Angiotensin Receptor Blockers and the Risk of Suspected Drug-Induced Liver Injury: A Retrospective Cohort Study Using Electronic Health Record-Based Common Data Model in South Korea.

INTRODUCTION: Angiotensin receptor blockers are widely used antihypertensive drugs in South Korea. In 2021, the Korea Ministry of Food and Drug Safety acknowledged the need for national compensation for a drug-induced liver injury (DILI) after azilsartan use. However, little is known regarding the association between angiotensin receptor blockers and DILI. OBJECTIVE: We conducted a retrospective cohort study in incident users of angiotensin receptor blockers from a common data model database (1 January, 2017-31 December, 2021) to compare the risk of DILI among specific angiotensin receptor blockers against valsartan. METHODS: Patients were assigned to treatment groups at cohort entry based on prescribed angiotensin receptor blockers. Drug-induced liver injury was operationally defined using the International DILI Expert Working Group criteria. Cox regression analyses were conducted to derive hazard ratios and the inverse probability of treatment weighting method was applied. All analyses were performed using R. RESULTS: In total, 229,881 angiotensin receptor blocker users from 20 university hospitals were included. Crude DILI incidence ranged from 15.6 to 82.8 per 1000 person-years in treatment groups, most were cholestatic and of mild severity. Overall, the risk of DILI was significantly lower in olmesartan users than in valsartan users (hazard ratio: 0.73 [95% confidence interval 0.55-0.96]). In monotherapy patients, the risk was significantly higher in azilsartan users than in valsartan users (hazard ratio: 6.55 [95% confidence interval 5.28-8.12]). CONCLUSIONS: We found a significantly higher risk of suspected DILI in patients receiving azilsartan monotherapy compared with valsartan monotherapy. Our findings emphasize the utility of real-world evidence in advancing our understanding of adverse drug reactions in clinical practice.

Macular superficial vascular density on optical coherence tomography angiography in children with unilateral anisometropic and bilateral hyperopic amblyopia.

We analyzed whether macular superficial vascular density (SVD) and foveal vascular zone (FAZ) on optical coherence tomography angiography (OCTA) can distinguish between bilateral ametropic and anisometropic amblyopia. We included 42, 33, and 50 eyes in the bilateral ametropic amblyopia, anisometropic amblyopia, and normal control groups, respectively. Using macular swept-source optical coherence tomography angiography, we measured and analyzed the superficial FAZ areas and five sectoral macular SVDs after magnification correction. The anisometropic amblyopic eye group showed significantly increased foveal SVDs (p < 0.001) and significantly decreased superficial FAZ areas (p < 0.001), compared with the remaining groups. Additionally, the bilateral ametropic amblyopia group had significantly decreased nasal SVDs. SVDs and superficial FAZ areas differed among hyperopic amblyopia subtypes. These findings may reflect vascular distribution differences and macular changes in hyperopic amblyopia subtypes compared with normal eyes.

Investigation of hepatic adverse events due to quetiapine by using the common data model.

PURPOSE: Quetiapine is a drug used to treat schizophrenia, bipolar disorder, and major depressive disorder. However, it can cause mild or severe hepatic adverse events and rarely fatal liver damage. This study was aimed at investigating hepatic toxicity caused by quetiapine use by analyzing the information captured from hospital electronic health records by using the Observational Medical Outcomes Partnership common data model (CDM). METHODS: This was a retrospective observational study involving a nested case-control method. A CDM based on an electronic health record database from five hospitals between January 2009 and May 2020 was used. We analyzed the status of quetiapine use, adverse events, and hepatic impairment. RESULTS: The numbers of patients with non-serious and severe hepatic adverse reactions were 2566 (5.05%) and 835 (1.64%) out of 50 766 patients, respectively. After adjusting for covariates, the odds ratio of hepatic adverse events was 2.35 (95% CI: 2.03-2.72), and the odds ratio of severe hepatic adverse events was 1.76 (95% CI: 1.16-2.66). CONCLUSION: Our findings suggest that quetiapine should be cautiously used, and hepatic function should be monitored in patients using quetiapine because it can cause mild or severe hepatic adverse events, complications, and in rare cases, fatal liver damage.

