Search

Abhimanyu S Ahuja,1,* Alfredo A Paredes III,2,* Mallory LS Eisel,3,* Sejal Kodwani,4 Isabella V Wagner,5 Darby D Miller,5 Syril Dorairaj5 1Department of Ophthalmology, Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA; 2Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA; 3College of Medicine, Florida State University, Tallahassee, FL, USA; 4Windsor University School of Medicine, Cayon, St. Kitts, KN; 5Department of Ophthalmology, Mayo Clinic Florida, Jacksonville, FL, USA*These authors contributed equally to this workCorrespondence: Abhimanyu S Ahuja, Casey Eye Institute, Oregon Health and Science University, 515 SW Campus Drive, Portland, Oregon, 97239, USA, Email ahujaa@ohsu.eduAbstract: Cataract surgery is one of the most performed procedures worldwide, and cataracts are rising in prevalence in our aging population. With the increasing utilization of artificial intelligence (AI) in the medical field, we aimed to understand the extent of present AI applications in ophthalmic microsurgery, specifically cataract surgery. We conducted a literature search on PubMed and Google Scholar using keywords related to the application of AI in cataract surgery and included relevant articles published since 2010 in our review. The literature search yielded information on AI mechanisms such as machine learning (ML), deep learning (DL), and convolutional neural networks (CNN) as they are being incorporated into pre-operative, intraoperative, and post-operative stages of cataract surgery. AI is currently integrated in the pre-operative stage of cataract surgery to calculate intraocular lens (IOL) power and diagnose cataracts with slit-lamp microscopy and retinal imaging. During the intraoperative stage, AI has been applied to risk calculation, tracking surgical workflow, multimodal imaging data analysis, and instrument location via the use of “smart instruments”. AI is also involved in predicting post-operative complications, such as posterior capsular opacification and intraocular lens dislocation, and organizing follow-up patient care. Challenges such as limited imaging dataset availability, unstandardized deep learning analysis metrics, and lack of generalizability to novel datasets currently present obstacles to the enhanced application of AI in cataract surgery. Upon addressing these barriers in upcoming research, AI stands to improve cataract screening accessibility, junior physician training, and identification of surgical complications through future applications of AI in cataract surgery.Plain language summary: Although barriers remain for the generalizability and standardization of artificial intelligence in cataract surgery, there are growing applications improving efficiency, data analysis, safety, training, and patient outcomes in pre-operative, intraoperative, and post-operative stages.Keywords: cataract surgery, artificial intelligence, deep learning, convolutional neural networks

Nithya Boopathiraj,1 Isabella V Wagner,1 Paul Connor Lentz,2 Christian Draper,3 Chelsey Krambeer,1 Yazan S Abubaker,1 Bryan Chin Hou Ang,1,4,5 Darby D Miller,1 Syril Dorairaj1 1Department of Ophthalmology, Mayo Clinic, Jacksonville, FL, USA; 2Department of Ophthalmology, Mayo Clinic Alix School of Medicine, Jacksonville, FL, USA; 3Department of Ophthalmology, Eye Consultants, Spokane, WA, USA; 4Department of Ophthalmology, Tan Tock Seng Hospital, National Healthcare Group Eye Institute, Singapore; 5Department of Ophthalmology, Woodlands Health, National Healthcare Group Eye Institute, SingaporeCorrespondence: Syril Dorairaj, Department of Ophthalmology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA, Tel +1-904-953-2377, Fax +1-904-953-7040, Email dorairaj.syril@mayo.eduPurpose: To compare the safety and effectiveness of standalone Kahook Dual Blade (KDB) excisional goniotomy to standalone ab-interno Xen gel stent implantation in eyes with moderate-to-severe open-angle glaucoma (OAG).Methods: A single-center, retrospective study including eyes with moderate-to-severe OAG undergoing standalone KDB goniotomy or Xen gel stent implantation was conducted. Intraocular pressure (IOP), the number of antiglaucoma medications taken daily, and best-corrected visual acuity (BCVA) were recorded at baseline and for up to 36-months. Primary outcomes assessed included changes from baseline in IOP and the number of antiglaucoma medications taken. Intergroup comparisons were conducted using independent-samples Student’s t-tests. The incidence of intraoperative and postoperative adverse events and the need for glaucoma surgical re-interventions were also recorded.Results: Eyes receiving standalone KDB (n=26) or Xen gel stent (n=45) surgery were analyzed. The baseline mean IOP and number of antiglaucoma medications in both groups were as follows: KDB: 23.2 ± 6.0 mmHg, 2.2 ± 1.4 medications; Xen: 22.7 ± 8.8 mmHg, 3.0 ± 1.0 medications. At 36 months, IOP was reduced to 16.6 ± 5.4 mmHg in KDB eyes (n=23, − 23.5%; p=0.0004) and 15.3 ± 5.6 mmHg in Xen gel stent eyes (n=15, − 22.1%; p=0.006), while number of antiglaucoma medications was reduced to 1.1 ± 0.7 (− 30.8%; p=0.0005) and 2.2 ± 1.4 (− 25.6%; p=0.01), respectively. Three eyes (11.5%) in the KDB group and 19 eyes (42.2%) in the Xen gel stent group required additional surgery before month 36 due to refractory high IOP.Conclusion: Both KDB goniotomy and Xen gel stent implantation significantly lowered the IOP and antiglaucoma medication burden in patients with moderate-to-severe OAG. While the Xen gel stent is frequently used to treat moderate-to-severe OAG patients with uncontrolled IOP, standalone KDB goniotomy may be equally effective as a long-term intervention, reducing the need for subsequent glaucoma surgery.Keywords: kahook dual blade, micro-invasive glaucoma surgery, open angle glaucoma, xen gel stent

Nithya Boopathiraj,1 Isabella V Wagner,1 Paul Connor Lentz,1,2 Leticia Checo,1 Emily Aashna Dorairaj,3 Abhimanyu S Ahuja,4 Darby D Miller,1 Syril Dorairaj1 1Department of Ophthalmology, Mayo Clinic, Jacksonville, FL, USA; 2Department of Ophthalmology, Mayo Clinic Alix School of Medicine, Jacksonville, FL, USA; 3Department of Medicine, Charles E. Schmidt College of Medicine, Boca Raton, FL, USA; 4Department of Ophthalmology, Casey Eye Institute, Oregon Health and Science University, Portland, OR, USACorrespondence: Syril Dorairaj, Department of Ophthalmology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA, Tel +1 904-953-2377, Fax +1 904-953-7040, Email dorairaj.syril@mayo.eduPurpose: To evaluate the safety and effectiveness of the Ahmed ClearPath® (ACP) 250 mm2 glaucoma drainage device (GDD) in managing refractory primary open-angle glaucoma (POAG).Patients and Methods: This was a retrospective case series focused on adult patients diagnosed with severe POAG who underwent implantation of an ACP GDD. Over a 36-month follow-up period, data on intraocular pressure (IOP), the number of glaucoma medications, and complications were recorded. The primary objectives were to assess the reductions from baseline in both IOP and medication usage, through 36 months. Secondary objectives included the proportion of eyes achieving an IOP reduction of ≥ 20% from baseline at 36 months. Intraoperative and postoperative complications were also assessed.Results: Twelve eyes from 11 patients (mean age: 71.3 ± 14.1 years) met the inclusion criteria and were included in the study. All patients had severe POAG (n=11), with the majority being Caucasian (n=8) and female (n=10). The mean (standard deviation) IOP and number of glaucoma medications at baseline were 29 (7.6) mmHg and 3 (0.9), respectively. At 36 months, mean IOP was reduced to 10.6 (5.5) mmHg (− 61.8%; p= 0.0008) and mean number of medications was reduced to 0.9 (0.9) (− 71.4%; p=0.0005), with 88.9% of eyes achieving an IOP reduction by ≥ 20%. No vision threatening complications were observed.Conclusion: To our knowledge this is the first study to report 36-month outcomes of the novel ACP device in the treatment of refractory POAG. The safety profile and efficacy of the ACP was found to be comparable to that of other commonly utilized GDD models.Keywords: primary open angle glaucoma, intraocular pressure, glaucoma drainage device

