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Ching-Long Chen,1,2 Yi-Hao Chen,1,2 Ming-Cheng Tai,2 Chang-Min Liang,2 Da-Wen Lu,1,2 Jiann-Torng Chen1,2 1Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan; 2Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan Abstract: Proliferative vitreoretinopathy (PVR) is the main cause of failure following retinal detachment surgery. Transforming growth factor (TGF)-β2-induced epithelial-to-mesenchymal transition (EMT) plays an important role in the development of PVR, and EMT inhibition decreases collagen gel contraction and fibrotic membrane formation, resulting in prevention of PVR. Resveratrol is naturally found in red wine and has inhibitory effects on EMT. Resveratrol is widely used in cardioprotection, neuroprotection, chemotherapy, and antiaging therapy. The purpose of this study was to investigate the effects of resveratrol on TGF-β2-induced EMT in ARPE-19 cells in vitro. We found that resveratrol suppressed the decrease of zona occludens-1 (ZO-1) and caused an increase of alpha-smooth muscle actin expression in TGF-β2-treated ARPE-19 cells, assessed using Western blots; moreover, it also suppressed the decrease in ZO-1 and the increase of vimentin expression, observed using immunocytochemistry. Resveratrol attenuated TGF-β2-induced wound closure and cell migration in ARPE-19 cells in a scratch wound test and modified Boyden chamber assay, respectively. We also found that resveratrol reduced collagen gel contraction – assessed by collagen matrix contraction assay – and suppressed the phosphorylation of Smad2 and Smad3 in TGF-β2-treated ARPE-19 cells. These results suggest that resveratrol mediates anti-EMT effects, which could be used in the prevention of PVR. Keywords: resveratrol, epithelial-to-mesenchymal transition, proliferative vitreoretinopathy, transforming growth factor-β2, retinal pigment epithelial cells

Clinical Relevance: Meibomian gland dysfunction and dry eye disease are closely related conditions that often coexist and can contribute to the development of each other. Understanding the similarities and differences between these diseases can assist clinicians in implementing effective treatments for both conditions in a clinical setting., Background: Dry eye disease is a multifactorial disease of the tears and ocular surface. This study aimed to evaluate the demographic characteristics of patients with meibomian gland dysfunction in Taiwan, investigate the association between meibomian gland dysfunction and dry eye parameters, and estimate the prevalence of meibomian gland dysfunction among patients with dry eye symptoms at a tertiary referral centre., Methods: This cross-sectional study enrolled patients aged ≥20 years who complained of dry eye symptoms and visited a tertiary centre between September 2019 and March 2020. The patients completed the Ocular Surface Disease Index and Standard Patient Evaluation of Eye Dryness questionnaires before undergoing ocular examination. The lipid layer thickness and meiboscale scores were recorded. In addition, the study measured tear film break-up time, examined corneal staining, and evaluated the number of meibomian glands yielding liquid secretions using a slit lamp., Results: The study evaluated 202 eyes of 202 patients with a mean age of 58.05 ± 13.34 years. The prevalence of meibomian gland dysfunction was 93%. Mean meiboscale score and age were negatively associated, and tear film break-up time was positively associated with the mean number of meibomian glands yielding liquid secretions. Hyperlipidaemia and smoking were the main risk factors for Meibomian gland dysfunction., Conclusions: The prevalence of meibomian gland dysfunction among patients with dry eye symptoms was extremely high at the tertiary centre, highlighting the strong relationship between Meibomian gland dysfunction and dry eye disease. Clinicians should consider meibomian gland dysfunction as a possible cause of dry eye.

In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors. A genome-wide association study was conducted in 2,850 women of European ancestry with breast cancer using TP53 and PIK3CA mutation status (positive or negative) as well as specific functional categories [e.g., TP53 gain-of-function (GOF) and loss-of-function, PIK3CA activating] as phenotypes. Germline variants showing evidence of association were selected for validation analyses and tested in multiple independent datasets. Discovery association analyses found five variants associated with TP53 mutation status with P values <1 × 10-6 and 33 variants with P values <1 × 10-5. Forty-four variants were associated with PIK3CA mutation status with P values <1 × 10-5. In validation analyses, only variants at the ESR1 locus were associated with TP53 mutation status after multiple comparisons corrections. Combined analyses in European and Malaysian populations found ESR1 locus variants rs9383938 and rs9479090 associated with the presence of TP53 mutations overall (P values 2 × 10-11 and 4.6 × 10-10, respectively). rs9383938 also showed association with TP53 GOF mutations (P value 6.1 × 10-7). rs9479090 showed suggestive evidence (P value 0.02) for association with TP53 mutation status in African ancestry populations. No other variants were significantly associated with TP53 or PIK3CA mutation status. Larger studies are needed to confirm these findings and determine if additional variants contribute to ancestry-specific differences in mutation frequency., Significance: Emerging data show ancestry-specific differences in TP53 and PIK3CA mutation frequency in breast tumors suggesting that germline variants may influence somatic mutational processes. This study identified variants near ESR1 associated with TP53 mutation status and identified additional loci with suggestive association which may provide biological insight into observed differences., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Background: Hyperopia is a significant refractive error in children, often leading to vision impairment. This study aimed to investigate whether partial or full spectacle correction is benefit for hyperopia in preschool-aged children. Methods: A retrospective study was conducted on hyperopic children visited to teaching medical center outpatient clinic between October 2011 and October 2018, and were categorized into three groups: full correction, overcorrection, and undercorrection. The study was approved by the institutional ethical committee of Tri-Service General Hospital. Results: Following a minimum of one-year follow-up period, no statistically significant differences were observed in best-corrected visual acuity (BCVA) among children receiving full, over, or under spectacle correction. Notably, the overcorrection group exhibited a significant reduction in spherical equivalent (SE) compared to both the full and under correction groups, indicating a better SE with spectacle overcorrection. Conclusions: Spectacle overcorrection may offer potential benefits for enhancing SE in preschool children with hyperopia. Nevertheless, further investigation through randomized controlled trials is warranted to establish the validity of this approach and its impact on visual outcomes in this hyperopic pediatric population., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Aims: To compare the refractive and visual outcomes of femtosecond laser-assisted astigmatic keratotomy (FSAK) and toric intraocular lens (IOL) implantation for correcting astigmatism in cataract patients., Methods: Studies were retrieved from the Ovid-Medline, EMBASE, Cochrane Central Register of Controlled Trials and Scopus which compared FSAK and toric IOL for astigmatism correction in cataract patients. Outcome measures included postoperative refractive cylinder, correction index, uncorrected distance visual acuity (UDVA), the proportion of patients achieving a residual refractive cylinder of 1.00 dioptre or less, target-induced astigmatism (TIA) and surgically induced astigmatism (SIA). The trial sequential analysis (TSA) was used to collect firm evidence supporting our conclusion., Results: 9 studies encompassing 590 participants were analysed. The meta-analysis revealed that toric IOLs could result in less postoperative refractive cylinder and provide better UDVA compared with FSAK. The TSA disclosed strong evidence of lower postoperative refractive cylinder in the toric IOL group compared with that of the FSAK group. FSAK showed a smaller correction index and lower mean TIA and SIA compared with toric IOLs., Conclusions: For cataract patients, both FSAK and toric IOLs are effective methods for correcting astigmatism. However, toric IOLs offer less postoperative astigmatism and result in better postoperative UDVA compared with FSAK. In vector analysis of astigmatism, toric IOLs can also produce higher TIA and SIA. Additionally, neither method is associated with severe untreatable complications. Therefore, the conclusion is that toric IOLs are the preferred choice for astigmatism correction in cataract patients and FSAK serves as a viable alternative when toric IOLs are contraindicated., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Early-stage lung adenocarcinoma (LUAD) patients remain at substantial risk for recurrence and disease-related death, highlighting the unmet need of biomarkers for the assessment and identification of those in an early stage who would likely benefit from adjuvant chemotherapy. To identify circulating miRNAs useful for predicting recurrence in early-stage LUAD, we performed miRNA microarray analysis with pools of pretreatment plasma samples from patients with stage I LUAD who developed recurrence or remained recurrence-free during the follow-up period. Subsequent validation in 85 patients with stage I LUAD resulted in the development of a circulating miRNA panel comprising miR-23a-3p, miR-320c, and miR-125b-5p and yielding an area under the curve (AUC) of 0.776 in predicting recurrence. Furthermore, the three-miRNA panel yielded an AUC of 0.804, with a sensitivity of 45.8% at 95% specificity in the independent test set of 57 stage I and II LUAD patients. The miRNA panel score was a significant and independent factor for predicting disease-free survival ( p < 0.001, hazard ratio [HR] = 1.64, 95% confidence interval [CI] = 1.51-4.22) and overall survival ( p = 0.001, HR = 1.51, 95% CI = 1.17-1.94). This circulating miRNA panel is a useful noninvasive tool to stratify early-stage LUAD patients and determine an appropriate treatment plan with maximal efficacy.

