DNA Methylation Regulates Alternative Polyadenylation via CTCF and the Cohesin Complex.

Dysregulation of DNA methylation and mRNA alternative cleavage and polyadenylation (APA) are both prevalent in cancer and have been studied as independent processes. We discovered a DNA methylation-regulated APA mechanism when we compared genome-wide DNA methylation and polyadenylation site usage between DNA methylation-competent and DNA methylation-deficient cells. Here, we show that removal of DNA methylation enables CTCF binding and recruitment of the cohesin complex, which, in turn, form chromatin loops that promote proximal polyadenylation site usage. In this DNA demethylated context, either deletion of the CTCF binding site or depletion of RAD21 cohesin complex protein can recover distal polyadenylation site usage. Using data from The Cancer Genome Atlas, we authenticated the relationship between DNA methylation and mRNA polyadenylation isoform expression in vivo. This DNA methylation-regulated APA mechanism demonstrates how aberrant DNA methylation impacts transcriptome diversity and highlights the potential sequelae of global DNA methylation inhibition as a cancer treatment.

Systematic review and data synthesis on the treatment of sexual violence victimization by an intimate partner.

This study aims to conduct a systematic review and synthesis on the treatment of sexual violence victimization by an intimate partner evaluating specifically the impact of treatment on mental health outcomes of female sexual intimate partner violence (IPV) survivors. We followed the Cochrane Handbook for Systemic Reviews of Interventions guidelines for the process of conducting systematic reviews. We were unable to conduct meta-analyses due to the substantial heterogeneity of the interventions for IPV. A qualitative summary of 6 controlled studies identified no benefit to the treatment of sexual coercion, posttraumatic stress disorder, depression, or anxiety for female sexual IPV survivors. However, we are limited by a paucity of data for each outcome on this subject. In conclusion, sexual coercion is a complex issue that has adverse effects on mental health and the well-being of the survivors. More research is needed that investigates what kind of interventions are effective for this specific population.

BEST1 Variant Associated with an Atypical Macular and Peripheral Retinal Phenotype.

PURPOSE: Best vitelliform macular dystrophy (BVMD) is an inherited macular dystrophy associated with over 250 pathogenic variants of the Bestrophin-1 (BEST1) gene. While several of the types of lesions of BVMD are well-described, reports of phenotypic variations associated with rare genetic variants are limited. METHODS: Retrospective case-series performed in 2021 at a tertiary eye care center. PATIENTS: Three members of one family referred to a tertiary eye care clinic for evaluation of their autosomal dominant macular dystrophy. RESULTS: Study subjects presented with atypical findings of peripheral schisis-like lesions and atrophy with abnormal electroretinogram (ERG) in addition to typical macular lesions found in BVMD. Genetic analyses identified a heterozygous BEST1 c.227T>A, p.(Ile76Asn) pathogenic variant in all three subjects. CONCLUSIONS: This study represents the first report of the phenotype associated with the c.227T>A, p.(Ile76Asn) BEST1 variant, which - while mentioned twice in the literature - has not been previously described. The phenotype is unique, comprising features of typical BVMD with ERG and peripheral findings, suggestive of a panretinal dysfunction.

Deep Learning Algorithm Detects Presence of Disorganization of Retinal Inner Layers (DRIL)-An Early Imaging Biomarker in Diabetic Retinopathy.

Purpose: To develop and train a deep learning-based algorithm for detecting disorganization of retinal inner layers (DRIL) on optical coherence tomography (OCT) to screen a cohort of patients with diabetic retinopathy (DR). Methods: In this cross-sectional study, subjects over age 18, with ICD-9/10 diagnoses of type 2 diabetes with and without retinopathy and Cirrus HD-OCT imaging performed between January 2009 to September 2019 were included in this study. After inclusion and exclusion criteria were applied, a final total of 664 patients (5992 B-scans from 1201 eyes) were included for analysis. Five-line horizontal raster scans from Cirrus HD-OCT were obtained from the shared electronic health record. Two trained graders evaluated scans for presence of DRIL. A third physician grader arbitrated any disagreements. Of 5992 B-scans analyzed, 1397 scans (∼30%) demonstrated presence of DRIL. Graded scans were used to label training data for the convolution neural network (CNN) development and training. Results: On a single CPU system, the best performing CNN training took ∼35 mins. Labeled data were divided 90:10 for internal training/validation and external testing purpose. With this training, our deep learning network was able to predict the presence of DRIL in new OCT scans with a high accuracy of 88.3%, specificity of 90.0%, sensitivity of 82.9%, and Matthews correlation coefficient of 0.7. Conclusions: The present study demonstrates that a deep learning-based OCT classification algorithm can be used for rapid automated identification of DRIL. This developed tool can assist in screening for DRIL in both research and clinical decision-making settings. Translational Relevance: A deep learning algorithm can detect disorganization of retinal inner layers in OCT scans.

Clinical Utility of Spectral-Domain Optical Coherence Tomography Marker Disorganization of Retinal Inner Layers in Diabetic Retinopathy.

BACKGROUND AND OBJECTIVE: Disorganization of retinal inner layers (DRIL) is a potential spectral-domain optical coherence tomography (SD-OCT) imaging biomarker with clinical utility in diabetic retinopathy (DR). PATIENTS AND METHODS: A cross-sectional study was conducted at a large academic center. The cohort was composed of 1,175 patients with type 2 diabetes with and without retinopathy on initial examination between September 2009 and January 2019 (n = 2,083 eyes). DR risk and progression factors were obtained from the medical record. Trained graders masked to patients' clinical histories evaluated SD-OCT scans for DRIL. RESULTS: Of 2,083 eyes, 28.1% (n = 585) demonstrated presence of DRIL with high interrater reliability (K = 0.88, 95% CI 0.86-0.90). DRIL was associated with worse visual acuity (VA) (P < 0.001) and DR severity (P < 0.0001). Insulin users had more severe DR (P < 0.0001). DR-related factors, race (Black, White) and sex (male) were significantly associated with DRIL (P < 0.05). CONCLUSIONS: DRIL was strongly associated with DR severity and worse VA, supporting its utility as an unfavorable prognostic indicator. [Ophthalmic Surg Lasers Imaging Retina 2023;54:692-700.].