Detection of abnormal extraocular muscles in small datasets of computed tomography images using a three-dimensional variational autoencoder.

We sought to establish an unsupervised algorithm with a three-dimensional (3D) variational autoencoder model (VAE) for the detection of abnormal extraocular muscles in small datasets of orbital computed tomography (CT) images. 334 CT images of normal orbits and 96 of abnormal orbits diagnosed as thyroid eye disease were used for training and validation; 24 normal and 11 abnormal orbits were used for the test. A 3D VAE was developed and trained. All images were preprocessed to emphasize extraocular muscles and to suppress background noise (e.g., high signal intensity from bones). The optimal cut-off value was identified through receiver operating characteristic (ROC) curve analysis. The ability of the model to detect muscles of abnormal size was assessed by visualization. The model achieved a sensitivity of 79.2%, specificity of 72.7%, accuracy of 77.1%, F1-score of 0.667, and AUROC of 0.801. Abnormal CT images correctly identified by the model showed differences in the reconstruction of extraocular muscles. The proposed model showed potential to detect abnormalities in extraocular muscles using a small dataset, similar to the diagnostic approach used by physicians. Unsupervised learning could serve as an alternative detection method for medical imaging studies in which annotation is difficult or impossible to perform.

Application of Deep Learning-Based Medical Image Segmentation via Orbital Computed Tomography.

Recently, deep learning-based segmentation models have been widely applied in the ophthalmic field. This study presents the complete process of constructing an orbital computed tomography (CT) segmentation model based on U-Net. For supervised learning, a labor-intensive and time-consuming process is required. The method of labeling with super-resolution to efficiently mask the ground truth on orbital CT images is introduced. Also, the volume of interest is cropped as part of the pre-processing of the dataset. Then, after extracting the volumes of interest of the orbital structures, the model for segmenting the key structures of the orbital CT is constructed using U-Net, with sequential 2D slices that are used as inputs and two bi-directional convolutional long-term short memories for conserving the inter-slice correlations. This study primarily focuses on the segmentation of the eyeball, optic nerve, and extraocular muscles. The evaluation of the segmentation reveals the potential application of segmentation to orbital CT images using deep learning methods.

Anti-inflammatory effect of glucagon-like Peptide-1 receptor agonist on the neurosensory retina in an acute optic nerve injury rat model.

PURPOSE: To explore the possibility of using glucagon-like peptide-1 receptor agonist (GLP-1RA) as a new treatment for neuroinflammation, by analyzing retinal pathological changes in an optic nerve crush rat model. METHODS: Eight-week-old male Sprague-Dawley rats were divided into lixisenatide (LIX, n = 10), traumatic control (T-CON, n = 10), and normal control (n = 5) groups. The optic nerves of left eyes in the LIX and T-CON groups were crushed in a standardized manner. The LIX group was treated with subcutaneous injections of lixisenatide (200 µg/kg/day) for 5 days. One week after initiating treatment, quantitative polymerase chain reaction, Western blot, and immunohistochemistry analyses were performed on the retinal tissues of each group to identify inflammatory markers. RESULTS: The LIX group showed significantly lower mRNA levels of interleukin 1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), thioredoxin interacting protein (TXNIP), and glial fibrillary acidic protein (GFAP) than the T-CON group. Also, the LIX group exhibited decreased TXNIP and GFAP expression compared with the T-CON group, and similar expression to the normal control group, according to Western blot analysis. Significantly increased immunohistochemistry staining of Brn3a and decreased TUNEL staining were seen in the LIX group compared with the T-CON group, indicating that lixisenatide contributes to retinal ganglion cell survival in cases of acute optic nerve injury. CONCLUSIONS: Neuroinflammation was significantly reduced in lixisenatide-treated retinas compared with untreated retinas in our acute optic nerve injury rat model. The neuroprotective effect of lixisenatide indicates that it can serve a new treatment option against clinically intractable traumatic optic neuropathy.

Association between the use of allopurinol and risk of increased thyroid-stimulating hormone level.