Isabella V Wagner,1 Nithya Boopathiraj,1 Connor Lentz,1 Emily Aashna Dorairaj,2 Christian Draper,3 Devesh Kumar,4 Leticia Checo,1 Darby D Miller,1 Chelsey Krambeer,1 Syril Dorairaj1 1Department of Ophthalmology, Mayo Clinic, Jacksonville, FL, USA; 2Department of Medicine, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA; 3Department of Ophthalmology, Eye Consultants, Spokane, WA, USA; 4Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, WI, USACorrespondence: Syril Dorairaj, Department of Ophthalmology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, USA, Tel +1 904-953-2377, Fax +1 904-953-7040, Email dorairaj.syril@mayo.eduPurpose: To report clinical outcomes of successful excisional goniotomy with the Kahook Dual Blade (KDB), through 60 months.Patients and methods: This was a noncomparative, single-surgeon, retrospective review of eyes receiving successful KDB goniotomy with or without concomitant phacoemulsification between October 2015 and January 2016 with five years of uninterrupted follow-up. Intraocular pressure (IOP), number of glaucoma medications, best corrected visual acuity (BCVA), and complications were recorded. Primary outcomes included changes from baseline in IOP, medication use, and BCVA, through five years.Results: Fifty-two eyes of 28 patients were analyzed. Most eyes had mild primary open angle glaucoma (73%). Of the eyes analyzed, 41 underwent combined surgery and 11 underwent standalone surgery. With all eyes combined, mean (standard deviation) baseline IOP was 21.0 (4.1) mmHg and mean baseline medication use was 1.8 (1.1) medications per eye. Across time points at months 6, 12, 24, 36, 48, and 60, mean postoperative IOP ranged from 13.0 to 13.7 mmHg, representing mean reductions of 7.3– 8.0 mmHg (34.7– 38.3%; p < 0.0001 at every time point). Similarly, mean medication use ranged from 0.4 to 0.6 medications per eye, representing mean reductions of 1.2– 1.4 medications (66– 75.5%; p < 0.0001 at every time point). Mean logMAR BCVA improved from 0.321 (0.177) preoperatively to 0.015 (0.035) at month 60 (p < 0.0001).Conclusion: In eyes not requiring secondary surgical procedures (eg, long-term surgical successes), excisional goniotomy provided clinically and statistically significant reductions in both IOP and the need for medications that were highly consistent through five years of follow-up. KDB goniotomy appears to be highly successful in Caucasian patients with open angle glaucoma on ≥ 1 IOP-lowering medications at baseline and with no history of prior ocular surgery. Successful excisional goniotomy with the KDB can be expected to improve long-term glaucoma-related visual outcomes through IOP reduction and to improve quality of life through medication reduction.Keywords: glaucoma, goniotomy, intraocular pressure, IOP-lowering medications, phacoemulsification, minimally invasive glaucoma surgery

Darby D Miller,1 Syed A Hasan,1 Nathaniel L Simmons,2 Michael W Stewart1 1Department of Ophthalmology, Mayo Clinic, Jacksonville, FL 32224, USA; 2Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA Purpose: To comprehensively review the literature regarding recurrent corneal erosion (RCE) and to present treatment options and recommendations for management.Overview: RCE usually presents with sharp, unilateral pain upon awakening, in an eye with an underlying basement membrane dystrophy, prior ocular trauma, stromal dystrophy or degeneration, or prior surgery for refractive errors, cataracts, or corneal transplantation. Making the correct diagnosis requires a careful slit-lamp examination of both eyes coupled with a high degree of suspicion. Several treatments are commonly used for RCE but new therapies have been introduced recently. Conservative treatment consists of antibiotic and preservative-free lubricating drops, with topical cycloplegics and oral analgesics to control pain. Patients who are unresponsive to these therapies may benefit from therapeutic bandage contact lenses (BCL). Newer therapies include oral matrix metalloproteinase (MMP) inhibitors, blood-derived eye drops, amniotic membrane graft application, and judicious application of topical corticosteroids. Once the epithelium is healed, a course of hypertonic saline solution and/or ointment can be used. Surgical procedures may be performed in patients who fail conservative therapy. Punctal occlusion with plugs increases the tear film volume. Epithelial debridement with diamond burr polishing (DBP), anterior stromal puncture (ASP), or alcohol delamination should be considered in selected patients. DBP can be used for patients with basement membrane dystrophies and is the preferred treatment overall due to a low recurrence rate. ASP can be used for erosions outside the central visual axis. Excimer laser phototherapeutic keratectomy is an attractive option in eyes with central RCE since it precisely removes tissue while preserving corneal transparency. In patients with RCE who are also candidates for refractive surgery, photorefractive keratectomy can be considered.Summary: Newly introduced therapies for RCE enable therapy to be individualized and lower the recurrence rate. Keywords: recurrent corneal erosion, anterior basement membrane dystrophy, map-dot-fingerprint dystrophy, epithelial basement membrane dystrophy, corneal abrasion

Maya Salomon-Ben Zeev,1 Darby Douglas Miller,2,3 Robert Latkany1,21The Dry Eye Center at Physician Eyecare of New York, 2New York Eye and Ear Infirmary, 3Laser and Corneal Surgery Associates, New York, NY, USAAbstract: Dry eye is one of the most commonly encountered problems in ophthalmology. Signs can include punctate epithelial erosions, hyperemia, low tear lakes, rapid tear break-up time, and meibomian gland disease. Current methods of diagnosis include a slit-lamp examination with and without different stains, including fluorescein, rose bengal, and lissamine green. Other methods are the Schirmer test, tear function index, tear break-up time, and functional visual acuity. Emerging technologies include meniscometry, optical coherence tomography, tear film stability analysis, interferometry, tear osmolarity, the tear film normalization test, ocular surface thermography, and tear biomarkers. Patient-specific considerations involve relevant history of autoimmune disease, refractive surgery or use of oral medications, and allergies or rosacea. Other patient considerations include clinical examination for lid margin disease and presence of lagophthalmos or blink abnormalities. Given a complex presentation and a variety of signs and symptoms, it would be beneficial if there was an inexpensive, readily available, and reproducible diagnostic test for dry eye.Keywords: cornea, dry eye, tear film, stain

