Long-Term Regular Use of Low-Dose Aspirin and Neovascular Age-Related Macular Degeneration: National Sample Cohort 2010-2015.

PURPOSE: The association between long-term cardioprotective aspirin use and neovascular age-related macular degeneration (AMD) is controversial. This study was undertaken to estimate the risk of neovascular AMD with long-term regular use of low-dose aspirin. DESIGN: Retrospective population-based study, using a nationwide cohort from a variety of clinics and hospitals in South Korea. PARTICIPANTS: Nonregular aspirin users and regular aspirin users under national health insurance, aged ≥45 years, who were followed from 2010 to 2015, were identified. METHODS: Incidence per 10 000 person-years for neovascular AMD was estimated. Long-term regular use of low-dose aspirin was defined as sustained intake of ≤100 mg aspirin with ≥1044 days prescription between 2005 and 2009. Nonregular aspirin users included occasional users or nonusers. The analyses included a propensity score-adjusted analysis in a large, randomly selected, unmatched whole cohort (n = 482 613); propensity score-matched analysis in a matched cohort (n = 74 196); and maximally adjusted analysis in the unmatched whole cohort (n = 482 613). MAIN OUTCOME MEASURES: Incidence of newly developed neovascular AMD using the registration code for intractable disease under national health insurance. RESULTS: Incidence of neovascular AMD was 3.5 among nonregular aspirin users and 7.2 among regular aspirin users per 10 000 person-years in the unmatched whole cohort. However, propensity score-adjusted analyses revealed no association between aspirin use and neovascular AMD (adjusted hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.73-1.30). Likewise, propensity score-matched analyses showed no association; incidences of neovascular AMD were 7.5 and 7.1 among nonregular aspirin users and regular aspirin users (crude HR, 0.94; 95% CI, 0.70-1.28), respectively. A maximally adjusted model, including age, sex, income, residential area, and history of 100 randomly selected types of generic drugs, showed no association (adjusted HR, 0.95; 95% CI, 0.71-1.28). CONCLUSIONS: We found no association between long-term regular use of low-dose aspirin for 5 years and future incidence of neovascular AMD. Thus, this large-scale study suggests that regular, long-term use of low-dose aspirin appears to be safe with respect to the new development of neovascular AMD.

Association Between Osteoporosis and Age-Related Macular Degeneration: The Korea National Health and Nutrition Examination Survey.

Purpose: Previous studies have reported a possible link between low bone mineral density and AMD. The aim of the present study was to investigate the association between osteoporosis and AMD in a South Korean cohort. Methods: This cross-sectional, nationwide study included 3496 women and 2789 men who had participated in the Korean National Health and Nutrition Examination Survey from 2008 to 2011. All retinal photographs were graded using an international classification and grading system. Osteoporosis was assessed using dual-energy x-ray absorptiometry. Multivariate logistic regression analysis was performed to examine the relationship between osteoporosis and AMD after adjustment for potential confounders, including age, the body mass index, dietary calcium intake, and the serum vitamin D level. The odds ratios (OR) for other aging-related eye diseases, including cataract, open-angle glaucoma, and diabetic retinopathy, were analyzed in accordance with the presence of osteoporosis. Results: Multivariate regression analysis revealed that osteoporosis was significantly associated with all types of AMD (early and late: OR, 1.31; P = 0.017) and early AMD (OR, 1.36; P = 0.007) in women. Late AMD was not associated with osteoporosis (OR, 0.84; P = 0.670). In men, osteoporosis was not associated with any type of AMD. In women, the status of osteoporosis in the femoral neck showed a linear relationship with AMD (P = 0.004). Although osteoporosis was associated with AMD in women, it showed no association with other age-related eye diseases; this suggested a disease-specific association. Conclusions: Our findings suggest that osteoporosis plays a role in AMD development in postmenopausal women.

Association of Corticosteroid Use With Incidence of Central Serous Chorioretinopathy in South Korea.

