Pathomic model based on histopathological features and machine learning to predict IDO1 status and its association with breast cancer prognosis.

PURPOSE: To establish a pathomic model using histopathological image features for predicting indoleamine 2,3-dioxygenase 1 (IDO1) status and its relationship with overall survival (OS) in breast cancer. METHODS: A pathomic model was constructed using machine learning and histopathological images obtained from The Cancer Genome Atlas database to predict IDO1 expression. The model performance was evaluated based on the area under the curve, calibration curve, and decision curve analysis (DCA). Prediction scores (PSes) were generated from the model and applied to divide the patients into two groups. Survival outcomes, gene set enrichment, immune microenvironment, and tumor mutations were assessed between the two groups. RESULTS: Survival analysis followed by multivariate correction revealed that high IDO1 is a protective factor for OS. Further, the model was calibrated, and it exhibited good discrimination. Additionally, the DCA showed that the proposed model provided a good clinical net benefit. The Kaplan-Meier analysis revealed a positive correlation between high PS and improved OS. Univariate and multivariate Cox regression analyses demonstrated that PS is an independent protective factor for OS. Moreover, differentially expressed genes were enriched in various essential biological processes, including extracellular matrix receptor interaction, angiogenesis, transforming growth factor ß signaling, epithelial mesenchymal transition, cell junction, tryptophan metabolism, and heme metabolic processes. PS was positively correlated with M1 macrophages, CD8 + T cells, T follicular helper cells, and tumor mutational burden. CONCLUSION: These results indicate the potential ability of the proposed pathomic model to predict IDO1 status and the OS of breast cancer patients.

Age-period-cohort analysis of the global burden of visual impairment according to major causes: an analysis of the Global Burden of Disease Study 2019.

BACKGROUND: Cataract, glaucoma and age-related macular degeneration (AMD) are major causes of visual impairment. As these are age-related conditions, the prevalence of associated visual impairment is anticipated to increase as the population ages. However, age-period-cohort effects on the disease burden have not been investigated. METHODS: This was a population-based study using aggregated data from the Global Burden of Disease Study 2019. Age-period-cohort analysis was conducted using age-standardised prevalence rates (ASPRs) of visual impairment caused by cataract, glaucoma and AMD as disease burden indicator. RESULTS: In 2019, the estimated global ASPRs of visual impairment due to cataract, glaucoma and AMD were 1207.9, 94.7 and 96.8 per 100 000 people, respectively. Between 1990 and 2019, the global visual impairment ASPRs for glaucoma and AMD declined by 15.4% and 2.0%, respectively, whereas that for cataract increased by 5.0%. Wide heterogeneity was observed in age-period-cohort effects on ASPRs across different Sociodemographic Index (SDI) regions. Low-middle SDI regions had the largest ASPR reductions for all three eye diseases and showed improvement in both period and cohort effects. In contrast, in high-middle SDI regions, visual impairment ASPRs significantly increased during the study period with unfavourable patterns. CONCLUSIONS: The wide heterogeneity in age-period-cohort effects reflects different stages of societal transition and vision health. The unfavourable trends in age-period-cohort effects on disease prevalence identified in specific groups provide key information that may be used to identify priority groups in need of treatment and prevention.

Universal crRNA Acylation Strategy for Robust Photo-Initiated One-Pot CRISPR-Cas12a Nucleic Acid Diagnostics.

Spatiotemporal regulation of clustered regularly interspaced short palindromic repeats (CRISPR) system is attractive for precise gene editing and accurate molecular diagnosis. Although many efforts have been made, versatile and efficient strategies to control CRISPR system are still desirable. Here, we proposed a universal and accessible acylation strategy to regulate the CRISPR-Cas12a system by efficient acylation of 2'-hydroxyls (2'-OH) on crRNA strand with photolabile agents (PLGs). The introduction of PLGs confers efficient suppression of crRNA function and rapid restoration of CRISPR-Cas12a reaction upon short light exposure regardless of crRNA sequences. Based on this strategy, we constructed a universal PhotO-Initiated CRISPR-Cas12a system for Robust One-pot Testing (POIROT) platform integrated with recombinase polymerase amplification (RPA), which showed two orders of magnitude more sensitive than the conventional one-step assay and comparable to the two-step assay. For clinical sample testing, POIROT achieved high-efficiency detection performance comparable to the gold-standard quantitative PCR (qPCR) in sensitivity and specificity, but faster than the qPCR method. Overall, we believe the proposed strategy will promote the development of many other universal photo-controlled CRISPR technologies for one-pot assay, and even expand applications in the fields of controllable CRISPR-based genomic editing, disease therapy, and cell imaging.