Background: Clinical management of Asian BRCA1 and BRCA2 pathogenic variants (PV) carriers remains challenging due to imprecise age-specific breast (BC) and ovarian cancer (OC) risks estimates. We aimed to refine these estimates using six multi-ethnic studies in Asia., Methods: Data were collected on 271 BRCA1 and 301 BRCA2 families from Malaysia and Singapore, ascertained through population/hospital-based case-series (88%) and genetic clinics (12%). Age-specific cancer risks were estimated using a modified segregation analysis method, adjusted for ascertainment., Findings: BC and OC relative risks (RRs) varied across age groups for both BRCA1 and BRCA 2. The age-specific RR estimates were similar across ethnicities and country of residence. For BRCA1 carriers of Malay, Indian and Chinese ancestry born between 1950 and 1959 in Malaysia, the cumulative risk (95% CI) of BC by age 80 was 40% (36%-44%), 49% (44%-53%) and 55% (51%-60%), respectively. The corresponding estimates for BRCA2 were 29% (26-32%), 36% (33%-40%) and 42% (38%-45%). The corresponding cumulative BC risks for Singapore residents from the same birth cohort, where the underlying population cancer incidences are higher compared to Malaysia, were higher, varying by ancestry group between 57 and 61% for BRCA1, and between 43 and 47% for BRCA2 carriers. The cumulative risk of OC by age 80 was 31% (27-36%) for BRCA1 and 12% (10%-15%) for BRCA2 carriers in Malaysia born between 1950 and 1959; and 42% (34-50%) for BRCA1 and 20% (14-27%) for BRCA2 carriers of the same birth cohort in Singapore. There was evidence of increased BC and OC risks for women from >1960 birth cohorts (p-value = 3.6 × 10 -5 for BRCA1 and 0.018 for BRCA 2)., Interpretation: The absolute age-specific cancer risks of Asian carriers vary depending on the underlying population-specific cancer incidences, and hence should be customised to allow for more accurate cancer risk management., Funding: Wellcome Trust [grant no: v203477/Z/16/Z]; CRUK (PPRPGM-Nov20∖100002)., Competing Interests: Z.Z received honorarium from AstraZeneca. J.N received research funding from AstraZeneca and MiRXES. A.C.A is listed as creator of the BOADICEA model which has been licensed by Cambridge Enterprise, from which University of Cambridge may receive royalties. N.A.M.T received honoraria for lectures from Zuellig Pharma Sdn Bhd and Astra Zeneca, received support for attending meetings and/or travel from MSD and Astra Zeneca. S.Y.Y received speaker's honoraria from Astra Zeneca, she is the president of Genetic Counselling Society Malaysia., (© 2024 The Author(s).)

This study compared the visual outcomes and complications between sutureless scleral-fixated intraocular lens and iris claw intraocular lens implantation in aphakia without adequate capsule and/or zonule support. Studies comparing the clinical outcomes of scleral-fixated intraocular lens and iris claw intraocular lens implantation published until April 2022 were retrieved from the PubMed, EMBASE, Cochrane Library, and Google Scholar databases. The outcomes included postoperative final visual acuity, surgical time, surgery-induced astigmatism, and complications. The weighted mean difference and odds ratio were calculated. Two randomized controlled trials and five cohort studies, including 244 and 290 eyes in the scleral-fixated intraocular lens group and iris claw group, respectively, were included. Scleral-fixated intraocular lens implantation results in a better postoperative final corrected distance visual acuity compared with iris claw intraocular lens implantation; however, it is more time-consuming. Scleral-fixated intraocular lens implantation seems to have lesser incidences of surgery-induced astigmatism. Furthermore, both procedures have a similar complication rate. Therefore, based on current best evidence, these two procedures should be considered according to patient's conditions., (© 2024. The Author(s).)

Clinical Relevance: Corneal epithelial healing after refractive surgery is a clinically significant issue, especially for surface ablation procedures, and this can be monitored using optical coherence tomography (OCT)., Background: The aim of this work is to investigate the corneal epithelial thickness and irregularity by OCT after transepithelial photorefractive keratectomy (t-PRK) and analyse its correlation with visual and refractive outcomes., Methods: Patients aged ≥18 years with myopia, with or without astigmatism, who underwent t-PRK between May 2020 and August 2021 were included. All participants were subjected to complete ophthalmic examinations and OCT pachymetry at every follow-up visit. Patients were followed up at 1 week and 1, 3, and 6 months postoperatively., Results: A total of 67 patients (126 eyes) were enrolled in this study. One month postoperatively, spherical equivalent refraction and visual acuity achieved preliminary stability. However, central corneal epithelial thickness (CCET) and standard deviation of the corneal epithelial thickness (SD cet ) took 3-6 months to progressive recovery. Patients with higher baseline spherical equivalent refraction were associated with slower epithelial recovery. At every follow-up time point, a significant superior-inferior difference in the minimum corneal epithelial thickness area was observed. Higher stromal haze was correlated with higher spherical equivalent refraction (both baseline and residual) but had no relation with visual outcomes. There was a significant correlation between higher CCET with a better uncorrected distance visual acuity and lower corneal epithelial thickness irregularity., Conclusions: CCET and SD cet measured by OCT seem to be a good auxiliary indicator for reflecting the status of corneal wound recovery after t-PRK surgery. However, a well-designed randomised control study is needed to confirm the study results.