Importance: Information on the incidence of central serous chorioretinopathy (CSC) in individuals who receive corticosteroids is scarce but clinically important because these agents are useful and widely used. Objective: To estimate the annual and 5-year incidence of CSC in South Korea in the overall population and in those who have used corticosteroid medications. Design, Setting, and Participants: A cohort study of a population-based random sample included East Asian adults for whom records are held in the Korean National Health Insurance Service database for calendar years 2011 through 2015. The data analysis was performed from July 1, 2017 to January 5, 2018. Exposures: Any type of corticosteroid use from 2002 through 2015. Main Outcomes and Measures: Incidence of CSC. Results: The data set contained data from 868 939 adults (4 117 768 person-years). From 2011 through 2015, 1423 individuals (among whom the mean [SD] age was 46.8 [16.4] years and 1091 [76.7%] were male) with newly diagnosed CSC were identified. From 2002 to 2015, 783 099 individuals in the data set (90.1%) had ever used corticosteroids. The incidence of CSC per 10 000 person-years was 3.5 (5.4 in men; 1.6 in women) among the total population, 2.5 (3.0 in men; 1.2 in women) in those who had never used corticosteroids, and 3.6 (5.7 in men; 1.6 in women) among those who had ever used corticosteroids. The risk of CSCR with individuals who had ever used corticosteroids was estimated as an adjusted hazard ratio of 1.81 (95% CI, 1.47-2.23) compared with those who have never used these drugs. Current or recent corticosteroid use showed a positive association with the incidence of CSC (depending on duration of use, adjusted hazard ratio ranged from 1.54 to 2.15). Corticosteroid use in 2006 through 2009 was associated with an increased incidence of CSC after 2011 (adjusted hazard ratio 1.57 [95% CI, 1.13-2.18]). Conclusions and Relevance: In 2002 through 2015, 90.1% of adults in Korea received corticosteroids at least once. Although there was a clear difference in relative risk, this data analysis could not replicate the more than 30-fold increase in the risk ratio of CSC that has been reported previously. The incidence of CSC in the most vulnerable group, middle-aged men, was estimated to be approximately 1 case per 1000 corticosteroid users in the year following medication use. The overall incidence among those who had ever used corticosteroids and those who had never used these drugs was 2.5 and 3.6 per 10 000 person-years, respectively. This study provides additional evidence to support the potential role of corticosteroids in CSC.

Multi-categorical deep learning neural network to classify retinal images: A pilot study employing small database.

Deep learning emerges as a powerful tool for analyzing medical images. Retinal disease detection by using computer-aided diagnosis from fundus image has emerged as a new method. We applied deep learning convolutional neural network by using MatConvNet for an automated detection of multiple retinal diseases with fundus photographs involved in STructured Analysis of the REtina (STARE) database. Dataset was built by expanding data on 10 categories, including normal retina and nine retinal diseases. The optimal outcomes were acquired by using a random forest transfer learning based on VGG-19 architecture. The classification results depended greatly on the number of categories. As the number of categories increased, the performance of deep learning models was diminished. When all 10 categories were included, we obtained results with an accuracy of 30.5%, relative classifier information (RCI) of 0.052, and Cohen's kappa of 0.224. Considering three integrated normal, background diabetic retinopathy, and dry age-related macular degeneration, the multi-categorical classifier showed accuracy of 72.8%, 0.283 RCI, and 0.577 kappa. In addition, several ensemble classifiers enhanced the multi-categorical classification performance. The transfer learning incorporated with ensemble classifier of clustering and voting approach presented the best performance with accuracy of 36.7%, 0.053 RCI, and 0.225 kappa in the 10 retinal diseases classification problem. First, due to the small size of datasets, the deep learning techniques in this study were ineffective to be applied in clinics where numerous patients suffering from various types of retinal disorders visit for diagnosis and treatment. Second, we found that the transfer learning incorporated with ensemble classifiers can improve the classification performance in order to detect multi-categorical retinal diseases. Further studies should confirm the effectiveness of algorithms with large datasets obtained from hospitals.

Accurate application of a precontoured-locking plate for proximal humeral fractures in Asians: a cadaveric study.

OBJECTIVES: The purpose of this study was to identify the optimal position for a precontoured-locking plating (PHILOS(®)) of the proximal humerus in Asians in terms of conformity and to determine the prevalence of screw exits in the position of the highest conformity. METHODS: Twenty adult humeri and 14 cadaveric shoulders were included in this study. After placing the precontoured plate in the well-fitted position on the humerus, we measured the distance between the upper margin of the plate and the tip of greater tuberosity (GT) (distance A) and the distance between the anterior margin of the plate and lateral border of the bicipital groove (BG) (distance B). The prevalence of K-wire exits was assessed. In the 14 cadaver shoulders, the mutual relation between the most inferior locking sleeve of the optimally positioned plate and the axillary nerve was evaluated to assess the potential for axillary nerve injury. RESULTS: The precontoured plate was well-fitted and remained in a relatively constant position in all specimens. Distance A was an average of 3.6 mm (range 1.4-5.5 mm), and distance B was an average of 2.5 mm (range 0-4.6 mm). The K wire closest to the BG pierced it in four cases (20 %), and most inferior K wires exited at an average distance of 3.8 mm (range 1.6-9.0 mm) from the inferior articular margin of the humeral head. Regarding involvement of the BG, articular width was the only significant variable in the logistic regression model, with an odds' ratio of 0.610. The axillary nerve was located at an average vertical distance of 59.7 mm (range 51.8-66.9 mm) from the tip of the GT in a vertically neutral position. The results did not differ between the left and right sides (t = 0.326, p = 0.755). Although the axillary nerve was slightly inferior to the most inferior locking holes of the proximal humerus, it was located in the path of their locking sleeves on the deltoid muscle. CONCLUSION: The optimal position for the highest conformity led to ideal fixation of the proximal humerus and inferomedial support screw in Asians. However, the precontoured plate sometimes had screw exits that involved the BG, and articular width had a large impact on involvement of the BG. If locking sleeves for the most inferior holes were introduced on the deltoid muscle in a neutral position, there was high potential for injury to the axillary nerve in Koreans.

