limits the capability for accurate and versatile targeting of brain subregions. In addition, there lacks a fully functional preclinical neuromodulation system suitable to conduct behavioral studies. Here, we report a miniature ultrasound system for neuromodulation applications that is capable of highly accurate multiregion targeting based on acoustic holography. Our work includes the design and implementation of an acoustic lens for targeting brain regions with compensation for skull aberration through time-reversal recording and a phase conjugation mirror. Moreover, we utilize MEMS and 3D-printing technology to implement a 0.75-g lightweight neuromodulation system and present in vivo characterization of the packaged system in freely moving mice. This preclinical system is capable of accurately targeting the desired individual or multitude of brain regions, which will enable versatile and explorative behavior studies using ultrasound neuromodulation to facilitate widespread clinical adoption.

Due to the limitations, such as intermittent bacterial shedding or poor sensitivity, of the current diagnostic tools for Johne’s disease, novel biomarkers are urgently needed to aid control of the disease. Here, we explored the fecal microbiota of Johne’s disease-affected cattle and tried to discover distinct microbial characteristics which have the potential to be novel noninvasive biomarkers.

There is an increasing interest in developing next-generation wearable ultrasound patch systems because of their wide range of applications, such as home healthcare systems and continuous monitoring systems for physiological conditions. A wearable ultrasound patch system requires a stable interface to the skin, an ultrasound coupling medium, a flexible transducer array, and miniaturized operating circuitries. In this study, we proposed a patch composed of calcium (Ca)-modified silk, which serves as both a stable interface and a coupling medium for ultrasound transducer arrays. The Ca-modified silk patch provided not only a stable and conformal interface between the epidermal ultrasound transducer and human skin with high adhesion but also offered acoustic impedance close to that of human skin. The Ca-modified silk patch was flexible and stretchable (∼400% strain) and could be attached to various materials. In addition, because the acoustic impedance of the Ca-modified silk patch was 2.15 MRayl, which was similar to that of human skin (1.99 MRayl), the ultrasound transmission loss of the proposed patch was relatively low (∼0.002 dB). We also verified the use of the Ca-modified silk patch in various ultrasound applications, including ultrasound imaging, ultrasound heating, and transcranial ultrasound stimulation for neuromodulation. The comparable performance of the Ca-modified patch to that of a commercial ultrasound gel and its durability against various environmental conditions confirmed that the Ca-modified silk patch could be a promising candidate as a coupling medium for next-generation ultrasound patch systems.

The establishment of experimental conditions for transcriptional regulator network (TRN) reconstruction in bacteria continues to be impeded by the limited knowledge of activating conditions for transcription factors (TFs). Here, we present a novel genome-scale model-driven workflow for designing experimental conditions, which optimally activate specific TFs. Our model-driven workflow was applied to elucidate transcriptional regulation under nitrogen limitation by Nac and NtrC, in Escherichia coli. We comprehensively predict alternative nitrogen sources, including cytosine and cytidine, which trigger differential activation of Nac using a model-driven workflow. In accordance with the prediction, genome-wide measurements with ChIP-exo and RNA-seq were performed. Integrative data analysis reveals that the Nac and NtrC regulons consist of 97 and 43 genes under alternative nitrogen conditions, respectively. Functional analysis of Nac at the transcriptional level showed that Nac directly down-regulates amino acid biosynthesis and restores expression of tricarboxylic acid (TCA) cycle genes to alleviate nitrogen-limiting stress. We also demonstrate that both TFs coherently modulate α-ketoglutarate accumulation stress due to nitrogen limitation by co-activating amino acid and diamine degradation pathways. A systems-biology approach provided a detailed and quantitative understanding of both TF’s roles and how nitrogen and carbon metabolic networks respond complementarily to nitrogen-limiting stress.