Purpose: Mammographic density (MD), after accounting for age and body mass index (BMI), is a strong heritable risk factor for breast cancer. Genome-wide association studies (GWAS) have identified 64 SNPs in 55 independent loci associated with MD in women of European ancestry. Their associations with MD in Asian women, however, are largely unknown., Method: Using linear regression adjusting for age, BMI, and ancestry-informative principal components, we evaluated the associations of previously reported MD-associated SNPs with MD in a multi-ethnic cohort of Asian ancestry. Area and volumetric mammographic densities were determined using STRATUS (N = 2450) and Volpara™ (N = 2257). We also assessed the associations of these SNPs with breast cancer risk in an Asian population of 14,570 cases and 80,870 controls., Results: Of the 61 SNPs available in our data, 21 were associated with MD at a nominal threshold of P value < 0.05, all in consistent directions with those reported in European ancestry populations. Of the remaining 40 variants with a P-value of association > 0.05, 29 variants showed consistent directions of association as those previously reported. We found that nine of the 21 MD-associated SNPs in this study were also associated with breast cancer risk in Asian women (P < 0.05), seven of which showed a direction of associations that was consistent with that reported for MD., Conclusion: Our study confirms the associations of 21 SNPs (19/55 or 34.5% out of all known MD loci identified in women of European ancestry) with area and/or volumetric densities in Asian women, and further supports the evidence of a shared genetic basis through common genetic variants for MD and breast cancer risk., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: This study aimed to evaluate corneal topographic findings in patients with thyroid eye disease (TED) using a Galilei camera and compare their corneal topographic parameters with those of control patients., Methods: This retrospective cross-sectional study included 52 eyes of 26 patients with TED (study group) and 40 eyes of 20 controls treated at a tertiary medical center in Taiwan between January and December 2021. All participants underwent basic ophthalmological examinations, corneal topography examination using a Galilei dual Scheimpflug camera, thyroid function examination, and orbital computed tomography. The corneal topographic parameters and cross-sectional area of the extraocular muscles were compared between the TED and control groups., Results: Several corneal topographic parameters, including the Inferior-Superior Index, Keratoconus Prediction Index, Surface Asymmetry Index, Surface Regularity Index, simulated keratometry astigmatism, and anterior instantaneous astigmatism axis, differed significantly between the groups (P ≤ 0.05). The anterior instantaneous astigmatism axis was more oblique in the TED group than in the control group. A scatter plot revealed a more scattered distribution in the anterior instantaneous astigmatism axis in the TED group than in the control group. However, the corneal topographic parameters did not differ significantly among the different thyroid dysfunction groups., Conclusions: The corneas of patients with TED are suspicious and keratoconus-like, and TED can increase anterior corneal astigmatism in the oblique axis, albeit with large variations in the extent of change. These TED-related corneal changes may aid in the early diagnosis of TED, especially "silent" TED., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Purpose: To compare the effects of different combinations of radical nephroureterectomy (RNU) and bladder cuff excision (BCE) surgical procedures on intravesical recurrence (IVR) in patients with upper tract urothelial carcinoma (UTUC)., Materials and Methods: This retrospective observational study included 452 patients who underwent RNU with BCE for UTUC between January 2010 and December 2020. The patients were classified into three groups based on different combinations of RNU and BCE surgical procedures: open RNU with open BCE (group 1, n=104), minimally invasive (MIS) RNU with open BCE (group 2, n=196), and MIS RNU with intracorporeal BCE (group 3, n=152). Data on demographics, body mass index, history, preoperative renal function, perioperative status, tumor characteristics, histopathology, and recurrence conditions were collected. Multivariate Cox regression analyses were performed to determine the impact of the surgical procedures on IVR. P-values < 0.05 were considered statistically significant., Results: After a median follow-up of 29.5 months, the IVR rate was 29.6% and the IVR-free survival rate was the lowest in group 2 (group 1 vs. group 2 vs. group 3: 69.0% vs. 55.1% vs. 67.5%; log-rank P=0.048). The overall survival rate was comparable among the three groups. Multivariate analysis revealed that group 2 had a significantly higher risk of IVR than group 1 (hazard ratio=1.949, 95% confidence interval=1.082-3.511, P=0.026), while groups 1 and 3 had similar risks., Conclusions: For patients with UTUC, MIS RNU with open BCE is associated with a higher risk of IVR than open RNU with open BCE and MIS RNU with intracorporeal BCE., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Purpose: To develop a deep convolutional neural network that enables the prediction of postoperative visual outcomes after epiretinal membrane surgery based on preoperative optical coherence tomography images and clinical parameters to refine surgical decision making., Methods: A total of 529 patients with idiopathic epiretinal membrane who underwent standard vitrectomy with epiretinal membrane peeling surgery by two surgeons between January 1, 2014, and June 1, 2020, were enrolled. The newly developed Heterogeneous Data Fusion Net was introduced to predict postoperative visual acuity outcomes (improvement ≥2 lines in Snellen chart) 12 months after surgery based on preoperative cross-sectional optical coherence tomography images and clinical factors, including age, sex, and preoperative visual acuity. The predictive accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve of the convolutional neural network model were evaluated., Results: The developed model demonstrated an overall accuracy for visual outcome prediction of 88.68% (95% CI, 79.0%-95.7%) with an area under the receiver operating characteristic curve of 97.8% (95% CI, 86.8%-98.0%), sensitivity of 87.0% (95% CI, 67.9%-95.5%), specificity of 92.9% (95% CI, 77.4%-98.0%), precision of 0.909, recall of 0.870, and F1 score of 0.889. The heatmaps identified the critical area for prediction as the ellipsoid zone of photoreceptors and the superficial retina, which was subjected to tangential traction of the proliferative membrane., Conclusion: The novel Heterogeneous Data Fusion Net demonstrated high accuracy in the automated prediction of visual outcomes after weighing and leveraging multiple clinical parameters, including optical coherence tomography images. This approach may be helpful in establishing personalized therapeutic strategies for epiretinal membrane management.