Isolation and characterization of tumorspheres from a recurrent pineoblastoma patient: Feasibility of a patient-derived xenograft.

The existence of tumorspheres (TSs) might confer treatment resistance to pineoblastoma (PB). The existence of PB TSs with cellular immortalization potential has not yet been reported. We developed a procedure for isolating TSs from recurrent PB (rPB) and tested whether their properties made them suitable for use as a patient-derived xenograft (PDX). Immunocytochemical staining, RT-PCR and quantitative real-time PCR showed that, among stemness proteins, CD133, musashi and podoplanin were expressed at elevated levels in rPB TSs, but nestin was not. rPB TSs cultured under neuro-glial differentiation conditions expressed TUBB3, but not GFAP, MBP or NeuN. Unlike glioblastoma TSs, rPB TSs showed no clear evidence of invasion in 3D invasion assay or increased expression of genes associated with epithelial-mesenchymal transition. An orthotopic xenograft showed that tumor xenografts replicated the histopathological features of the patient tumor and expressed similar genome profiles, as determined by short tandem repeat genotyping. These data demonstrate the isolation and the characterization of rPB TSs for the first time. Using an orthotopic xenograft, we showed that rPB TSs could replicate the patient tumor, demonstrating their potential as a PDX for precision medicine.

Isolation of tumor spheres and mesenchymal stem-like cells from a single primitive neuroectodermal tumor specimen.

PURPOSE: It has been reported that cancer stem cells (CSCs) can be isolated from primitive neuroectodermal tumor (PNET) specimens. Moreover, mesenchymal stem-like cells (MSLCs) have been isolated from Korean glioma specimens. Here, we tested whether tumor spheres and MSLCs can be simultaneously isolated from a single PNET specimen, a question that has not been addressed. METHODS: We isolated single-cell suspensions from PNET specimens, then cultured these cells using methods for MSLCs or CSCs. Cultured cells were analyzed for surface markers of CSCs using immunocytochemistry and for surface markers of bone marrow-derived mesenchymal stem cells (BM-MSCs) using fluorescence-activated cell sorting (FACS). Tumor spheres were exposed to neural differentiation conditions, and MSLCs were exposed to mesenchymal differentiation conditions. Possible locations of MSLCs within PNET specimens were determined by immunofluorescence analysis of tumor sections. RESULTS: Cells similar to tumor spheres and MSLCs were independently isolated from one of two PNET specimens. Spheroid cells, termed PNET spheres, were positive for CD133 and nestin, and negative for musashi and podoplanin. PNET spheres were capable of differentiation into immature neural cells and astrocytes, but not oligodendrocytes or mature neural cells. FACS analysis revealed that adherent cells isolated from the same PNET specimen, termed PNET-MSLCs, had surface markers similar to BM-MSCs. These cells were capable of mesenchymal differentiation. Immunofluorescence labeling indicated that some CD105(+) cells might be closely related to endothelial cells and pericytes. CONCLUSION: We showed that both tumor spheres and MSLCs can be isolated from the same PNET specimen. PNET-MSLCs occupied a niche in the vicinity of the vasculature and could be a source of stroma for PNETs.

Inhibitory morphogens and monopodial branching of the embryonic chicken lung.

BACKGROUND: Branching morphogenesis generates a diverse array of epithelial patterns, including dichotomous and monopodial geometries. Dichotomous branching can be instructed by concentration gradients of epithelial-derived inhibitory morphogens, including transforming growth factor-ß (TGFß), which is responsible for ramification of the pubertal mammary gland. Here, we investigated the role of autocrine inhibitory morphogens in monopodial branching morphogenesis of the embryonic chicken lung. RESULTS: Computational modeling and experiments using cultured organ explants each separately revealed that monopodial branching patterns cannot be specified by a single epithelial-derived autocrine morphogen gradient. Instead, signaling by means of TGFß1 and bone morphogenetic protein-4 (BMP4) differentially affect the rates of branching and growth of the airways. Allometric analysis revealed that development of the epithelial tree obeys power-law dynamics; TGFß1 and BMP4 have distinct but reversible effects on the scaling coefficient of the power law. CONCLUSIONS: These data suggest that although autocrine inhibition cannot specify monopodial branching, inhibitory morphogens define the dynamics of lung morphogenesis.