Trends in prevalence rates of blindness among patients with diabetic retinopathy in high-income countries from 1990 to 2019: A joinpoint regression analysis.

AIMS: Diabetic retinopathy (DR) is the leading cause of blindness in patients with diabetes mellitus (DM). We investigated its trends in high-income countries to gain insights into preventing DR-related blindness in diabetes-epidemic areas. METHODS: For joinpoint regression analysis, we extracted data from the Global Burden of Disease 2019 study and analysed the prevalence trends of DR-related blindness according to DM type, patients' sex and age, region, and nation. RESULTS: Overall, the age-standardised prevalence rate (ASPR) of DR-related blindness has decreased. The prevalence rates of blindness decreased more sharply for Type 1 DM than for Type 2 DM. The ASPR was higher and the decreasing trend was less pronounced in women than in men. Southern Latin America had the highest ASPR, whereas Australasia had the lowest ASPR. Singapore experienced the greatest decline, whereas unfavourable trends were observed in the USA. CONCLUSIONS: Despite decrease in the overall ASPR of DR-related blindness during the study period, large improvement opportunities were identified. As DM prevalence increases and the population ages rapidly in high-income countries, novel effective screening, treatment, and prevention strategies are urgently needed to improve the visual outcomes of individuals with DM or at risk of DM.

Correlation between spherical equivalent and biometry parameters in adult Cynomolgus macaque.

PURPOSE: To characterize the distribution of refractive and ocular biometry parameters and analyze the effect factors of the refractive status in cynomolgus monkey colonies. METHODS: A Population-based cross-sectional study was conducted in adult cynomolgus macaque colonies. Animals were anesthetized with Zoletil 50. Intraocular pressure was measured using the Icare tonometer. Cycloplegic refraction (three drops of 1% tropicamide) and corneal radius of curvature (CRC) were measured using an autorefractor. The spherical equivalent (SE) was calculated. Biometric measurements, including the anterior chamber depth (ACD), lens thickness (LT), and axial length (AL), were obtained by A-scan ultrasonography. The AL-to-CR ratio (AL/CRC) was calculated. Central corneal thickness (CCT) and choroidal thickness (ChT) were measured using the Heidelberg Spectralis HRA OCT. Multiple regression analysis was performed to explore the association between refraction and ocular biometry. RESULTS: Among 263 cynomolgus monkeys (aged 5-26 years), which consisted of 520 eyes, 29.42% had hyperopia, 27.12% had emmetropia, 33.27% had mild-to-moderate myopia and 10.19% had high myopia. The mean SE was -1.27 ± 3.44 Diopters (D). The mean CRC, CCT, AL, and ChT was 5.70 ± 0.22 mm, 454.30 ± 32.40 µm, 18.76 ± 0.89 mm and 188.96 ± 38.19 µm, respectively. The LT was the thickest in the hyperopic eyes. CRC was the lowest, and CCT was the thickest in high myopic eyes. AL increased, while ChT decreased as SE decreased. For the SE variance, AL alone explained 40.5%; age, AL, and CRC together explained 57.5%. CONCLUSIONS: The refractive characteristics and biometry parameters of cynomolgus monkeys are highly comparable to those of humans. AL, CRC, and ChT showed the similar variation tendency in cynomolguses when compared to humans. Cynomolgus monkeys with naturally-occurring refractive errors may be a good animal model for refractive studies.

Prevalence Patterns and Onset Prediction of High Myopia for Children and Adolescents in Southern China via Real-World Screening Data: Retrospective School-Based Study.