Depth-resolved Corneal Biomechanical Changes Measured Via Optical Coherence Elastography Following Corneal Crosslinking.

Purpose: To evaluate depth-resolved changes of corneal biomechanical properties in eyes with corneal ectasia after corneal crosslinking (CXL) using optical coherence elastography. Methods: In a prospective pilot series of eyes with corneal ectasia, a custom high-speed swept source optical coherence tomography system was used to image the cornea before and 3 months after CXL during a low-speed applanating deformation while monitoring applanation force. Cross-correlation was applied to track frame-by-frame two-dimensional optical coherence tomography speckle displacements, and the slope of force versus local axial displacement behavior during the deformation was used to produce a two-dimensional array of axial stiffness (k). These values were averaged for anterior (ka) and posterior (kp) stromal regions and expressed as a ratio (ka/kp) to assess depth-dependent differences in stiffness. CXL was performed according to the Dresden protocol with a system approved by the U.S. Food and Drug Administration. Results: Four eyes from four patients with keratoconus (n = 3) or post-LASIK ectasia (n = 1) underwent optical coherence elastography before and 3 months after CXL. The mean ka/kp was 1.03 ± 0.07 before CXL compared with 1.34 ± 0.17 after the CXL procedure. All four eyes demonstrated at least a 20% increase in the ka/kp. Conclusions: Preferential stiffening of the anterior stroma with the standard CXL protocol was demonstrated with optical coherence elastography in live human subjects. Translational Relevance: Although ex vivo studies have demonstrated anterior stiffening effects after CXL using various destructive and nondestructive methods, this report presents the first evidence of such changes in serial live human measurements.

Patient-Reported Complications after Intravitreal Injection and Their Predictive Factors.

PURPOSE: The intravitreal injection (IVI) of pharmacologic agents is the most commonly performed ocular procedure and is associated with a host of complications. Most IVI-related complications data are derived from randomized controlled clinical trials, which report a high adverse event rate. The nature of these protocol-driven trials limit their applicability to the diverse circumstances seen in routine clinical practice. The goal of this study was to determine the prevalence of patient-reported IVI-related complications, their risk factors, and the manner in which patients sought treatment at a tertiary eye care center. DESIGN: Retrospective, institutional review board-approved study. PARTICIPANTS: Forty-four thousand seven hundred thirty-four injections in 5318 unique patients at the Cleveland Clinic Cole Eye Institute from 2012 through 2016. METHODS: Intravitreal injection. MAIN OUTCOME MEASURES: Complication occurrence within 15 days of injection. RESULTS: From 2012 through 2016, a total of 44734 injections were performed in 5318 unique patients. Overall, complication rates were low, representing 1.9% of all injections, with 1031 unique complications in 685 patients (12.9%). The most common minor complications, or those not requiring intervention, were irritation (n = 312) and subconjunctival hemorrhage (n = 284). The most common serious complications, or those requiring intervention, were corneal abrasion (n = 46) and iritis (n = 31). Most complications (66%) were managed adequately by a telephone or Epic (Epic Systems Corp., Verona, WI) electronic message encounter only. Importantly, no injection protocol parameter, such as type of anesthesia, preparation, or post-injection medication, increased the risk of a complication. However, a patient's gender, age, number of previous injections, and provider strongly influenced the risk of patient-reported complications. CONCLUSIONS: Overall, complication rates seen in routine clinical practice were low compared with clinical trial reporting. Providers should feel confident in the safety and administration of IVI during times when follow-up office visits and resources may be limited. When performing an IVI, factors such as a patient's gender, age, number of previous injections, and provider must be taken into account to ensure the best possible outcomes.

Identifying health correlates of intimate partner violence against pregnant women.

PURPOSE: Violence against women during pregnancy is a serious public health concern due to its significant adverse health consequences for both the mother and the baby. This study aims to systematically identify common health problems and synergistic health correlates of intimate partner violence (IPV) that specifically affect pregnant women. METHODS: We mine large-scale electronic health record (EHR) data from the IBM Explorys database to identify health problems that are prevalent in both IPV and pregnancy populations, as well those that are synergistically associated with the presence of IPV during pregnancy. For this purpose, we develop methods that enhance the statistical reliability of identified patterns by constructing confidence intervals that take into account systematic bias and measurement errors in addition to the variance in estimation. RESULTS: We identify with high confidence 668 and 2750 terms that are respectively prevalent in respectively IPV and pregnancy populations. Of these terms, 279 are common. We also identify 16 synergistic health correlates with high confidence. Our results suggest that mental health, substance abuse, and genitourinary complications are prevalent among pregnant women exposed to IPV. The synergistic terms we identify reveal potential conditions that can be direct consequences of trauma (e.g., tibial fracture), long-term health consequences (e.g., chronic rhinitis), markers associated with the demograhics of affected populations (e.g., acne), and risk factors that potentially increase vulnerability during pregnancy (e.g., disorders of attention and motor control). CONCLUSIONS: Our results indicate that IPV significantly affects the well-being of pregnant women in multiple ways. The findings of this study can be useful for screening of IPV in pregnant women. Finally, the methodology presented here can also be useful for investigating the synergy between other medical conditions using EHR databases with privacy constraints.