Objective: To quantify the potential effect of iron defortification in the USA on iron-deficiency anaemia (IDA).Methods: Monte Carlo models were built to simulate iron nutrition in the US population. A hypothetical cohort of 15 000 persons from the general population was used in 15-year simulations to compare the prevalence of IDA with and without fortification.Results: With iron fortification, the prevalence of IDA was 2.4% for children aged 3-5 years, 5.4% for women aged 20-49 years, and 0.14% for men aged 20-49 years. The corresponding IDA estimates under iron defortification were 4.5%, 8.2% and 0.46%, respectively. Defortification had little effect on the distribution of iron indicators at or above the 50th percentile within each of these three groups and little effect on the distributions of iron indicators among adult men.Conclusion: Iron defortification is likely to increase IDA among children and women of reproductive age, but is not likely to have meaningful effects on the iron status of men or the majority of women and children. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study examined the relationship between substance use and psychosocial functioning in schizophrenia. METHODS: Participants were enrolled in the Clinical Antipsychotic Trials of Intervention Effectiveness. This study used baseline assessments and examined psychosocial functioning assessed by the Quality of Life Scale. Participants were classified as being abstinent, using substances, or having a substance use disorder. RESULTS: Of the 1,460 participants, 23 percent used substances and 37 percent had a substance use disorder. Of the 544 with a substance use disorder, 87 percent used alcohol, 44 percent used marijuana, and 36 percent used cocaine. Compared with participants who used substances, those with a substance use disorder had higher rates of polysubstance use. Compared with those who were abstinent, those who used substances had higher overall psychosocial functioning, and those with a substance use disorder had similar overall functioning but lower scores on the common objects and activities subscales. Among participants with a substance use disorder, those who used cocaine had lower overall functioning. CONCLUSIONS: Compared with abstinence, substance use and substance use disorder, unless they involved cocaine use, were generally associated with higher or equivalent overall psychosocial functioning. Patterns of substance use were similar to those in the community, suggesting that treatment of substance use disorders in schizophrenia should focus on reconnecting substance users to nonusing peer groups. [ABSTRACT FROM AUTHOR]

This article describes one mother's experiences raising an adolescent daughter who is blind and has learning disabilities. It focuses especially on ways in which she helped her daughter improve reading and writing skills by finding a meaningful purpose for those skills in daily life. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the published literature on the efficacy of amniotic membrane grafting (AMG) in the management of acute chemical and thermal ocular surface burns with respect to the rate of corneal re-epithelialization and improvement of visual acuity or corneal clarity., Methods: Literature searches were conducted in the PubMed database in May 2023 and updated in January 2024 and were limited to the English language without date restrictions. The searches yielded 474 citations; 58 were reviewed in full text, and 9 met the inclusion criteria. Four studies were rated level II, and 5 studies were rated level III. This assessment focuses on 3 level II articles that provided consistent primary and secondary outcomes but demonstrated suboptimal study design with respect to power calculations and lacked a priori sample-size calculations., Results: Amniotic membrane grafting significantly improved corneal re-epithelialization compared with medical therapy alone in eyes with moderate-grade burns. For severely burned eyes, AMG demonstrated no advantage over medical therapy. Additionally, AMG demonstrated no significant advantage over medical therapy for improved visual acuity or corneal clarity for moderate or severe ocular surface burns., Conclusions: The best available level II evidence suggests that AMG in the setting of acute ocular surface burns has efficacy in hastening re-epithelialization in moderate burns. As an adjuvant to medical therapy, it did not demonstrate a benefit in improving re-epithelialization in severe burns or visual acuity or corneal clarity in either moderate or severe burns., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate racial/ethnic differences in the use of microinvasive glaucoma surgery (MIGS) for the management of mild-moderate primary open-angle glaucoma (POAG) in the United States., Design: Retrospective cohort study., Participants: Patients with a diagnosis of mild or moderate POAG, as defined by current procedural terminology (CPT) codes, were included. The experimental group comprised African American (AA) patients and the control group consisted of patients without an AA designation in the TriNetX database., Methods: Propensity scoring was used to match cohorts for age at diagnosis, Charlson Comorbidity Index, sex, nicotine dependence, glaucoma medications, family history of POAG, Body Mass Index, and weight. Outcome was incidence of MIGS over 1 year of follow up. Odds ratios were calculated between cohorts MAIN OUTCOME MEASURE: Incidence of MIGS over 1 year of follow-up post-POAG diagnosis., Results: 63,418 POAG patients were included (50% AA, 50% non-AA). AA patients were found to undergo MIGS at a significantly lower rate (1,268 of 31,709) compared to non-AA patients (1,508 of 31,709) (OR 0.834, 95% CI: 0.773 - 0.900)., Conclusion: Although POAG is understood to be more prevalent among African Americans, these patients display lower utilization of MIGS, suggesting a possible nationwide racial disparity in the management of POAG., (Copyright © 2024. Published by Elsevier Inc.)

Cancers develop resistance to inhibitors of oncogenes mainly due to target-centric mechanisms such as mutations and splicing. While inhibitors or antagonists force targets to unnatural conformation contributing to protein instability and resistance, activating tumor suppressors may maintain the protein in an agonistic conformation to elicit sustainable growth inhibition. Due to the lack of tumor suppressor agonists, this hypothesis and the mechanisms underlying resistance are not understood. In estrogen receptor (ER)-positive breast cancer (BC), androgen receptor (AR) is a druggable tumor suppressor offering a promising avenue for this investigation. Spatial genomics suggests that the molecular portrait of AR-expressing BC cells in tumor microenvironment corresponds to better overall patient survival, clinically confirming AR's role as a tumor suppressor. Ligand activation of AR in ER-positive BC xenografts reprograms cistromes, inhibits oncogenic pathways, and promotes cellular elasticity toward a more differentiated state. Sustained AR activation results in cistrome rearrangement toward transcription factor PROP paired-like homeobox 1, transformation of AR into oncogene, and activation of the Janus kinase/signal transducer (JAK/STAT) pathway, all culminating in lineage plasticity to an aggressive resistant subtype. While the molecular profile of AR agonist-sensitive tumors corresponds to better patient survival, the profile represented in the resistant phenotype corresponds to shorter survival. Inhibition of activated oncogenes in resistant tumors reduces growth and resensitizes them to AR agonists. These findings indicate that persistent activation of a context-dependent tumor suppressor may lead to resistance through lineage plasticity-driven tumor metamorphosis. Our work provides a framework to explore the above phenomenon across multiple cancer types and underscores the importance of factoring sensitization of tumor suppressor targets while developing agonist-like drugs., Competing Interests: Competing interests statement:R.N. is a consultant to Oncternal Therapeutics Inc., San Diego, CA. The SARD UT-105 is licensed to Oncternal Therapeutics by the University of Tennessee Research Foundation under an exclusive licensing agreement. S.P., D.-J.H., Y.H., D.D.M., and R.N. are coinventors in SARD patents.