BACKGROUND: Patients with high myopia have an increased lifetime risk of complications. The prevalence patterns of high myopia in children and adolescents in southern China are unclear. Early identification of high-risk individuals is critical for reducing the occurrence and development of high myopia and avoiding the resulting complications. OBJECTIVE: This study aimed to determine the prevalence of high myopia in children and adolescents in southern China via real-world screening data and to predict its onset by studying the risk factors for high myopia based on machine learning. METHODS: This retrospective school-based study was conducted in 13 cities with different gross domestic products in southern China. Through data acquisition and filtering, we analyzed the prevalence of high myopia and its association with age, school stage, gross domestic product, and risk factors. A random forest algorithm was used to predict high myopia among schoolchildren and then assessed in an independent hold-out group. RESULTS: There were 1,285,609 participants (mean age 11.80, SD 3.07, range 6-20 years), of whom 658,516 (51.2%) were male. The overall prevalence of high myopia was 4.48% (2019), 4.88% (2020), and 3.17% (2021), with an increasing trend from the age of 11 to 17 years. The rates of high myopia increased from elementary schools to high schools but decreased at all school stages from 2019 to 2021. The coastal and southern cities had a higher proportion of high myopia, with an overall prevalence between 2.60% and 5.83%. Age, uncorrected distance visual acuity, and spherical equivalents were predictive factors for high myopia onset in schoolchildren. The random forest algorithm achieved a high accuracy of 0.948. The area under the receiver operator characteristic curve (AUC) was 0.975. Both indicated sufficient model efficacy. The performance of the model was validated in an external test with high accuracy (0.971) and a high AUC (0.957). CONCLUSIONS: High myopia had a high incidence in Guangdong Province. Its onset in children and adolescents was well predicted with the random forest algorithm. Efficient use of real-world data can contribute to the prevention and early diagnosis of high myopia.

Ultrasensitive CRISPR/Cas13a-Mediated Photoelectrochemical Biosensors for Specific and Direct Assay of miRNA-21.

Sensitive and specific assay of microRNAs (miRNAs) is beneficial to early disease screening. Herein, we for the first time proposed clustered regularly interspaced short palindromic repeats (CRISPR)/Cas13a-mediated photoelectrochemical biosensors for the direct assay of miRNA-21. In this study, compared with traditional nucleic acid-based signal amplification strategies, the CRISPR/Cas13a system can greatly improve the specificity and sensitivity of target determination due to its accurate recognition and high-efficient trans-cleavage capability without complex nucleic acid sequence design. Moreover, compared with the CRISPR/Cas12a-based biosensing platform, the developed CRISPR/Cas13a-mediated biosensor can directly detect RNA targets without signal transduction from RNA to DNA, thereby avoiding signal leakage and distortion. Generally, the proposed biosensor reveals excellent analysis capability with a wider linear range from 1 fM to 5 nM and a lower detection limit of 1 fM. Additionally, it also shows satisfactory stability in the detection of human serum samples and cell lysates, manifesting that it has great application prospects in the areas of early disease diagnosis and biomedical research.

The relationship between baseline axial length and axial elongation in myopic children undergoing orthokeratology.

PURPOSE: To investigate the correlation between the baseline axial length (AL) and axial elongation in myopes undergoing orthokeratology (ortho-k). METHODS: This was a retrospective study. During the 1-year follow-up, 1176 children (aged 8-14 years) were included and divided into an ortho-k group (n = 588) and a single-vision spectacle group (n = 588). The ortho-k group participants (8-11 years of age) who completed the 3-year follow-up (n = 150) were further divided into three subgroups stratified by their baseline AL: subgroup 1 (AL < 24.5 mm), subgroup 2 (24.5 ≤ AL < 26 mm) and subgroup 3 (AL ≥ 26 mm). AL was measured at baseline and during the annual visit. RESULTS: The ortho-k group exhibited slower 1-year axial elongation (39% reduction) than the spectacle group. The 1-year axial elongation was negatively correlated with initial age in both groups. A negative association between 1-year axial elongation and baseline AL was observed in the ortho-k group but not in the spectacle group. However, this relationship only existed in ortho-k participants 8-11 years of age. For the younger ortho-k participants who completed the 3-year follow-up, the annual axial elongation was significantly higher in subgroup 1 for the first and second years but not in the third year compared with subgroups 2 and 3. CONCLUSION: Axial elongation was negatively correlated with baseline AL in the ortho-k group. Children aged 8-11 years with longer baseline AL (≥24.5 mm) demonstrated slower annual axial elongation during the first 2 years of ortho-k treatment, which may provide insight into establishing individual guidelines for controlling myopia using ortho-k in children with different baseline characteristics.

Comparisons of Using Cycloplegic Biometry Versus Non-cycloplegic Biometry in the Calculation of the Cycloplegic Refractive Lens Powers.