Purpose To evaluate the role of substance P (SP)/neurokinin-1 receptor (NK1R) system in the regulation of pathologic corneal lymphangiogenesis in dry eye disease (DED). Methods Immunocytochemistry, angiogenesis assay, and Western blot analysis of human dermal lymphatic endothelial cells (HDLECs) were conducted to assess the involvement of SP/NK1R system in lymphangiogenesis. DED was induced in wild-type C57BL/6 J mice using controlled-environment chamber without scopolamine. Immunohistochemistry, corneal fluorescein staining, and phenol red thread test were used to evaluate the effect of SP signaling blockade in the corneal lymphangiogenesis. The expression of lymphangiogenic factors in the corneal and conjunctival tissues of DED mouse model was quantified by real-time polymerase chain reaction. Results NK1R expression and pro-lymphangiogenic property of SP/NK1R system in HDLECs were confirmed by Western blot analysis and angiogenesis assay. Blockade of SP signaling with L733,060, an antagonist of NK1R, or NK1R-targeted siRNA significantly inhibited lymphangiogenesis and expression of vascular endothelial growth factor (VEGF) receptor 3 stimulated by SP in HDLECs. NK1R antagonist also suppressed pathological corneal lymphangiogenesis and ameliorated the clinical signs of dry eye in vivo. Furthermore, NK1R antagonist effectively suppressed the lymphangiogenic factors, including VEGF-C, VEGF-D, and VEGF receptor 3 in the corneal and conjunctival tissues of DED. Conclusions SP/NK1R system promotes lymphangiogenesis in vitro and NK1R antagonism suppresses pathologic corneal lymphangiogenesis in DED in vivo.

Purpose: To compare the long-term changes in surgically induced astigmatism (SIA) in patients who underwent 23-gauge sutureless vitrectomy and cataract surgery together with patients who underwent cataract surgery only.Methods: We retrospectively reviewed SIA changes for 1 year after surgery in patients who received only cataract surgery using phacoemulsification (group 1) and patients who underwent 23-gauge sutureless vitrectomy and cataract surgery together (group 2). Flat keratometry (K1), steep keratometry (K2), and astigmatism axis were measured with automatic keratometry before and after the surgery. Vector analysis was used to calculate SIA at 1, 3, 6, and 12 months postoperatively. We then examined whether the SIA values at each time point were different between the two groups.Results: A total of 86 eyes were included in this study (group 1, n = 45; group 2, n = 41). The mean SIA values calculated at 1, 3, 6, and 12 months after surgery in group 1 were 0.83 ± 0.37, 0.69 ± 0.39, 0.60 ± 0.33, and 0.59 ± 0.33, respectively. In group 2, the values were 0.82 ± 0.47, 0.69 ± 0.38, 0.62 ± 0.28, and 0.61 ± 0.30, respectively. Over time, SIA decreased in both groups (all p < 0.001). There was no significant difference in the mean SIA between the two groups at each follow-up time point after surgery (p = 0.296, p = 0.728, p = 0.361, and p = 0.356, respectively).Conclusions: When 23-gauge sutureless vitrectomy and cataract surgery were performed together, the astigmatism change caused by surgery did not show a significant difference compared with that of the group who received cataract surgery only. Thus, 23-gauge sutureless vitrectomy may not significantly affect corneal astigmatism.

Genome-scale studies of the bacterial regulatory network have been leveraged by declining sequencing cost and advances in ChIP (chromatin immunoprecipitation) methods. Of which, ChIP-exo has proven competent with its near-single base-pair resolution. While several algorithms and programs have been developed for different analytical steps in ChIP-exo data processing, there is a lack of effort in incorporating them into a convenient bioinformatics pipeline that is intuitive and publicly available. In this paper, we developed ChIP-exo Analysis Pipeline (ChEAP) that executes the one-step process, starting from trimming and aligning raw sequencing reads to visualization of ChIP-exo results. The pipeline was implemented on the interactive web-based Python development environment - Jupyter Notebook, which is compatible with the Google Colab cloud platform to facilitate the sharing of codes and collaboration among researchers. Additionally, users could exploit the free GPU and CPU resources allocated by Colab to carry out computing tasks regardless of the performance of their local machines. The utility of ChEAP was demonstrated with the ChIP-exo datasets of RpoN sigma factor in