Scope: Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition of unknown etiology, although recent evidence suggests that it is caused by an excessive immune response to mucosal antigens. We determined the anti-inflammatory properties of novel compound DJ-X-013 in vitro in lipopolysaccharide (LPS)-induced macrophages and in an in vivo dextran sodium sulfate (DSS)-induced model of colitis., Methods and Results: To evaluate the anti-inflammatory properties of DJ-X-013, we used LPS-activated RAW 264.7 macrophages in vitro and a DSS-induced experimental model of colitis in vivo. We examine cellular morphology, and tissue architecture by histology, flow cytometry, RT-qPCR, multiplex, and immunoblot analysis to perform cellular and molecular studies. DJ-X-013 treatment altered cell morphology and expression of inflammatory cytokines in LPS-activated macrophages as compared to cells treated with LPS alone. DJ-X-013 also impeded the migration of RAW 264.7 macrophages by modulating cytoskeletal organization and suppressed the expression of NF-κB and inflammatory markers as compared to LPS alone. DJ-X-013 treatment improved body weight, and colon length and attenuated inflammation in the colon of DSS-induced colitis. Intriguingly, DSS-challenged mice treated with DJ-X-013 induced the numbers of myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), and natural killer T cells (NKT) in the colon lamina propria (LP) relative to DSS. DJ-X-013 also reduced the influx of neutrophils, TNF-α producing macrophages, restricted the number of Th17 cells, and suppressed inflammatory cytokines and NF-κB in the LP relative to DSS., Conclusion: DJ-X-013 is proposed to be a therapeutic strategy for ameliorating inflammation and experimental colitis., Competing Interests: Declaration of Competing Interest The authors declare that they do not have any competing interests that might influence this study and have had no involvement with study sponsors., (Published by Elsevier Masson SAS.)

Introduction: This study aims to evaluate the long-term clinical outcomes of excisional goniotomy with the Kahook Dual Blade (KDB) in the management of various types of glaucoma., Methods: This was a retrospective, noncomparative chart review of 90 eyes of 53 patients with glaucoma that underwent standalone KDB goniotomy (KDB-alone group) or KDB goniotomy with concomitant phacoemulsification (KDB-phaco group) between October 2015 and October 2017. Surgical success was defined as an intraocular pressure (IOP) reduction by ≥ 20% at the last follow-up with no surgical reinterventions required and a final IOP ≥ 4 mmHg and ≤ 21 mmHg. We also report on changes from baseline in IOP, number of glaucoma medications, best-corrected visual acuity (BCVA), and visual field parameters, for up to 72 months., Results: At 72 months, mean (standard deviation [SD]) IOP was reduced from 17.5 (5.7) to 13.6 (3.0) mmHg (P < 0.0001) in the KDB-phaco group and from 23.3 (5.9) to 15.1 (6.2) mmHg (P = 0.0593) in the KDB-alone group. The mean (SD) number of glaucoma medications was reduced from 1.3 (1.0) to 0.8 (0.9) (P < 0.0001) in the KDB-phaco group and from 1.2 (1.0) to 0.7 (0.8) (P = 0.3409) in the KDB-alone group. During the 72-month follow-up, surgical success was achieved in 24 of the 52 available eyes (46.2%). Four eyes underwent a glaucoma surgical reintervention by 72 months., Conclusions: Excisional goniotomy with the KDB effectively lowered the IOP (by an average of 28.0% from baseline) and maintained or further reduced glaucoma medication burdens (by an average of 30.8% from baseline) under an excellent safety profile, independent of phacoemulsification status. The procedure exhibited favorable success for up to 6 years, providing valuable insights into its long-term efficacy as a glaucoma treatment., (© 2024. The Author(s).)

Purpose: To review the evidence on the safety and effectiveness of epithelium-off corneal collagen cross-linking (CXL) for the treatment of progressive corneal ectasia., Methods: A literature search of the PubMed database was most recently conducted in March 2024 with no date restrictions and limited to studies published in English. The search identified 359 citations that were reviewed in abstract form, and 43 of these were reviewed in full text. High-quality randomized clinical trials comparing epithelium-off CXL with conservative treatment in patients who have keratoconus (KCN) and post-refractive surgery ectasia were included. The panel deemed 6 articles to be of sufficient relevance for inclusion, and these were assessed for quality by the panel methodologist; 5 were rated level I, and 1 was rated level II. There were no level III studies., Results: This analysis includes 6 prospective, randomized controlled trials that evaluated the use of epithelium-off CXL to treat progressive KCN (5 studies) and post-laser refractive surgery ectasia (1 study), with a mean postoperative follow-up of 2.4 years (range, 1-5 years). All studies showed a decreased progression rate in treated patients compared with controls. Improvement in the maximum keratometry (Kmax) value, corrected distance visual acuity (CDVA), and uncorrected distance visual acuity (UDVA) was observed in the treatment groups compared with control groups. A decrease in corneal thickness was observed in both groups but was greater in the CXL group. Complications were rare., Conclusions: Epithelium-off CXL is effective in reducing the progression of KCN and post-laser refractive surgery ectasia in most treated patients with an acceptable safety profile., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Androgen receptor (AR) and its ligand androgens are important for development and physiology of various tissues. AR and its ligands also play critical role in the development of various diseases, making it a valuable therapeutic target. AR ligands, both agonists and antagonists, are being widely used to treat pathological conditions, including prostate cancer and hypogonadism. Despite AR being studied widely over the last five decades, the last decade has seen striking advances in the knowledge on AR and discoveries that have the potential to translate to the clinic. This review provides an overview of the advances in AR biology, AR molecular mechanisms of action, and next generation molecules that are currently in development. Several of the areas described in the review are just unraveling and the next decade will bring more clarity on these developments that will put AR at the forefront of both basic biology and drug development., 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 © 2024 Elsevier Inc. All rights reserved.)

Topical anesthetics for control of pain from corneal abrasions can cause drug-related toxicity that delays corneal healing. This report documents three cases where topical anesthetic drops were prescribed in the emergency department for pain control, after which patients developed persistent ocular pain, epithelial toxicity with impaired healing, and significant loss of vision. On consultation with the ophthalmology service, each patient was instructed to discontinue the topical anesthetic drops but to continue topical antibiotics. Soon thereafter, symptoms resolved, and the corneas healed within 72 hours. This report emphasizes the harm that can result from injudicious and/or unmonitored use of topical anesthetics for corneal abrasions. We advise emergency medicine and primary care providers against providing topical anesthetics to patients with corneal abrasions., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Mayo Clinic Institutional Review Board issued approval 24-004713. This retrospective study was performed in accordance with the tenets of the Declaration of Helsinki and was approved by the Mayo Clinic IRB on April 29, 2024. The study was determined to be of low risk to the subjects. There is no personal identifying information within this work. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Miller et al.)