Allopurinol is the first-line agent for patients with gout, including those with moderate-to-severe chronic kidney disease. However, increased thyroid-stimulating hormone (TSH) levels are observed in patients with long-term allopurinol treatment. This large-scale, nested case-control, retrospective observational study analysed the association between allopurinol use and increased TSH levels. A common data model based on an electronic medical record database of 19,200,973 patients from seven hospitals between January 1997 and September 2020 was used. Individuals aged > 19 years in South Korea with at least one record of a blood TSH test were included. Data of 59,307 cases with TSH levels > 4.5 mIU/L and 236,508 controls matched for sex, age (± 5), and cohort registration date (± 30 days) were analysed. An association between the risk of increased TSH and allopurinol use in participants from five hospitals was observed. A meta-analysis (I2 = 0) showed that the OR was 1.51 (95% confidence interval: 1.32-1.72) in both the fixed and random effects models. The allopurinol intake group demonstrated that increased TSH did not significantly affect free thyroxine and thyroxine levels. After the index date, some diseases were likely to occur in patients with subclinical hypothyroidism and hypothyroidism. Allopurinol administration may induce subclinical hypothyroidism.

The Anti-Inflammatory Effects of Glucagon-Like Peptide Receptor Agonist Lixisenatide on the Retinal Nuclear and Nerve Fiber Layers in an Animal Model of Early Type 2 Diabetes.

This study explored the anti-inflammatory effects of a glucagon-like peptide-1 receptor agonist (GLP-1RA), known as lixisenatide, on the eyes of early type 2 diabetic mice. Diabetic (db/db) mice were divided into three groups: GLP-1RA [lixisenatide (LIX)], insulin (INS) with controlled hyperglycemia based on the glucose concentration of lixisenatide, and diabetic control (D-CON). Nondiabetic control mice (db/dm) were also characterized for comparison. After 8 weeks of treatment, mRNA levels of inflammatory markers, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, immunohistochemical staining; Western blot of glial fibrillary acidic protein (GFAP) and thioredoxin-interacting protein; and retinal thickness were assessed in the central and peripheral neurosensory retina. LIX showed decreased immunohistochemical staining for both thioredoxin-interacting protein and GFAP in the central and peripheral neurosensory retina compared with D-CON and INS, and decreased expression of these proteins in the neurosensory retina and immunohistochemical staining in the optic nerve head for GFAP compared with D-CON. The inner nuclear layer in the peripheral retina in LIX was only thinner than those of D-CON and INS. In an early type 2 diabetic mouse model, lixisenatide treatment showed superior anti-inflammatory effects on the retina and optic nerve head independent of hyperglycemia. Thus, the neuroprotective effects of lixisenatide treatment in the peripheral inner nuclear layer should be evaluated in early type 2 diabetic retinopathy.

The Association between Macular Thickness and Axial Length in Myopic Eyes.

PURPOSE: To investigate the relationship between macular thickness and axial length (AL) in myopic eyes. METHODS: We included 441 myopic eyes in this study and measured macular thickness at the fovea and in other macular regions, using optical coherence tomography. We got thickness difference indices (TDIs) which by definition are the values of thickness difference obtained by subtracting the foveal thickness from that of each macula sector to evaluate macular contour. We then analyzed the relationships between AL and foveal thickness and AL and the TDIs of each macular sector. RESULTS: In polynomial regression analyses, foveal thickness slope was relatively flat up to an AL of 25.5 mm and began to rise from 25.5-26.0 mm. The TDIs were also relatively flat up to AL of 25.5mm and started to show steepened negative slopes from around AL of 25.5 mm. When grouping myopia participants as high myopia or non-high myopia based on AL of 25.5mm, all macular indices of the high myopia group showed significant correlation with AL (all p values <0.01). But all indices of non-high myopia group had no significant correlation with AL. CONCLUSIONS: Average macular thickness profiles showed that appreciable changes started at an AL of 25.5mm.

Surgical and sensory outcomes in patients with intermittent exotropia according to preoperative refractive error.