Background: Microdissection testicular sperm extraction (mTESE) is the mainstay of sperm retrieval in men with nonobstructive azoospermia (NOA). Some experts believe that a resting period of ≥6 months is required between procedures to ensure better sperm retrieval rates and fewer complications. However, no scientific studies have investigated how long patients should wait before arranging a second mTESE procedure. This retrospective study aimed to evaluate whether good success rates are still achieved when a repeat mTESE procedure is performed within 6 months., Methods: Total 146 patients with NOA who underwent mTESE twice from the same testis between May 2012 and September 2019 were retrospectively collected. These patients were categorized into three groups according to the time interval between the two mTESE surgeries, with 44, 60, and 42 patients undergoing a repeat mTESE after <3 months (group I), between 3 and 6 months (group II), and >6 months (group III) after the first procedure, respectively., Results: No significant differences were observed between groups in terms of patient characteristics and preoperative hormone profiles. Overall sperm retrieval rates did not differ among the three groups (93.2%, 90.0%, and 88.1% in groups I, II, and III, respectively [ p = 0.719]), nor did fertility outcomes, including rates of fertilization, biochemical pregnancy, clinical pregnancy, and cumulative live births., Conclusion: Sperm retrieval rates for repeat mTESE procedures were consistently high, even when the second procedure was performed within 6 months of the first. Repeat mTESE within 6 months is not a limitation for patients with NOA, if required clinically., Competing Interests: Conflicts of interest: Dr. William J. Huang, an editorial board member at Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)

Background: Laparoscopic nephroureterectomy (LNU) has become popular in treating upper urinary tract urothelial carcinoma (UTUC) and an emerging trend was observed in robotic approaches. Therefore, we compared robot-assisted radical nephroureterectomy (RANU) and LNU for the treatment of UTUC. Materials and Methods: This observational and retrospective case-series study included UTUC patients who underwent LNU or RANU. A pure laparoscopic approach was adopted in the LNU treatment group, and bladder cuff excision (BCE) was performed mostly with the open approach. Either the da Vinci Si or Xi surgical system was used for RANU. Extravesical BCE was performed, and bladder defects were closed intracorporeally. Perioperative and oncologic outcomes were compared between the LNU and RANU groups. Results: A total of 231 patients who underwent RANU ( n  = 87) or LNU ( n  = 144) were included. No significant differences were noted between the groups in terms of demographics, tumor characteristics, operative time, catheter time, or complications. Compared with LNU, RANU had a lower intraoperative blood loss (30 vs. 150 mL, p  < 0.001) and shorter postoperative hospital stay (8 vs. 9 days, p  = 0.009). The 5-year overall survival, cancer-specific survival, and bladder recurrence-free survival were comparable between the groups. Conclusion: Compared with LNU, RANU had similar perioperative and oncologic outcomes but was superior in terms of intraoperative blood loss and postoperative length of hospital stay. However, considering the potential biases owing to the heterogeneity of our cases, the interpretation of the results must be very cautious.

Aim: Oral health and ocular diseases may be associated with collagen defects and inflammation status. However, the results from prior studies are conflicting. The aim of this study was to explore the association of dental caries and periodontitis with myopia in young adults., Materials and Methods: A total of 938 military personnel aged 19-39 years receiving both oral and eye examinations from 2018 through 2020 were included in this study in Taiwan. The severity of myopia was graded as no myopia (diopters > - 0.5, N = 459), low myopia (diopters: - 0.5 to -5.9, N = 225) and high myopia (diopters ≤ - 6.0, N = 254). A multiple logistic regression analysis with adjustments for age, body mass index, systolic blood pressure, smoking, alcohol consumption, missing teeth numbers, blood leucocyte counts, triglycerides, high-density lipoprotein, and uric acid were used to determine the associations of actively dental caries, filled teeth and stage II/III periodontitis with myopia., Results: The presence of any actively dental caries was significantly associated with a higher risk of any myopia (low or high) (odds ratio [OR] and 95% confidence intervals [95% CI] 1.42 [1.04-1.94]), whereas there was no association for filled teeth. Moreover, the association for stage II/III periodontitis was only observed with high myopia (OR: 1.52 [1.07-2.15]) and was not observed with low myopia., Conclusions: Our findings suggest that only actively dental caries and a higher severity of periodontitis were associated with myopia among young adults, thus highlighting the dental inflammation status in the oral cavity as a potential link to ocular diseases., (© 2022. The Author(s).)

There is substantial interest in mining neoantigens for cancer applications. Non-canonical proteins resulting from frameshift mutations have been identified as neoantigens in cancer. We investigated the landscape of non-canonical proteins in non-small cell lung cancer (NSCLC) and their induced immune response in the form of autoantibodies. A database of cryptoproteins was computationally constructed and comprised all alternate open reading frames (altORFs) and ORFs identified in pseudogenes, noncoding RNAs, and untranslated regions of mRNAs that did not align with known canonical proteins. Proteomic profiles of seventeen lung adenocarcinoma (LUAD) cell lines were searched to evaluate the occurrence of cryptoproteins. To assess the immunogenicity, immunoglobulin (Ig)-bound cryptoproteins in plasmas were profiled by mass spectrometry. The specimen set consisted of plasmas from 30 newly diagnosed NSCLC cases, pre-diagnostic plasmas from 51 NSCLC cases, and 102 control plasmas. An analysis of LUAD cell lines identified 420 cryptoproteins. Plasma Ig-bound analyses revealed 90 cryptoproteins uniquely found in cases and 14 cryptoproteins that had a fold-change >2 compared to controls. In pre-diagnostic samples, 17 Ig-bound cryptoproteins yielded an odds ratio ≥2. Eight Ig-bound cryptoproteins were elevated in both pre-diagnostic and newly diagnosed cases compared to controls. Cryptoproteins represent a class of neoantigens that induce an autoantibody response in NSCLC.

Purpose: With the development of poly (ADP-ribose) polymerase inhibitors for treatment of patients with cancer with an altered BRCA1 or BRCA2 gene, there is an urgent need to ensure that there are appropriate strategies for identifying mutation carriers while balancing the increased demand for and cost of cancer genetics services. To date, the majority of mutation prediction tools have been developed in women of European descent where the age and cancer-subtype distributions are different from that in Asian women., Methods: In this study, we built a new model (Asian Risk Calculator) for estimating the likelihood of carrying a pathogenic variant in BRCA1 or BRCA2 gene, using germline BRCA genetic testing results in a cross-sectional population-based study of 8,162 Asian patients with breast cancer. We compared the model performance to existing mutation prediction models. The models were evaluated for discrimination and calibration., Results: Asian Risk Calculator included age of diagnosis, ethnicity, bilateral breast cancer, tumor biomarkers, and family history of breast cancer or ovarian cancer as predictors. The inclusion of tumor grade improved significantly the model performance. The full model was calibrated (Hosmer-Lemeshow P value = .614) and discriminated well between BRCA and non- BRCA pathogenic variant carriers (area under receiver operating curve, 0.80; 95% CI, 0.75 to 0.84). Addition of grade to the existing clinical genetic testing criteria targeting patients with breast cancer age younger than 45 years reduced the proportion of patients referred for genetic counseling and testing from 37% to 33% ( P value = .003), thereby improving the overall efficacy., Conclusion: Population-specific customization of mutation prediction models and clinical genetic testing criteria improved the accuracy of BRCA mutation prediction in Asian patients., Competing Interests: Andrew LeeEmployment: IlluminaPatents, Royalties, Other Intellectual Property: I am an inventor of the BOADICEA model that is licensed to Cambridge Enterprise (part of the University of Cambridge) for commercialization. I have received royalties from Cambridge Enterprise Nur Aishah Mohd TaibConsulting or Advisory Role: Roche, AstraZeneca, MSD Veronique K.M. TanHonoraria: AstraZeneca (Inst), Roche (Inst)Consulting or Advisory Role: Bertis (Inst) Douglas F. EastonPatents, Royalties, Other Intellectual Property: Royalties from Boadicea risk prediction tool (Inst) Antonis C. AntoniouPatents, Royalties, Other Intellectual Property: Inventor of the BOADICEA model, which has been licensed to Cambridge Enterprise for commercialization. I may receive royalties if commercialization is realized (Inst) Soo Hwang TeoSpeakers' Bureau: AstraZeneca, Pfizer, RocheNo other potential conflicts of interest were reported.