Purpose: The purpose of this study was to evaluate and compare the anatomic characteristics of eyes with Fuchs endothelial corneal dystrophy (FECD) with eyes without FECD., Methods: This study was a retrospective chart review performed at an academic medical center. Patients with FECD were identified through a search of the electronic medical records. Eligible patients underwent Scheimpflug imaging and optical biometry and were compared with age and sex-matched control subjects who underwent similar testing in preparation for cataract surgery. Several measurements of the cornea, anterior chamber, and eyes were evaluated using multivariable linear regression models and multivariable logistic regression models., Results: A total of 404 eyes (202 eyes with FECD and 202 control eyes) were included in this study. Compared with controls, eyes with FECD had shallower AC depths, lower AC volumes, and narrower angles. Conversely, the spherical equivalent before cataract surgery, corneal pachymetry, and corneal volume were higher in eyes with FECD. On Scheimpflug imaging analysis, these anatomical differences were present in FECD eyes with and without corneal edema. After adjusting for sex, these differences remained statistically significant. Shorter axial length was found to be statistically significant in male eyes but not in female eyes with FECD., Conclusions: This study reports new ocular characteristics in FECD eyes with and without edema. Optical biometry and Scheimpflug imaging established that the anatomic findings in eyes with FECD were not simply due to the larger volume of an edematous cornea but rather unique to eyes with FECD. These findings will provide reliable, normative data for future studies examining surgical, medical, and anatomical factors in FECD., Competing Interests: K. H. Baratz: Consultant, Design Therapeutics. M. W. Stewart: Consultant: Bayer, Alkahest, Biogen, Revana. The remaining authors have no funding or conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To review the published literature on the safety and outcomes of keratolimbal allograft (KLAL) transplantation and living-related conjunctival limbal allograft (lr-CLAL) transplantation for bilateral severe/total limbal stem cell deficiency (LSCD)., Methods: Literature searches were last conducted in the PubMed database in February 2023 and were limited to the English language. They yielded 523 citations; 76 were reviewed in full text, and 21 met the inclusion criteria. Two studies were rated level II, and the remaining 19 studies were rated level III. There were no level I studies., Results: After KLAL surgery, best-corrected visual acuity (BCVA) improved in 42% to 92% of eyes at final follow-up (range, 12-95 months). The BCVA was unchanged in 17% to 39% of eyes and decreased in 8% to 29% of eyes. Two of 14 studies that evaluated the results of KLAL reported a notable decline in visual acuity over time postoperatively. Survival of KLAL was variable, ranging from 21% to 90% at last follow-up (range, 12-95 months) and decreased over time. For patients undergoing lr-CLAL surgery, BCVA improved in 31% to 100% of eyes at final follow-up (range, 16-49 months). Of the 9 studies evaluating lr-CLAL, 4 reported BCVA unchanged in 30% to 39% of patients, and 3 reported a decline in BCVA in 8% to 10% of patients. The survival rate of lr-CLAL ranged from 50% to 100% at final follow-up (range, 16-49 months). The most common complications were postoperative elevation of intraocular pressure, persistent epithelial defects, and acute allograft immune rejections., Conclusions: Given limited options for patients with bilateral LSCD, both KLAL and lr-CLAL are viable choices that may provide improvement of vision and ocular surface findings. The studies trend toward a lower rejection rate and graft failure with lr-CLAL. However, the level and duration of immunosuppression vary widely between the studies and may impact allograft rejections and long-term graft survival. Complications related to immunosuppression are minimal. Repeat surgery may be needed to maintain a viable ocular surface. Reasonable long-term success can be achieved with both KLAL and lr-CLAL with appropriate systemic immunosuppression., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Improving survival for patients diagnosed with metastatic disease and overcoming chemoresistance remain significant clinical challenges in treating breast cancer. Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by a lack of therapeutically targetable receptors (ER/PR/HER2). TNBC therapy includes a combination of cytotoxic chemotherapies, including microtubule-targeting agents (MTAs) like paclitaxel (taxane class) or eribulin (vinca class); however, there are currently no FDA-approved MTAs that bind to the colchicine-binding site. Approximately 70 % of patients who initially respond to paclitaxel will develop taxane resistance (TxR). We previously reported that an orally bioavailable colchicine-binding site inhibitor (CBSI), VERU-111, inhibits TNBC tumor growth and treats pre-established metastatic disease. To further improve the potency and metabolic stability of VERU-111, we created next-generation derivatives of its scaffold, including 60c., Results: 60c shows improved in vitro potency compared to VERU-111 for taxane-sensitive and TxR TNBC models, and suppress TxR primary tumor growth without gross toxicity. 60c also suppressed the expansion of axillary lymph node metastases existing prior to treatment. Comparative analysis of excised organs for metastasis between 60c and VERU-111 suggested that 60c has unique anti-metastatic tropism. 60c completely suppressed metastases to the spleen and was more potent to reduce metastatic burden in the leg bones and kidney. In contrast, VERU-111 preferentially inhibited liver metastases and lung metastasis repression was similar. Together, these results position 60c as an additional promising CBSI for TNBC therapy, particularly for patients with TxR disease., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The corresponding author, Dr. Wei Li, is a scientific consultant for Veru, Inc. Veru licensed the compounds including 60c described in this report, for potential commercial development., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Effective management of head and neck cancer (HNC) poses a significant challenge in the field of oncology, due to its intricate pathophysiology and limited treatment options. The most common HNC malignancy is head and neck squamous cell carcinoma (HNSCC). HNSCC treatment includes a combination of surgery, radiation, and chemotherapy. While HNSCC is treatable if diagnosed early, this is often not the case and is considered incurable once in its late stages and metastatic disease has developed. Therapies are also limited once resistant disease has occurred. SP-1-39, a novel colchicine-binding site inhibitor (CBSI), has been recently reported for its potential efficacy in a variety of cancer cell lines including breast, melanoma, pancreatic, and prostate. SP-1-39 also shows abilities to overcome paclitaxel resistance in a paclitaxel-resistant prostate cancer xenograft model. To evaluate the potential of SP-1-39 as a new HNSCC treatment option, herein we systematically performed preclinical studies in HNSCC models using SP-1-39 and demonstrated that, in vitro, SP-1-39 inhibits the proliferation of 2 HNSCC cell lines with low nanomolar IC 50 values (1.4 to 2.1 nM), induces HNSCC cell apoptosis in a dose-dependent manner, interferes with migration of HNSCC cells, and leads to HNSCC cell cycle arrest in the G2/M phase. In vivo, SP-1-39 suppresses the primary tumor growth of a Detroit 562 subcutaneous xenograft mouse model in 6- to 8-wk-old, male NSG (NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ) mice, with no detectable cytotoxic effects at a low dose of 2.5 mg/kg. This efficacy of SP-1-39 is better when compared with the treatment using a reference chemotherapy drug, paclitaxel at 10 mg/kg. Collectively, these data demonstrate that SP-1-39 is a promising candidate for further development for more efficacious HNSCC treatment., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: W.L. and D.D.M. are listed as inventors for compound SP-1-39 described in this study. W.L. and D.D.M. also received sponsored research agreements (SRAs) from Veru, Inc., although the SRAs are not directly related to this study. W.L. is scientific consultant for Veru, Inc. However, Veru, Inc. did not have any influence on this study and only required reviewing this study prior to submission for publication for potential intellectual property purposes.