BACKGROUND/OBJECTIVES: To analyze the surgical and sensory outcomes of intermittent exotropia according to refractive errors and the factors associated with surgical success. SUBJECTS/METHODS: A total of 326 children were divided into three groups according to preoperative refractive error; hyperopic eyes with SE ≥+2D (hyperopic group), eyes with SE between -1D and +2D (emmetropic group), and myopic eyes with SE ≤-1D (myopic group). The surgical outcomes and the sensory outcomes measured by near and distant stereoacuity were compared among the three groups. RESULTS: The surgical success rate in hyperopic group was significantly lower compared to myopic group at last follow-up (P = 0.012). Preoperative near stereopsis was not different among three groups, however, the distance stereopsis was significantly deteriorated in the hyperopic group compared to the other two groups (Titmus; P = 0.168, FD2; P < 0.001, DR; P = 0.048). There was postoperative improvement in both near and distant stereopsis in all three groups (Titmus; P = 0.009, FD2; P = 0.021, DR; P = 0.036) and no significant difference was found in the postoperative distant stereopsis among the three groups. CONCLUSIONS: Preoperative refractive error is a prognostic factor of surgical success in patients with intermittent exotropia. Patients with hyperopia achieved less favorable surgical outcome compared to myopic patients. The preoperative distant stereoacuity was decreased in hyperopic patients compared to myopic patients, which eventually improved after surgery and showed no significant difference at postoperative measurements.

Expression of MyoD, insulin like growth factor binding protein, thioredoxin and p27 in secondarily overacting inferior oblique muscles with superior oblique palsy.

BACKGOUND: To identify and compare specific protein levels between overacting inferior oblique (IO) muscles in superior oblique (SO) palsy patients and normal IO muscles. METHODS: We obtained 20 IO muscle samples from SO palsy patients with IO overaction ≥ + 3 who underwent IO myectomies (IOOA group), and 20 IO samples from brain death donors whose IO had functioned normally, according to their ophthalmological chart review (control group). We used MyoD for identifying satellite cell activation, insulin-like growth factor binding protein 5 (IGFBP5) for IGF effects, thioredoxin for oxidative stress, and p27 for satellite cell activation or oxidative stress in both groups. Using immunohistochemistry and Western blot, we compared expression levels of the four proteins (MyoD, IGFBP5, thioredoxin, and p27). RESULTS: Levels of thioredoxin and p27 were decreased significantly in the IOOA group. MyoD and IGFBP5 levels showed no significant difference between the groups. CONCLUSIONS: Based on these findings, the overacting IOs of patients with SO palsy had been under oxidative stress status versus normal IOs. Pathologically overacting extraocular muscles may have an increased risk of oxidative stress compared with normal extraocular muscles.

Distant stereoacuity in children with anisometropic amblyopia.

PURPOSE: To characterize changes in distant stereoacuity using Frisby-Davis Distance test (FD2) and Distant Randot test (DR) during treatment for anisometropic amblyopia, to determine factors that influence posttreatment stereoacuity and to compare the two distant stereotests. METHODS: Fifty-eight anisometropic amblyopic patients with an interocular difference of ≥1.00 diopter who achieved the visual acuity 20/20 following amblyopia treatment were retrospectively included. Stereoacuity using FD2 and DR for distant and Titmus test for near measurement were assessed and compared at the initial, intermediate, and final visit. Multivariate regression models were used to identify factors associated with initial and final stereoacuity. RESULTS: The two distant stereotests revealed a significant improvement in distant stereoacuity after successful amblyopia treatment. Distant stereoacuity using FD2 showed the greatest improvement during the follow up period. The number of nil scores was higher in DR than FD2 at each period. In multivariate analysis, better final stereoacuity was associated with better initial amblyopic eye acuity in both distant stereotests, but not in the Titmus test. Comparing the two distant stereotests, final stereoacuity using FD2 was associated with initial stereoacuity and was moderately related with the Titmus test at each period, but final stereoacuity using DR was not. CONCLUSIONS: Distant stereoacuity measured with both FD2 and DR showed significant improvement when the visual acuity of the amblyopic eye achieved 20/20. Changes in distant stereoacuity by FD2 and DR during the amblyopia treatment were somewhat different.

Effect of trapping vascular endothelial growth factor-A in a murine model of dry eye with inflammatory neovascularization.