Background: Family history, and genetic and non-genetic risk factors can stratify women according to their individual risk of developing breast cancer. The extent of overlap between these risk predictors is not clear., Methods: In this case-only analysis involving 7600 Asian breast cancer patients diagnosed between age 30 and 75 years, we examined identification of high-risk patients based on positive family history, the Gail model 5-year absolute risk [5yAR] above 1.3%, breast cancer predisposition genes (protein-truncating variants [PTV] in ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, or TP53), and polygenic risk score (PRS) 5yAR above 1.3%., Results: Correlation between 5yAR (at age of diagnosis) predicted by PRS and the Gail model was low (r=0.27). Fifty-three percent of breast cancer patients (n=4041) were considered high risk by one or more classification criteria. Positive family history, PTV carriership, PRS, or the Gail model identified 1247 (16%), 385 (5%), 2774 (36%), and 1592 (21%) patients who were considered at high risk, respectively. In a subset of 3227 women aged below 50 years, the four models studied identified 470 (15%), 213 (7%), 769 (24%), and 325 (10%) unique patients who were considered at high risk, respectively. For younger women, PRS and PTVs together identified 745 (59% of 1276) high-risk individuals who were not identified by the Gail model or family history., Conclusions: Family history and genetic and non-genetic risk stratification tools have the potential to complement one another to identify women at high risk., (© 2022. The Author(s).)

While prognosis and risk of progression are crucial in developing precise therapeutic strategy in neovascular age-related macular degeneration (nAMD), limited predictive tools are available. We proposed a novel deep convolutional neural network that enables feature extraction through image and non-image data integration to seize imperative information and achieve highly accurate outcome prediction. The Heterogeneous Data Fusion Net (HDF-Net) was designed to predict visual acuity (VA) outcome (improvement ≥ 2 line or not) at 12th months after anti-VEGF treatment. A set of pre-treatment optical coherence tomography (OCT) image and non-image demographic features were employed as input data and the corresponding 12th-month post-treatment VA as the target data to train, validate, and test the HDF-Net. This newly designed HDF-Net demonstrated an AUC of 0.989 (95% CI 0.970-0.999), accuracy of 0.936 [95% confidence interval (CI) 0.889-0.964], sensitivity of 0.933 (95% CI 0.841-0.974), and specificity of 0.938 (95% CI 0.877-0.969). By simulating the clinical decision process with mixed pre-treatment information from raw OCT images and numeric data, HDF-Net demonstrated promising performance in predicting individualized treatment outcome. The results highlight the potential of deep learning to simultaneously process a broad range of clinical data to weigh and leverage the complete information of the patient. This novel approach is an important step toward real-world personalized therapeutic strategy for typical nAMD., (© 2022. The Author(s).)

Purpose: The aim of this study was to develop a non-cytotoxic, biocompatible innovative acellular porcine cornea (APC) for corneal wound healing and corneal blindness treatment., Methods: APC was produced by using supercritical carbon dioxide (SCCO2) to decellularize the porcine cornea. Decellularization of the porcine cornea was examined by hematoxylin and eosin staining and 4,6-diamidino-2-phenylindole, dihydrochloride staining. The residual DNA content of APC was analyzed in comparison with the native porcine cornea. Virus inactivation up to at least 6 log10 was confirmed for the stepwise process of APC for 4 different model viruses. In addition, a series of in vitro and in vivo tests in accordance with ISO-10993 biocompatibility assay and animal performance tests were performed., Results: APC produced by the SCCO2 process revealed complete decellularization, without any residual non-collagenous proteins. The scanning electron microscopy structural features of the decellularized cornea were similar to those of human. APC was found to be nontoxic and exhibited excellent biocompatibility in both in vitro and in vivo studies. The animal performance test proved that APC exerted excellent adaptability on the cornea and no sign of irritation and good compatibility in lamellar corneal transplantation., Conclusions: APC manufactured by SCCO2 technology revealed complete cells and non-collagenous protein removal compared with the Triton-sodium dodecyl sulfate decellularization process. APC showed excellent biocompatibility in rabbit lamellar corneal transplantation with a follow-up to 1 year. APC can be a potential substitute for human-donated cornea for corneal transplantation in the near future., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups., Methods: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases)., Results: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk., Conclusion: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. All rights reserved.)

Background: Approximately 20% of lung adenocarcinoma (LUAD) is negative for the lineage-specific oncogene Thyroid transcription factor 1 (TTF-1) and exhibits worse clinical outcome with a low frequency of actionable genomic alterations. To identify molecular features associated with TTF-1-negative LUAD, we compared the transcriptomic and proteomic profiles of LUAD cell lines. SRGN , a chondroitin sulfate proteoglycan Serglycin, was identified as a markedly overexpressed gene in TTF-1-negative LUAD. We therefore investigated the roles and regulation of SRGN in TTF-1-negative LUAD., Methods: Proteomic and metabolomic analyses of 41 LUAD cell lines were done using mass spectrometry. The function of SRGN was investigated in 3 TTF-1-negative and 4 TTF-1-positive LUAD cell lines and in a syngeneic mouse model (n = 5 to 8 mice per group). Expression of SRGN was evaluated in 94 and 105 surgically resected LUAD tumor specimens using immunohistochemistry. All statistical tests were 2-sided., Results: SRGN was markedly overexpressed at mRNA and protein levels in TTF-1-negative LUAD cell lines (P < .001 for both mRNA and protein levels). Expression of SRGN in LUAD tumor tissue was associated with poor outcome (hazard ratio = 4.22, 95% confidence interval = 1.12 to 15.86, likelihood ratio test, P = .03), and with higher expression of Programmed cell death 1 ligand 1 (PD-L1) in tumor cells and higher infiltration of Programmed cell death protein 1-positive lymphocytes. SRGN regulated expression of PD-L1 as well as proinflammatory cytokines, including Interleukin-6, Interleukin-8, and C-X-C motif chemokine 1 in LUAD cell lines; increased migratory and invasive properties of LUAD cells and fibroblasts; and enhanced angiogenesis. SRGN was induced by DNA demethylation resulting from Nicotinamide N-methyltransferase-mediated impairment of methionine metabolism., Conclusions: Our findings suggest that SRGN plays a pivotal role in tumor-stromal interaction and reprogramming into an aggressive and immunosuppressive tumor microenvironment in TTF-1-negative LUAD., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent., Methods: Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease., Results: PTV 9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35-5.17], moderately vs well-differentiated 2.33 [1.56-3.49]), as well as luminal B [HER-] and triple-negative subtypes (vs luminal A 2.15 [1.58-2.92] and 2.85 [2.17-3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2-] subtype remained significant after excluding BRCA1/2 carriers. PTV 25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV 25genes carriership, but not PTV 9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16-2.28])., Conclusions: PTV 9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions., (© 2021. The Author(s).)