To report the efficacy and safety of large diameter scleral lenses and determine their suitability in Asian subjects with intractable ocular surface diseases. This prospective study enrolled intractable ocular surface diseases subjects with uncorrected visual acuity > counting finger but ≥ 0.3 logMAR and best-corrected visual acuity (BCVA) ≥ 0.3 logMAR, to fit large diameter scleral lenses for 12 weeks. 21 eyes (13 subjects) consisting ten eyes (47.6%) with persistent epithelial defects, 6 (28.6%) with graft-versus-host disease, 4 (19.0%) with Stevens–Johnson syndrome and one (4.8%) with severe dry eye were ultimately enrolled. Primary outcome measures were the visual acuity, corneal and conjunctival fluorescein staining, Ocular Surface Disease Index (OSDI), and National Eye Institute 25-Item Visual Function Questionnaire (NEI-VFQ-25). At week 12 with large diameter scleral lenses, BCVA improved from 0.77 logMAR to 0.27 logMAR (P P = 0.0036 and 0.0063, respectively). OSDI and NEI-VFQ-25 improved from 67.89 to 34.69 and 51.40 to 64.48, respectively (P Trial registration Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (Project No. HI12C0015 (A120018)). Clinical Trials.gov, NCT04535388. Registered 18 August 2020—Retrospectively registered, http://clinicaltrials.gov/ct2/show/NCT04535388.

Acoustic matching layer films (MLFs) were fabricated using B-stage thermosetting polymer resins with various volume fractions of alumina and tungsten powders. After making certain thickness MLFs, ultrasonic matching layers were fabricated using a simple molding process. The thickness of the matching layers can be precisely adjusted from several micrometer to hundreds of micrometer, without any grinding process. Experimental values of acoustic impedances of the matching layers were in good agreement with theoretical values calculated by the Devaney model. Using the optimized acoustic matching layer by the MLFs, the maximum intensity and the fractional bandwidth of the ultrasonic transducer were increased by 10% and 37% respectively. The effectiveness of the matching layer using MLFs was successfully verified.

The risks for hip fracture and vertebral fracture, but not the risk for distal radius fracture, were significantly higher in the blindness group than in the control group with a maximum 12-year follow-up. To evaluate the influence of visual impairment on the risk for osteoporotic fractures at common sites: hip, thoracic/lumbar vertebra, and distal radius. This longitudinal follow-up study used a database of a national sample cohort from 2002 to 2013 provided by the Korean National Health Insurance Service. Of a total of 1,125,691 subjects, 3918 patients with visual impairment and age ≥ 50 years were enrolled in a 1:4 ratio; 15,672 control participants were matched for age, sex, income, and region of residence. Stratified Cox proportional-hazards models were used to evaluate the crude and adjusted (for steroid medication, rheumatoid arthritis, depression, osteoporosis, diabetes mellitus, and stroke history) hazard ratios (HRs) for each fracture site. Fracture diagnoses were based on the ICD-10 codes: hip fracture (S720, S721, S722), vertebral fracture (S220, S320), and distal radius fracture (S525). The HRs for hip and vertebral fracture were significantly higher in the blindness group (adjusted HR = 2.46, p < 0.001 for hip fracture; adjusted HR = 1.42, p = 0.020 for thoracic/lumbar vertebral fracture) than in the matched control group. However, the HR for distal radius fracture was not higher in the blindness group. The HRs for all three fracture sites were not significantly higher in the non-blindness visual impairment group after adjustment. The risks for hip fracture and vertebral fracture were significantly higher in the blindness group. However, the risk for distal radius fracture was not related to visual impairment including blindness.

The influence of visual impairment and blindness on the risk of mortality has been reported in diverse cohort studies. However, the results reported have varied from nonsignificant to significant associations. In the present study, we evaluated the influence of blindness on the risk of mortality from 2002 to 2013 using a longitudinal database with a national sample cohort provided by the Korean National Health Insurance Service. Of a total of 1,125,691 subjects, 1,279 subjects who were registered as blind were enrolled, and 5,116 control participants were matched at a 1:4 ratio for age, sex, income, region of residence, and medical histories of hypertension, diabetes mellitus and dyslipidemia. The life/death information contained in this dataset was used for the analysis; this information was originally recorded by the medical doctors on the death certificates of the participants. The percentage of total deaths during the mean follow-up period of 111.0 ± 41.6 months was 28.1% in the blindness group and 19.7% in the matched control group. The risk of mortality was significantly higher in the blindness group than in the control group according to the Cox proportional hazards model with additional adjustments for ischemic heart disease, stroke, and depression (adjusted hazard ratio [HR] of mortality = 1.54, 95% confidence interval [CI] = 1.37–1.74, P