Ovarian cancer is the most lethal gynecological malignancy, with a 5-year survival rate of approximately 50%. The dismal prognosis is due in part to metastatic disease and acquired drug resistance to conventional chemotherapies such as taxanes. Colchicine binding site inhibitors (CBSIs) are attractive alternatives to taxanes because they could potentially achieve oral bioavailability and overcome drug resistance associated with the prolonged use of taxanes. VERU-111 is one of the most advanced CBSIs that is orally available, potent, well-tolerated, and has shown good efficacy in several preclinical solid tumor models. Here, we demonstrate for the first time the in vitro potency of VERU-111 as well as its efficacy at inhibiting tumor growth and metastasis in an orthotopic ovarian cancer mouse model. VERU-111 has nanomolar potency against ovarian cancer cell lines and strongly inhibits colony formation, proliferation, invasion, and migration. VERU-111 disrupts microtubule formation to induce mitotic catastrophe and, ultimately, apoptosis in a concentration-dependent manner. The efficacy of VERU-111 was comparable with standard chemotherapy paclitaxel, the current first-line treatment for ovarian cancer, with no observed synergy with combination paclitaxel + VERU-111 treatment. In vivo , VERU-111 markedly suppressed ovarian tumor growth and completely suppressed distant organ metastasis. Together, these results support VERU-111 for its potential as a novel therapy for ovarian cancer, particularly for late-stage metastatic disease. Significance Statement VERU-111 is an investigational new drug and has comparable efficacy as paclitaxel in suppressing tumor cell proliferation, colony formation, and migration in ovarian cancer models in vitro and has potent in vivo anti-tumor and anti-metastatic activity in an orthotopic ovarian cancer mouse model. VERU-111 has low systemic toxicity and, unlike paclitaxel, is orally bioavailable and is not a substrate for the major drug efflux transporters, making it a promising and attractive alternative to taxane-based therapy., (© 2024 The Authors. This is an open access article under the terms of the Creative Commons Attribution CC BY License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.)

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the Western world, with a higher prevalence among Europeans and North Americans than that in Africans, Hispanics, and Asians. Advanced AMD is categorized as atrophic (dry) or exudative (wet/neovascular age-related macular degeneration [nAMD]). Dry AMD is characterized by progressive geographic atrophy of the retinal pigment epithelium and outer retinal layers, whereas nAMD is characterized by new vessels that invade the subretinal and/or subretinal pigment epithelium spaces. Existing treatments delay the onset of advanced AMD and reverses vision loss for a couple of years before atrophy usually decreases central visual acuity. We searched PubMed and Medline databases from January 1, 1980, to December 1, 2023, using the following search terms: macular degeneration, choroidal neovascularization, geographic atrophy, drusen, age-related maculopathy, AMD, ARMD, and anti-VEGF . Relevant articles in English (or English translations) were retrieved and reviewed. Bibliographies of the identified manuscripts were also reviewed to identify relevant studies. Age-related macular degeneration most commonly affects people older than 55 years. Visual prognosis varies, with advanced lesions (nAMD and geographic atrophy) leading to rapid, progressive loss of central vision and contrast sensitivity. Although AMD is not a life-threatening disease, reduced vision profoundly compromises quality of life and necessitates living assistance for many patients. Over the past 2 decades, advances in prevention (vitamin supplementation) and therapy (antivascular endothelial growth factor and complement inhibitor drugs) have reduced vision loss and blindness. Further research is needed to decrease the incidence of blindness in patients with advanced disease., Competing Interests: Dr Stewart is the Professor of Ophthalmology Research of Knights Templar Eye Foundation, consultant for Alkahest, Bayer, Biogen, Revana, reports research support from 10.13039/100006396Alexion, and leadership role as IJCAHPO President. Dr Miller reports payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from the University of Florida Ophthalmology Grand Rounds, leadership role in the Legislative Chair, Florida Society of Ophthalmology and YO Advocacy Subcommittee Chair, American Academy of Ophthalmology. The other authors report no competing interests., (© 2024 The Authors.)

Purpose: To evaluate the safety and effectiveness of the Ahmed ClearPath ® (ACP) 250 mm 2 glaucoma drainage device (GDD) in managing refractory primary open-angle glaucoma (POAG)., Patients and Methods: This was a retrospective case series focused on adult patients diagnosed with severe POAG who underwent implantation of an ACP GDD. Over a 36-month follow-up period, data on intraocular pressure (IOP), the number of glaucoma medications, and complications were recorded. The primary objectives were to assess the reductions from baseline in both IOP and medication usage, through 36 months. Secondary objectives included the proportion of eyes achieving an IOP reduction of ≥ 20% from baseline at 36 months. Intraoperative and postoperative complications were also assessed., Results: Twelve eyes from 11 patients (mean age: 71.3 ± 14.1 years) met the inclusion criteria and were included in the study. All patients had severe POAG (n=11), with the majority being Caucasian (n=8) and female (n=10). The mean (standard deviation) IOP and number of glaucoma medications at baseline were 29 (7.6) mmHg and 3 (0.9), respectively. At 36 months, mean IOP was reduced to 10.6 (5.5) mmHg (-61.8%; p= 0.0008) and mean number of medications was reduced to 0.9 (0.9) (-71.4%; p=0.0005), with 88.9% of eyes achieving an IOP reduction by ≥20%. No vision threatening complications were observed., Conclusion: To our knowledge this is the first study to report 36-month outcomes of the novel ACP device in the treatment of refractory POAG. The safety profile and efficacy of the ACP was found to be comparable to that of other commonly utilized GDD models., Competing Interests: All authors report no conflicts of interest in this work., (© 2024 Boopathiraj et al.)

Background and Objective: PD-1 inhibitors have revolutionized cancer therapies and are being used to treat an expanding array of cancers. To best serve patients, clinicians should be familiar with the spectrum of skin manifestations associated with PD-1 inhibitor therapy. Here, we report a unique case of hypertrophic lichen planus (HLP) in a 64-year-old man treated with pembrolizumab; the presentation initially suggested a squamous cell carcinoma (SCC) morphology, then evolved into a morphology more typical of hypertrophic lichen planus. This case underscores the need for caution in diagnosing eruptive SCCs associated with PD-1 inhibitor therapy. In such instances, maintaining a high suspicion for lichenoid reactions as sequelae of PD-1 inhibitor treatment and starting an empiric trial of therapy for lichenoid dermatitis may be warranted to ensure timely management of lesions., Methods: We describe a case of hypertrophic lichen planus mimicking squamous cell carcinoma in the setting of PD-1 inhibitory therapy with pembrolizumab. A PubMed literature review was conducted to identify other cases and determine the incidence of lichenoid reactions imitating squamous cell carcinoma in the setting of PD-1 inhibitor use., Results: Our case is one of the few available pieces of literature describing eruptive hypertrophic lichen planus imitating SCC in the setting of PD-1 inhibitor use. Initial skin nodule biopsy appeared histologically compatible with squamous cell carcinoma. Repeat biopsy of the skin lesions revealed histological features consistent with hypertrophic lichen planus. Over time, lower extremity lesions evolved into a more typical appearance of hypertrophic lichen planus. Treatment with topical 0.05% clobetasol ointment and oral acitretin 25 mg led to complete resolution of lesions within 2-3 months., Conclusions: This case underscores the significance of maintaining vigilance for lichenoid reactions as potential sequelae of PD-1 inhibitor therapy. It highlights the variability in initial presentation and the potential for lesions to transform over time. Timely recognition and appropriate management, including high-potency topical corticosteroids and oral acitretin, are crucial for achieving favorable outcomes in patients experiencing such reactions. More studies are necessary to fully analyze the rate of HLP occurrence as a consequence of PD-1 inhibitor use., (© 2024. The Author(s).)