Purpose: Genome-wide association studies have identified numerous genetic variants that are associated with osteoporosis risk; however, most of them are present in the non-coding regions of the genome and the functional mechanisms are unknown. In this study, we aimed to investigate the potential variation in runt domain transcription factor 2 (RUNX2), which is an osteoblast-specific transcription factor that normally stimulates bone formation and osteoblast differentiation, regarding variants within RUNX2 binding sites and risk of osteoporosis in postmenopausal osteoporosis (PMOP)., Methods: We performed bioinformatics-based prediction by combining whole genome sequencing and chromatin immunoprecipitation sequencing to screen functional SNPs in the RUNX2 binding site using data from the database of Taiwan Biobank; Case-control studies with 651 postmenopausal women comprising 107 osteoporosis patients, 290 osteopenia patients, and 254 controls at Tri-Service General Hospital between 2015 and 2019 were included. The subjects were examined for bone mass density and classified into normal and those with osteopenia or osteoporosis by T-scoring with dual-energy X-ray absorptiometry. Furthermore, mRNA expression and luciferase reporter assay were used to provide additional evidence regarding the associations identified in the association analyses. Chi-square tests and logistic regression were mainly used for statistical assessment., Results: Through candidate gene approaches, 3 SNPs in the RUNX2 binding site were selected. A novel SNP rs6086746 in the PLCB4 promoter was identified to be associated with osteoporosis in Chinese populations. Patients with AA allele had higher risk of osteoporosis than those with GG+AG (adjusted OR = 6.89; 95% confidence intervals: 2.23-21.31, p = 0.001). Moreover, the AA genotype exhibited lower bone mass density (p < 0.05). Regarding mRNA expression, there were large differences in the correlation between PLCB4 and different RUNX2 alleles (Cohen's q = 0.91). Functionally, the rs6086746 A allele reduces the RUNX2 binding affinity, thus enhancing the suppression of PLCB4 expression (p < 0.05)., Conclusions: Our results provide further evidence to support the important role of the SNP rs6086746 in the etiology of osteopenia/osteoporosis, thereby enhancing the current understanding of the susceptibility to osteoporosis. We further studied the mechanism underlying osteoporosis regulation by PLCB4., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tsai, Fang, Wu, Tai, Kao, Huang, Chen, Hsiao, Chiu, Su, Wu and Su.)

Early detection of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcomes; however, PDAC is usually diagnosed late. Therefore, blood-based minimally invasive biomarker assays for limited volume clinical samples are urgently needed. A novel miRNA profiling platform (Abcam Fireplex-Oncology Panel) was used to investigate the feasibility of developing early detection miRNA biomarkers with 20 μL plasma from a training set (58 stage II PDAC cases and 30 controls) and two validation sets (34 stage II PDAC cases and 25 controls; 44 stage II PDAC cases and 18 controls). miR-34a-5p [AUC = 0.77; 95% confidence interval (CI), 0.66-0.87], miR-130a-3p (AUC = 0.74; 95% CI, 0.63-0.84), and miR-222-3p (AUC = 0.70; 95% CI, 0.58-0.81) were identified as significantly differentially abundant in plasma from stage II PDAC versus controls. Although none of the miRNAs individually outperformed the currently used serologic biomarker for PDAC, carbohydrate antigen 19-9 (CA19-9), combining the miRNAs with CA 19-9 improved AUCs from 0.89 (95% CI, 0.81-0.95) for CA 19-9 alone to 0.92 (95% CI, 0.86-0.97), 0.94 (95% CI, 0.89-0.98), and 0.92 (95% CI, 0.87-0.97), respectively. Gene set enrichment analyses of transcripts correlated with high and low expression of the three miRNAs in The Cancer Genome Atlas PDAC sample set. These miRNA biomarkers, assayed in limited volume plasma together with CA19-9, discriminate stage II PDAC from controls with good sensitivity and specificity. Unbiased profiling of larger cohorts should help develop an informative early detection biomarker assay for diagnostic settings. PREVENTION RELEVANCE: Development of minimally invasive biomarker assays for detection of premalignant disease and early-stage pancreatic cancer is key to improving patient survival. This study describes a limited volume plasma miRNA biomarker assay that can detect early-stage resectable pancreatic cancer in clinical samples necessary for effective prevention and clinical intervention., (©2021 American Association for Cancer Research.)

Background: Osteoarthritis (OA) is a multifactorial disease that is associated with several genetic factors. TFAP2A with a motif of C allele at rs6426749 demonstrates a higher binding ability, thereby increasing CDC42 expression, potentially affecting OA occurrence. In this study, we evaluated the role of rs6426749 polymorphisms on knee OA in a female Taiwanese population., Methods: We performed a case-control study of 368 OA cases and 379 controls between March 2017 and October 2018. Knee OA was defined using the Kellgren-Lawrence grading system, and genotypes were determined using the Sequenom MassArray iPLEX Gold assay. Stratified sex and body mass index (BMI) analyses were performed using logistic regression to explore interactions between genes and the environment. We also used expression quantitative trait loci data from the genotype-tissue expression project to conduct functional analyses., Results: The C allele of rs6426749 was associated with the risk of knee OA (odds ratio [OR] = 1.31, 95% confidence interval [CI], 1.01-1.71; p = 0.042), after adjusting for gender, age, and BMI. In addition, subgroup analyses indicated that females expressing C alleles showed an increased risk for knee OA (OR = 1.56; 95% CI, 1.12-2.18; p = 0.009). Females with a normal BMI and the C allele had the highest OA risk (OR = 1.73; 95% CI, 1.08-2.76; p = 0.022)., Conclusion: Our findings indicated that rs6426749 may be related to OA susceptibility in the Taiwanese population. This was particularly true for women with normal BMI., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2021, the Chinese Medical Association.)