INTRODUCTION: This study investigated the difference between the calculation of cycloplegic crystalline lens power (LP) using non-cycloplegic and cycloplegic biometry data in children, and associated factors were explored. METHODS: A total of 821 children were enrolled and only right eye was analyzed. The corneal radii (CR), corneal power (CP), anterior chamber depth (ACD), lens thickness (LT), and axial length (AL) before and after cycloplegia were obtained using IOLMaster 700. Anterior segment length (ASL) was defined as ACD plus LT. The cycloplegic LP was calculated with Bennett's formula. In addition, LP calculated with cycloplegic data was defined as cLP, otherwise it was defined as nLP. The ΔLP (defined as the value as cLP minus nLP) was compared among age, gender, and refractive states groups. Associated factors of ΔLP and |ΔLP| were explored by Pearson's correlation and multivariate linear regression. RESULTS: The mean age of the 821 subjects was 9.83 ± 2.97 years with a mean spherical equivalent refraction (SER) of - 1.06 ± 2.12 D. Overall, the ACD, LT, and ASL were significantly affected by cycloplegia agent (all p < 0.001; paired t test). Conversely, no statistically significant differences were documented in AL, CP, or AL/CR ratio before and after inducing cycloplegia (p = 0.917, p = 0.515, and p = 0.549, respectively). Significant difference was found between nLP and cLP (21.24 ± 1.58 D vs 21.43 ± 1.92 D, p = 0.001). The mean ΔLP was 0.11 ± 0.87 D (range from - 7.01 D to 7.08 D). Significant change in LP was found in low and medium groups, respectively (0.13 ± 0.81 D, p = 0.001; 0.11 ± 0.48 D, p = 0.043). In the multiple regression analysis, |ΔLP| was exclusively associated with ΔASL (ß = 0.172, [95% CI 0.112-0.300], p < 0.001). CONCLUSION: Our results indicated that using cycloplegic biometry could lead to an overestimation in LP for low and moderate myopia eyes. This finding is likely to facilitate the refractive development research in children. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT05247099.

Iodine deficiency up-regulates monocarboxylate transporter 8 expression of mouse thyroid gland.

BACKGROUND: Iodine deficiency is a major factor affecting thyroid auto-regulation, the quantity of iodine may greatly influence the synthesis of thyroid hormones (THs). It has long been believed that TH enters the cell through passive diffusion. Recent studies have suggested that several transporters could facilitate transportation of TH. The monocarboxylate transporter 8 (MCT8) was identified as a very active and specific TH transporter. The purpose of this study was to investigate whether iodine insufficient affected the expression of MCT8 in the thyroid gland. METHODS: Sixty BALB/c mice were randomly divided into two groups: control group was fed with standard feed (iodine concentration of 300 µg/kg); while low-iodine (LI) group received iodine-insufficient feed (iodine concentration of 20-40 µg/kg). After 3 months, 10 mice of each group were sacrificed. The remaining 20 mice of each group were kept till 6 months. From the LI group, we randomly selected 15 mice and injected triiodothyronine (T3, 100 µg/kg body weight per day) intraperitoneally for 24, 48 or 72 hours (5 mice for each time-point). Then, all the mice were sacrificed. Mouse serum thyroxine (T4), T3, and thyroid-stimulating hormone (TSH) levels were determined by chemiluminescence immunoassay (CIA). The protein content or messenger RNA (mRNA) level of thyroid MCT8 was measured by Western blotting analysis or real time RT-PCR respectively. MCT8 subcellular location in thyroid tissues was probed with immunohistochemistry (IHC) assay. RESULTS: We found that mouse serum T3 and T4 levels decreased and TSH level increased by the end of the third month. Consistent with these findings, there was significant goiter and hypothyroidism in the LI group. Meanwhile, the MCT8 mRNA increased to 1.36-fold of the level in the control group at the 3(rd) month. At 6(th) month, the serum T4 level in LI mice remained at a lower level, and MCT8 mRNA expression continued rising to nearly 1.60-fold compared with the control group. The protein content was also about 3 times higher than that in the control group. IHC results also revealed MCT8 was of higher expression and localized in the cytoplasm of thyroid follicular cells. After providing exogenous T3 to iodine deficient mice, the serum T3 and T4 gradually increased, whereas MCT8 mRNA and protein both started to decrease and returned to the same level as the control group. CONCLUSION: There is a compensatory increase in thyroid MCT8 expression to enhance its capability to transport TH from thyroid to the blood circulation in iodine deficient mice.