Multifocal intraocular lenses (MF-IOLs) are increasingly implanted as the need for good near- and intermediate-distance vision increases. Although retinal disease is known to be a relative contraindication for MF-IOL implantation, there are no detailed guidelines for MF-IOL implantation with respect to the type and severity of retinal diseases/statuses. In this study, because retinal diseases can affect the performance of MF-IOLs, we analyzed the opinions of 111 retinal specialists, who were members of the Korean Retina Society, on the implantation of diffractive MF-IOLs in eyes with 15 retinal diseases/statuses using a web-based survey. For each underlying condition, retinal specialists were asked to rate their approval regarding implantation of MF-IOLs on a scale from 1 (completely disapprove) to 7 (completely approve), under the assumption that there were no known contraindications except for a given retinal disease/status. As a result, retinal specialists disapproved MF-IOL implantation (median value of Likert score < 4) in the eyes with wet age-related macular degeneration, dry age-related macular degeneration with geographic atrophy, proliferative diabetic retinopathy, nonproliferative diabetic retinopathy with macular edema, previous macula-off retinal detachment, previous retinal vein occlusion, and epiretinal membrane, but the scores varied by disease/status. The factors that affected the specialists’ opinions were the type of practice and the frequency of MF-IOL implantation (p = 0.013 and p = 0.021, respectively; one-way ANOVA).

Neuroinflammation plays an important role in the pathogenesis of ocular surface disease, including dry eye disease (DED), but little is known about the contribution of substance P (SP) to DED. In this study, we investigated the expression of SP at the ocular surface and evaluated its effect on maturation of antigen-presenting cells (APCs), the key cell component involved in the induction of type 17 helper T-cell (Th17) response in DED. The effect of topical blockade of SP signaling was further investigated using neurokinin-1 receptor (NK1R) inhibitors on APC maturation, Th17 cell activation, and disease severity in a mouse model of DED. The results demonstrate that SP is constitutively expressed at the ocular surface, and trigeminal ganglion neurons are the major source of SP in DED. SP derived from trigeminal ganglion enhanced the expression of major histocompatibility complex class II maturation marker by bone marrow-derived dendritic cells, an effect that is abrogated by blockade of SP signaling using NK1R antagonist spantide. Finally, using a well-established murine model of DED, topical treatment of DED mice with NK1R antagonists CP-99,994 and L-733,060 suppressed APC acquisition of major histocompatibility complex class II, reduced Th17 cell activity, and ameliorated DED severity. These findings are of translational value, as they suggest that antagonizing NK1R-mediated SP signaling may be an effective strategy in suppressing Th17-mediated ocular surface disease.

Liquid-containing storage tanks are important structures in industrial complexes. Because earthquake damages to liquid storage tanks can cause structural collapse, fires, and hazardous material leaks, there have been continuous efforts to mitigate earthquake damages using seismic fragility analysis. In this regard, this study focuses on the seismic responses and fragility of liquid storage tanks. First, the characteristics of earthquake ground motions are a critical factor influencing the seismic fragility of structures; thus, this study employs real earthquake records observed in the target area, southeastern Korea, with the earthquake characteristics estimated based on the ratio of peak ground acceleration to peak ground velocity. When a liquid storage tank oscillates during an earthquake, additional forces can impact the tank wall owing to hydrodynamic pressures. Therefore, this study presents a sophisticated finite element (FE) model that reflects the hydrodynamic effect of an oscillating liquid. Another advantage of such an FE model is that detailed structural responses of the entire wall shells can be estimated; this is not possible in simplified lumped mass or surrogate models. Lastly, probabilistic seismic demand models are derived for three critical limit states: elastic buckling, elephant’s foot buckling, and steel yielding. Using the real earthquake ground motion records, constructed FE model, and limit states, a seismic fragility analysis is performed for a typical anchored steel liquid storage tank in Korea. In addition, for comparison purposes, a ring-stiffened model is investigated to derive a seismic fragility curve. The results of the seismic fragility assessment show that elastic buckling is the most vulnerable damage state. In contrast, elephant’s foot buckling and steel yielding indicate relatively severe damage levels. Furthermore, it is observed that ring stiffeners decrease the elastic buckling damage, although there is no practical effect on elephant’s foot buckling and steel yielding in all ground motion intensities.