Background: Uncontrolled intraocular pressure (IOP) plays a principal role in the deterioration of glaucoma, and the intraocular pressure is also accepted as the most important modifiable factor. Calcium ion has been found to play a vital role in regulating the resistance of the trabecular meshwork in humans. However, the relationship between serum total calcium and IOP has not been well-established., Methods: We investigated the association between serum total calcium and the IOP in a large population (14,037 eligible participants, consisting of 7712 men and 6325 women, were included) at the Tri-Service General Hospital from 2010 to 2016. Several models of covariate adjustments associated with IOP were designed. Univariate and multivariate regression analysis was performed for gender differences in the association between the serum total calcium level and IOP., Results: There was a significant relationship between serum total calcium levels and IOP in women and men with a β coefficient of 0.050 (95% confidence interval (CI), 0.030-0.069) and 0.025 (95%CI, 0.007-0.043). Notably, participants in the highest tertiles of serum total calcium levels had significantly higher IOP, in both the male and female participants., Conclusions: Our study shows that IOP is significantly associated with serum total calcium levels in a large Asian population. This study supports the notion that serum total calcium may play an important role in groups at high risk for elevated IOP.

This population-based retrospective cohort study investigated the prevalence of myopia among patients with Type 1 and Type 2 diabetes mellitus (DM) and evaluate risk factors for myopia in these groups. Records from 2000 to 2012 with at least one year of follow-up from the Taiwan National Health Insurance Research Database were included. This study included 35,538 patients with DM and 71,076 patients without DM. Patients with DM had a significantly higher adjusted hazard ratio for myopia in all age groups and both sexes compared with patients without DM. The subgroup analysis results revealed that the rates of myopia and astigmatism were significantly higher among patients with DM compared with patients without DM aged < 60 years. However, the rates of high myopia or myopia progression to high myopia did not differ significantly between the two groups. These findings indicate that DM is a critical risk factor for myopia and astigmatism among patients aged < 60 years. Therefore, active surveillance and earlier treatment of myopia are critical for patients with DM.

Sphingolipids constitute a class of bio-reactive molecules that transmit signals and exhibit a variety of physical properties in various cell types, though their functions in cancer pathogenesis have yet to be elucidated. Analyses of gene expression profiles of clinical specimens and a panel of cell lines revealed that the ceramide synthase gene CERS6 was overexpressed in non-small-cell lung cancer (NSCLC) tissues, while elevated expression was shown to be associated with poor prognosis and lymph node metastasis. NSCLC profile and in vitro luciferase analysis results suggested that CERS6 overexpression is promoted, at least in part, by reduced miR-101 expression. Under a reduced CERS6 expression condition, the ceramide profile became altered, which was determined to be associated with decreased cell migration and invasion activities in vitro. Furthermore, CERS6 knockdown suppressed RAC1-positive lamellipodia/ruffling formation and attenuated lung metastasis efficiency in mice, while forced expression of CERS6 resulted in an opposite phenotype in examined cell lines. Based on these findings, we consider that ceramide synthesis by CERS6 has important roles in lung cancer migration and metastasis., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

This retrospective, nationwide, matched-cohort study included 4488 new-onset keratoconus (KCN) patients, ≥12 years old, recruited between 2004 and 2011 from the Taiwan National Health Insurance Research Database. The control group included 26,928 non-KCN patients selected from the Taiwan Longitudinal Health Insurance Database 2000. Information for each patient was collected and tracked from the index date until December 2013. The incidence rate of mitral valve prolapse (MVP) was 1.77 times (95% confidence interval (CI) = 1.09-2.88; p = 0.0206) higher in KCN patients ≥40 years old and 1.49 times (95% CI = 1.12-1.98; p = 0.0060) higher in female KCN patients than in controls. After using the Cox proportional hazard regression analysis to adjust for potential confounders, including hypertension, hyperlipidemia, and congestive heart failure, KCN maintained an independent risk factor, MVP being 1.77 times (adjusted hazard ratio (HR) = 1.77, 95% CI = 1.09-2.88) and 1.48 times (adjusted HR = 1.48, 95% CI = 1.11-1.97) more likely to develop in patients ≥40 years old and female patients in the study cohort, respectively. We found that KCN patients ≥40 years of age and female KCN patients have increased risks of MVP. Therefore, it is recommended that KCN patients should be alerted to MVP.

Artificial intelligence (AI), known by some as the industrial revolution (IR) 4.0, is going to change not only the way we do things, how we relate to others, but also what we know about ourselves. This article will first examine what AI is, discuss its impact on industrial, social, and economic changes on humankind in the 21 st century, and then propose a set of principles for AI bioethics. The IR1.0, the IR of the 18 th century, impelled a huge social change without directly complicating human relationships. Modern AI, however, has a tremendous impact on how we do things and also the ways we relate to one another. Facing this challenge, new principles of AI bioethics must be considered and developed to provide guidelines for the AI technology to observe so that the world will be benefited by the progress of this new intelligence., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Tzu Chi Medical Journal.)

Background: Diabetic retinopathy (DR) is indicated as a major cause of blindness in the world. Emerging evidence supports the interaction of iron metabolism with diabetes. However, little research is available concerning the relationship between iron metabolism and DR. The intent of this paper is to describe the correlation between serum iron and the occurrence of DR., Methods: A total of 5321 participants who underwent related examinations as part of the National Health and Nutrition Examination Survey (2005-2008) were included. DR was defined by the criteria of the Early Treatment for Diabetic Retinopathy Study based on nonmydriatic fundus photography. The cutoff point of serum iron for DR was explored by the receiver operating characteristics curve. The relationship of serum iron with the occurrence of DR was explored by multivariate logistic regression models., Results: Participants with DR had significantly lower serum iron than the control group. Serum iron was negatively correlated with the occurrence of DR after the adjustment of pertinent variables (an odds ratio (OR) of 0.995 (95% CI: 0.992-0.999)). After dividing serum iron into quartiles, the third quartile was associated with DR with an OR of 0.601 (95% CI: 0.418-0.863). Furthermore, the cutoff point of serum iron had an inverse relationship for the occurrence of DR with an OR of 0.766 (95% CI: 0.597-0.984)., Conclusion: Serum iron has an inverse association with the occurrence of DR in diabetic adults. The assessment of serum iron levels might be a part of follow-up visits with diabetic patients.

Polygenic risk scores (PRS) have been shown to predict breast cancer risk in European women, but their utility in Asian women is unclear. Here we evaluate the best performing PRSs for European-ancestry women using data from 17,262 breast cancer cases and 17,695 controls of Asian ancestry from 13 case-control studies, and 10,255 Chinese women from a prospective cohort (413 incident breast cancers). Compared to women in the middle quintile of the risk distribution, women in the highest 1% of PRS distribution have a ~2.7-fold risk and women in the lowest 1% of PRS distribution has ~0.4-fold risk of developing breast cancer. There is no evidence of heterogeneity in PRS performance in Chinese, Malay and Indian women. A PRS developed for European-ancestry women is also predictive of breast cancer risk in Asian women and can help in developing risk-stratified screening programmes in Asia.