Purpose: Although musculoskeletal involvement is the common presentation, studies have reported the incidence of sports related ocular trauma. Here we present the case reports of two patients who sustained injury in one of the fast growing sports - the pickleball, during play without eye protection., Observations: Two patients with history of injury during pickleball play presented to our clinic with varying spectrum of ocular presentations. First patient had an anterior segment involvement with hyphema and elevated intraocular pressure, and the second patient had both anterior and posterior segment involvement causing angle recession and commotio retinae., Conclusion: Ocular injuries related to various sports have been extensively described, our intent is to increase the awareness about the possible ocular injuries related to rising pickleball and that improved safety measures and appropriate education to the players could prevent such ocular injuries., Competing Interests: 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., (© 2024 The Authors.)

Aim: To review the published literature evaluating the safety and efficacy outcomes of canaloplasty performed in the treatment of glaucoma., Background: Canaloplasty is a nonpenetrating glaucoma procedure involving combined 360° circumnavigation and viscodilation of Schlemm's canal. The procedure may be performed under an ab externo (with tensioning suture) or ab-interno (conjunctiva-sparing) approach. Given the wide variety of glaucoma procedure types and approaches, further investigation into the role of canaloplasty in ophthalmological practice is warranted. The objectives of this narrative review are to synthesize the existing literature in order to investigate indications, safety and efficacy outcomes, and the optimal place of canaloplasty in glaucoma treatment and management., Review of Results: A total of 60 articles were included in this review. Both ab externo and ab-interno canaloplasty (ABiC) were found to be significantly effective at reducing intraocular pressure (IOP) and glaucoma medication burdens in patients with mild-to-moderate open-angle glaucoma (OAG). These findings remained consistent regardless of phacoemulsification status. ABiC was found to exhibit a safety profile favorable compared to trabeculectomy and comparable to minimally invasive trabecular bypass implants., Conclusion: Canaloplasty is a nonpenetrating surgical intervention that is highly effective in treating patients with mild-to-moderate OAG across a large variety of clinical scenarios., Clinical Significance: These findings support the clinical use of canaloplasty in ophthalmological practice, clarify its patient profile, and compare procedural outcomes to other minimally invasive glaucoma surgery (MIGS) devices on the market., How to Cite This Article: Wagner IV, Towne C, Saade MC, et al. A Review of Canaloplasty in the Treatment and Management of Glaucoma. J Curr Glaucoma Pract 2024;18(2):79-85., Competing Interests: Source of support: Nil Conflict of interest: Dr Syril Dorairaj is associated as the Associate Managing Editor of this journal and this manuscript was subjected to this journal's standard review procedures, with this peer review handled independently of this editorial board member and his research group.Conflict of interest: Dr Syril Dorairaj is associated as the Associate Managing Editor of this journal and this manuscript was subjected to this journal's standard review procedures, with this peer review handled independently of this editorial board member and his research group., (Copyright © 2024; The Author(s).)

Purpose: To review the published literature on the diagnostic capabilities of the newest generation of corneal imaging devices for the identification of keratoconus., Methods: Corneal imaging devices studied included tomographic platforms (Scheimpflug photography, OCT) and functional biomechanical devices (imaging an air impulse on the cornea). A literature search in the PubMed database for English language studies was last conducted in February 2023. The search yielded 469 citations, which were reviewed in abstract form. Of these, 147 were relevant to the assessment objectives and underwent full-text review. Forty-five articles met the criteria for inclusion and were assigned a level of evidence rating by the panel methodologist. Twenty-six articles were rated level II, and 19 articles were rated level III. There were no level I evidence studies of corneal imaging for the diagnosis of keratoconus found in the literature. To provide a common cross-study outcome measure, diagnostic sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were extracted. (A perfect diagnostic test that identifies all cases properly has an AUC of 1.0.) RESULTS: For the detection of keratoconus, sensitivities for all devices and parameters (e.g., anterior or posterior corneal curvature, corneal thickness) ranged from 65% to 100%. The majority of studies and parameters had sensitivities greater than 90%. The AUCs ranged from 0.82 to 1.00, with the majority greater than 0.90. Combined indices that integrated multiple parameters had an AUC in the mid-0.90 range. Keratoconus suspect detection performance was lower with AUCs ranging from 0.66 to 0.99, but most devices and parameters had sensitivities less than 90%., Conclusions: Modern corneal imaging devices provide improved characterization of the cornea and are accurate in detecting keratoconus with high AUCs ranging from 0.82 to 1.00. The detection of keratoconus suspects is less accurate with AUCs ranging from 0.66 to 0.99. Parameters based on single anatomic locations had a wide range of AUCs. Studies with combined indices using more data and parameters consistently reported high AUCs., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Triple-negative breast cancer (TNBC) is an aggressive subtype with no targeted therapeutics. The luminal androgen receptor (LAR) subtype constitutes 15% of TNBC and is enriched for androgen receptor (AR) and AR target genes. Here, we show that a cohort of TNBC not only expresses AR at a much higher rate (∼80%) but also expresses AR splice variants (AR-SVs) (∼20%), further subclassifying LAR-TNBC. Higher AR and AR-SV expression and corresponding aggressive phenotypes are observed predominantly in specimens obtained from African American women. LAR TNBC specimens are enriched for interferon, Janus kinase (JAK)-signal activator and transducer (STAT), and androgen signaling pathways, which are exclusive to AR-expressing epithelial cancer cells. AR- and AR-SV-expressing TNBC cell proliferation and xenograft and patient-tumor explant growth are inhibited by AR N-terminal domain-binding selective AR degrader or by a JAK inhibitor. Biochemical analysis suggests that STAT1 is an AR coactivator. Collectively, our work identifies pharmacologically targetable TNBC subtypes and identifies growth-promoting interaction between AR and JAK-STAT signaling., Competing Interests: Declaration of interests R.N. is a consultant to Oncternal Therapeutics. The SARDs mentioned in this manuscript are licensed to Oncternal Therapeutics Inc., San Diego, CA, by the University of Tennessee Research Foundation (UTRF) under an exclusive licensing agreement. S.P., D.J.H., Y.H., D.D.M., and R.N. are co-inventors in patents related to UT-105 and receive royalties., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Glioblastoma (GBM) is an aggressive brain cancer with a poor prognosis. While surgical resection is the primary treatment, adjuvant temozolomide (TMZ) chemotherapy and radiotherapy only provide slight improvement in disease course and outcome. Unfortunately, most treated patients experience recurrence of highly aggressive, therapy-resistant tumours and eventually succumb to the disease. To increase chemosensitivity and overcome therapy resistance, we have modified the chemical structure of the PFI-3 bromodomain inhibitor of the BRG1 and BRM catalytic subunits of the SWI/SNF chromatin remodelling complex. Our modifications resulted in compounds that sensitized GBM to the DNA alkylating agent TMZ and the radiomimetic bleomycin. We screened these chemical analogues using a cell death ELISA with GBM cell lines and a cellular thermal shift assay using epitope tagged BRG1 or BRM bromodomains expressed in GBM cells. An active analogue, IV-129, was then identified and further modified, resulting in new generation of bromodomain inhibitors with distinct properties. IV-255 and IV-275 had higher bioactivity than IV-129, with IV-255 selectively binding to the bromodomain of BRG1 and not BRM, while IV-275 bound well to both BRG1 and BRM bromodomains. In contrast, IV-191 did not bind to either bromodomain or alter GBM chemosensitivity. Importantly, both IV-255 and IV-275 markedly increased the extent of DNA damage induced by TMZ and bleomycin as determined by nuclear γH2AX staining. Our results demonstrate that these next-generation inhibitors selectively bind to the bromodomains of catalytic subunits of the SWI/SNF complex and sensitize GBM to the anticancer effects of TMZ and bleomycin. This approach holds promise for improving the treatment of GBM., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Importance: Recently, several states have granted optometrists privileges to perform select laser procedures (laser peripheral iridotomy, selective laser trabeculoplasty, and YAG laser capsulotomy) with the aim of increasing access. However, whether these changes are associated with increased access to these procedures among each state's Medicare population has not been evaluated., Objective: To compare patient access to laser surgery eye care by estimated travel time and 30-minute proximity to an optometrist or ophthalmologist., Design, Setting, and Participants: This retrospective cohort database study used Medicare Part B claims data from 2016 through 2020 for patients accessing new patient or laser eye care (laser peripheral iridotomy, selective laser trabeculoplasty, YAG) from optometrists or ophthalmologists in Oklahoma, Kentucky, Louisiana, Arkansas, and Missouri. Analysis took place between December 2021 and March 2023., Main Outcome and Measures: Percentage of each state's Medicare population within a 30-minute travel time (isochrone) of an optometrist or ophthalmologist based on US census block group population and estimated travel time from patient to health care professional., Results: The analytic cohort consisted of 1 564 307 individual claims. Isochrones show that optometrists performing laser eye surgery cover a geographic area similar to that covered by ophthalmologists. Less than 5% of the population had only optometrists (no ophthalmologists) within a 30-minute drive in every state except for Oklahoma for YAG (301 470 [7.6%]) and selective laser trabeculoplasty (371 097 [9.4%]). Patients had a longer travel time to receive all laser procedures from optometrists than ophthalmologists in Kentucky: the shortest median (IQR) drive time for an optometrist-performed procedure was 49.0 (18.4-71.7) minutes for YAG, and the the longest median (IQR) drive time for an ophthalmologist-performed procedure was 22.8 (12.1-41.4) minutes, also for YAG. The median (IQR) driving time for YAG in Oklahoma was 26.6 (12.2-56.9) for optometrists vs 22.0 (11.2-40.8) minutes for ophthalmologists, and in Arkansas it was 90.0 (16.2-93.2) for optometrists vs 26.5 (11.8-51.6) minutes for ophthalmologists. In Louisiana, the longest median (IQR) travel time to receive laser procedures from optometrists was for YAG at 18.5 (7.6-32.6) minutes and the shortest drive to receive procedures from ophthalmologists was for YAG at 20.5 (11.7-39.7) minutes., Conclusions and Relevance: Although this study did not assess impact on quality of care, expansion of laser eye surgery privileges to optometrists was not found to lead to shorter travel times to receive care or to a meaningful increase in the percentage of the population with nearby health care professionals.