AIM: To evaluate whether trapping vascular endothelial growth factor A (VEGF-A) would suppress angiogenesis and inflammation in dry eye corneas in a murine corneal suture model. METHODS: We established two groups of animals, one with non-dry eyes and the other with induced dry eyes. In both groups, a corneal suture model was used to induce inflammation and neovascularization. Each of two groups was again divided into three subgroups according to the treatment; subgroup I (aflibercept), subgroup II (dexamethasone) and subgroup III (phosphate buffered saline, PBS). Corneas were harvested and immunohistochemical staining was performed to compare the extents of neovascularization and CD11b+ cell infiltration. Real-time polymerase chain reaction was performed to quantify the expression of inflammatory cytokines and VEGF-A in the corneas. RESULTS: Trapping VEGF-A with aflibercept resulted in significantly decreased angiogenesis and inflammation compared with the dexamethasone and PBS treatments in the dry eye corneas (all P<0.05), but with no such effects in non-dry eyes. The anti-inflammatory and anti-angiogenic effects of VEGF-A trapping were stronger than those of dexamethasone in both dry eye and non-dry eye corneas (all P<0.05). The levels of RNA expression of VEGF-A, TNF-alpha, and IL-6 in the aflibercept subgroup were significantly decreased compared with those in the PBS subgroup in the dry eye group. CONCLUSION: Compared with non-dry eye corneas, dry eye corneas have greater amounts of inflammation and neovascularization and also have a more robust response to anti-inflammatory and anti-angiogenic agents after ocular surface surgery. Trapping VEGF-A is effective in decreasing both angiogenesis and inflammation in dry eye corneas after ocular surface surgery.

Comparison of postoperative corneal changes between dry eye and non-dry eye in a murine cataract surgery model.

AIM: To compare the effects of the surgical insult of cataract surgery on corneal inflammatory infiltration, neovascularization (NV) and lymphangiogenesis (LY) between the dry eye and non-dry eye in murine cataract surgery models. METHODS: We established two groups of animals, one with normal eyes (non-dry eye) and the second with induced dry eyes. In both groups, we used surgical insults to mimic human cataract surgery, which consisted of lens extraction, corneal incision and suture. After harvesting of corneas on the 9(th) postoperative day and immunohistochemical staining, we compared NV, LY and CD11b+ cell infiltration in the corneas. RESULTS: Dry eye group had significantly more inflammatory infiltration (21.75%±7.17% vs 3.65%±1.49%; P=0.049). The dry eye group showed significantly more NV (48.21%±4.02% vs 26.24%±6.01%; P=0.016) and greater levels of LY (9.27%±0.48% vs 4.84%±1.15%; P=0.007). In corneas on which no surgery was performed, there was no induction of NV in both the dry and non-dry group, but dry eye group demonstrated more CD11b+ cells infiltration than the non-dry eye group (0.360%±0.160% vs 0.023%±0.006%; P=0.068). Dry eye group showed more NV than non-dry eye group in both topical PBS application and subconjunctival PBS injection (P=0.020 and 0.000, respectively). CONCLUSION: In a murine cataract surgery model, preexisting dry eye can induce more postoperative NV, LY, and inflammation in corneal tissue.

The effect of topical cyclosporine 0.05% on dry eye after cataract surgery.

PURPOSE: To evaluate the effectiveness of cyclosporine 0.05% for dry eye after cataract surgery. METHODS: Thirty-two newly diagnosed patients with dry eye syndrome 1 week after cataract surgery received a twice-daily treatment of cyclosporine 0.05% for one eye and normal saline 0.9% for the other. Disease severity was measured at 2 weeks, 1 month, 2 months, and 3 months by Schirmer test I (ST-I), tear film break-up time (tBUT), corneal temperature and dry eye symptom questionnaire (Ocular Surface Disease Index). RESULTS: Both groups increased in ST-I and tBUT over time. ST-I in the cyclosporine 0.05% group showed a significant increase at 3 months and tBUT in the cyclosporine 0.05% group showed an increase at 2 and 3 months. The dry eye symptom score was significantly reduced in the cyclosporine 0.05% group. CONCLUSIONS: Cyclosporine 0.05% can also be an effective treatment for dry eye after cataract surgery.