Supplemental Digital Content is Available in the Text., Purpose: To evaluate the validity and reliability of alternative methods for evaluating meibomian gland (MG) dropout without using an infrared light system: red-filtered or isolated red-channel images (RCIs) of the everted eyelid. Methods: We evaluated MG dropout in the everted upper and lower eyelids of 125 eyes of 64 patients with good-quality infrared meibography images (IMIs) and color digital photographs with and without a red filter. Red-filtered images (RFIs) were converted to black and white and adjusted for contrast/brightness [adjusted red-filtered images (aRFIs)]. RCIs were computationally isolated from color digital photographs obtained without a red filter. After randomization, the total meiboscore (0–6) was evaluated by 2 independent evaluators (interobserver reliability) masked to the image origin, and again after a 30-day interval (intraobserver reliability). Results: The meiboscores evaluated using the RFI, aRFI, and RCI were strongly positively correlated with those evaluated using the IMI (RFI: ρ = 0.788; aRFI: ρ = 0.735; RCI: ρ = 0.630; all P < 0.001, Spearman correlation analysis). Linear-weighted κ-values (κw) showed substantial agreement between the RFI and IMI (κw = 0.676, 95% CI = 0.594–0.759). The RFI had substantial intraobserver reliability (κw = 0.735, 95% CI = 0.685–0.785) and moderate interobserver reliability (κw = 0.467, 95% CI = 0.371–0.563). Computational adjustment of RFIs did not enhance the validity or reliability, and RCIs had limitations in some cases. Conclusions: MGs were successfully visualized using a red filter on a slit lamp and showed substantial agreement with visualization using the standard infrared method. Although interobserver reliability was only moderate, this alternative technique may be useful for evaluating MG dropout when an infrared meibography device is not available.

Background: Although polyunsaturated fatty acids are in the spotlight due to their physiological effects on inflammation and stress of livestock animals, the biological roles of their derivatives, termed lipid mediators, have been little reported in laying hens. Results: In this study, two hundred 33-week-old laying hens were fed 0, 0.9, 1.8, or 3.6% (w/w) dietary flaxseed (Lintex170) with a commercial basal diet for 4 weeks to determine the physiological effects of dietary flaxseed, an omega-3-rich ingredient, on host inflammation or stress states regarding lipid mediator profiles, and also its impact on laying performance. The physiological changes in the omega-6 to omega-3 ratio, lipid mediator profiles, serum proinflammatory cytokine (tumor necrosis factor-alpha, interleukin-1beta, interleukin-6) levels, serum corticosterone levels, and the ratio of heterophils to lymphocytes were monitored. Supplementing dietary flaxseed greatly reduced the omega-6 to omega-3 fatty acid ratio from 25.85 to 4.16 in eggs and from 19.23 to 4.08 in serum samples between groups fed with 0% and 3.6% dietary flaxseed after the experimental period. In addition, the lipid mediator profiles of laying hens were modulated by supplementation with flaxseed, mainly resulting in enrichment of omega-3 fatty acid-derived lipid mediators. Furthermore, the level of proinflammatory cytokines TNF-alpha decreased when fed 3.6% (w/w) dietary flaxseed. Two stress indices, corticosterone in the serum and the heterophil to lymphocyte ratio showed significant reductions in laying hens fed 3.6% (w/w) dietary flaxseed. Additionally, overall laying performance indices were significantly improved by supplementary flaxseed. Conclusion: Taken together, these findings suggest that the decreased omega-6 to omega-3 ratio and enrichment of omega-3-derived lipid mediators induced by dietary flaxseed may contribute to reducing the stress state in laying hens, improving laying performance. These findings broaden the understanding of lipid mediator profiles in laying hens, and the results will be applied to develop antiinflammatory and antistress feed additives for the poultry industry.

Corneal grafts interact with their hosts via complex immunobiological processes that sometimes lead to graft failure. Prediction of graft failure is often a tedious task due to the genetic and nongenetic heterogeneity of patients. As in other areas of medicine, a reliable prediction method would impact therapeutic decision-making in corneal transplantation. Valuable insights into the clinically observed heterogeneity of host responses to corneal grafts have emerged from multidisciplinary approaches, including genomics analyses, mechanical studies, immunobiology, and theoretical modeling. Here, we review the emerging concepts, tools, and new biomarkers that may allow for the prediction of graft survival.