Background: Previous meta-analyses have explored the association between the C677T polymorphism of methyltetrahydrofolate reductase (MTHFR) and chronic kidney disease (CKD) but there were no studies with a decisive conclusion. Furthermore, the high heterogeneity among different populations is not yet interpreted., Objectives: This study used trial sequential analysis (TSA) to evaluate whether the nowadays conclusion supported by current cumulative samples. We also applied case-weighted meta-regression to explore the potential gene-environment interactions., Methods: For the first stage of this study we conducted a case-control study involving 847 dialysis patients from 7 hemodialysis centers in Taipei during 2015 to 2018 and 755 normal controls from a health center in the Tri-Service General Hospital. The second stage combined the results from the first stage with previous studies. The previous studies were collected from PubMed, EMBASE, and Web of Science databases before January 2018., Results: From the case-control study, the T allele of MTHFR C677T appeared to have a protective effect on end-stage renal disease compared with the C allele [odds ratio (OR): 0.80, 95% CI (confidence interval) = 0.69-0.93]. However, the meta-analysis contradicted the results in Asian (OR = 1.12, 95% CI = 0.96-1.30). The same analysis was also applied in Caucasian and presented similar results from Asian (OR = 1.18, 95% CI = 0.98-1.42). The TSA showed our case-control study to be the decisive sample leading to a null association among Asian population. The high heterogeneity (I = 75%) could explain the contradictory results between the case-control study and the meta-analysis. However, further case-weighted meta-regression did not find any significant interaction between measured factors and MTHFR C677T on CKD., Conclusions: High heterogeneities were found in both Caucasian and Asian, which caused the null relationship in meta-analysis while there were significant effects in individual studies. Future studies should further explore the high heterogeneity that might be hidden in unmeasured gene-environment interactions, to explain the diverse findings among different populations.

Purpose: To improve disease severity classification from fundus images using a hybrid architecture with symptom awareness for diabetic retinopathy (DR)., Methods: We used 26,699 fundus images of 17,834 diabetic patients from three Taiwanese hospitals collected in 2007 to 2018 for DR severity classification. Thirty-seven ophthalmologists verified the images using lesion annotation and severity classification as the ground truth. Two deep learning fusion architectures were proposed: late fusion, which combines lesion and severity classification models in parallel using a postprocessing procedure, and two-stage early fusion, which combines lesion detection and classification models sequentially and mimics the decision-making process of ophthalmologists. Messidor-2 was used with 1748 images to evaluate and benchmark the performance of the architecture. The primary evaluation metrics were classification accuracy, weighted κ statistic, and area under the receiver operating characteristic curve (AUC)., Results: For hospital data, a hybrid architecture achieved a good detection rate, with accuracy and weighted κ of 84.29% and 84.01%, respectively, for five-class DR grading. It also classified the images of early stage DR more accurately than conventional algorithms. The Messidor-2 model achieved an AUC of 97.09% in referral DR detection compared to AUC of 85% to 99% for state-of-the-art algorithms that learned from a larger database., Conclusions: Our hybrid architectures strengthened and extracted characteristics from DR images, while improving the performance of DR grading, thereby increasing the robustness and confidence of the architectures for general use., Translational Relevance: The proposed fusion architectures can enable faster and more accurate diagnosis of various DR pathologies than that obtained in current manual clinical practice., Competing Interests: Disclosure: V.S. Tseng, None; C.-L. Chen, None; C.-M. Liang, None; M.-C. Tai, None; J.-T. Liu, None; P.-Y. Wu, None; M.-S. Deng, None; Y.-W. Lee, None; T.-Y. Huang, None; Y.-H. Chen, None, (Copyright 2020 The Authors.)

Purpose: We assessed whether mitomycin-C (MMC) has different antifibrotic mechanisms in trabeculectomy wound healing., Methods: We identified 2 concentrations of MMC as "low-dose" by using WST-1 assay, Lactic dehydrogenase assay, and fluorescence-activated cell sorting flow cytometry. Senescence-associated β-galactosidase (SA-β-gal) and fibrotic gene expression was examined through immunocytochemistry, flow cytometry, real-time quantitative reverse transcription polymerase chain reaction, Western blotting, zymography, and modified scratch assay in vitro. In vivo, 0.1 mL of MMC or normal saline was injected to Tenon's capsule before trabeculectomy in a rabbit model. SA-β-gal expression, apoptotic cell death, and collagen deposition in sites treated and not treated with MMC were evaluated using terminal dUTP nick end labeling assay and histochemical staining. Bleb function and intraocular pressure (IOP) levels were examined 3, 7, 14, 21, 28, and 35 days after trabeculectomy., Results: In vitro, human Tenon's fibroblast (HTF) senescence was confirmed by observing cell morphologic change, SA-β-gal accumulation, formation of senescence-associated heterochromatin, increased p16INK4a and p21CIP1/WAF1 expression, lower percentage of Ki-67-positive cells, and decreased COL1A1 release. Increased expression of α-SMA, COL1A1, and Smad2 signaling in TGF-β1-induced stress fibers were passivated in senescent HTFs. In addition, cellular migration enhanced by TGF-β1was inactivated. In vivo, histological examination indicated increased SA-β-gal accumulation, lower apoptosis ratios, and looser collagen deposition in sites treated with 0.2 μM MMC. Low-dose MMC-induced cellular senescence prolonged trabeculectomy bleb survival and reduced IOP levels in a rabbit model., Conclusion: Low-dose MMC-induced cellular senescence is involved in the antifibrotic mechanism of trabeculectomy wound healing., Competing Interests: The authors have declared that no competing interests exist.

Objective: To investigate the risk of recurrent corneal erosion (RCE) in patients with diabetes mellitus (DM)., Design, Setting and Participants: This retrospective, nationwide, matched cohort study included 239 854 patients with DM recruited between 2003 and 2005 from the Longitudinal Cohort of Diabetes Patients database. The control group included the same number of age-matched and sex-matched patients without DM selected from the Taiwan Longitudinal Health Insurance Database, 2000. Data for each patient were collected from the index date until December 2013., Main Outcomes and Measures: The incidence and risk of RCE were compared between the two groups. Cox proportional hazards regression was used to calculate the HR for RCE after adjustment for potential confounders. The cumulative RCE incidence rate was calculated using Kaplan-Meier analysis., Results: In total, 1236 patients with DM and 884 controls developed RCE during the follow-up period, resulting in an incidence rate of RCE in patients with DM (5.87/10 000 person-years (PY)) higher than that in the controls (4.23/10 000 PY). After adjustment for potential confounders, including hypertension, hyperlipidaemia, chronic renal disease and keratoconjunctivitis sicca, patients with DM were 1.35 times (95% CI, 1.24 to 1.48) more likely to develop RCE than the total sample cohort., Conclusions: DM increases the risk of RCE, which is an interdisciplinary issue. Therefore, close collaboration between endocrinologists and ophthalmologists is important in managing RCE following DM., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)