Polymerization of tubulin dimers to form microtubules is one of the key events in cell proliferation. The inhibition of this event has long been recognized as a potential treatment option for various types of cancer. Compound 1e was previously developed by our team as a potent inhibitor of tubulin polymerization that binds to the colchicine site. To further improve the potency and therapeutic properties of compound 1e , we hypothesized based on the X-ray crystal structure that modification of the pyrimidine dihydroquinoxalinone scaffold with additional hetero-atom (N, O, and S) substituents could allow the resulting new compounds to bind more tightly to the colchicine site and display greater efficacy in cancer therapy. We therefore synthesized a series of new pyrimidine dihydroquinoxalinone derivatives, compounds 10 , 12b-c , 12e , 12h , and 12j-l , and evaluated their cytotoxicity and relative ability to inhibit proliferation, resulting in the discovery of new tubulin-polymerization inhibitors. Among these, the most potent new inhibitor was compound 12k , which exhibited high cytotoxic activity in vitro, a longer half-life than the parental compound in liver microsomes (IC 50 = 0.2 nM, t 1/2 = >300 min), and significant potency against a wide range of cancer cell lines including those from melanoma and breast, pancreatic, and prostate cancers. High-resolution X-ray crystal structures of the best compounds in this scaffold series, 12e , 12j , and 12k , confirmed their direct binding to the colchicine site of tubulin and revealed their detailed molecular interactions. Further evaluation of 12k in vivo using a highly taxane-resistant prostate cancer xenograft model, PC-3/TxR, demonstrated the strong tumor growth inhibition at the low dose of 2.5 mg/kg (i.v., twice per week). Collectively, these results strongly support further preclinical evaluations of 12k as a potential candidate for development., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

A major challenge for new drug discovery in the area of androgen receptor (AR) antagonists lies in predicting the druggable properties that will enable small molecules to retain their potency and stability during further studies in vitro and in vivo . Indole (compound 8 ) is a first-in-class AR antagonist with very high potency (IC 50 = 0.085 μM) but is metabolically unstable. During the metabolic studies described herein, we synthesized new small molecules that exhibit significantly improved stability while retaining potent antagonistic activity for an AR. This structure-activity relationship (SAR) study of more than 50 compounds classified with three classes (Class I, II, and III) and discovered two compounds (32c and 35i ) that are potent AR antagonists (e.g., IC 50 = 0.021 μM, T 1/2 = 120 min for compound 35i ). The new antagonists exhibited improved in vivo pharmacokinetics (PK) with high efficacy antiandrogen activity in Hershberger and antiandrogen Enz-Res tumor xenograft models that overexpress AR (LNCaP-AR).

Extensive preclinical studies have shown that colchicine-binding site inhibitors (CBSIs) are promising drug candidates for cancer therapy. Although numerous CBSIs were generated and evaluated, but so far the FDA has not approved any of them due to undesired adverse events or insufficient efficacies. We previously reported two very potent CBSIs, the dihydroquinoxalinone compounds 5 m and 5t. In this study, we further optimized the structures of compounds 5 m and 5t and integrated them to generate a new analog, SB226. X-ray crystal structure studies and a tubulin polymerization assay confirmed that SB226 is a CBSI that could disrupt the microtubule dynamics and interfere with microtubule assembly. Biophysical measurements using surface plasmon resonance (SPR) spectroscopy verified the high binding affinity of SB226 to tubulin dimers. The in vitro studies showed that SB226 possessed sub-nanomolar anti-proliferative activities with an average IC 50 of 0.76 nM against a panel of cancer cell lines, some of which are paclitaxel-resistant, including melanoma, breast cancer and prostate cancer cells. SB226 inhibited the colony formation and migration of Taxol-resistant A375/TxR cells, and induced their G2/M phase arrest and apoptosis. Our subsequent in vivo studies confirmed that 4 mg/kg SB226 strongly inhibited the tumor growth of A375/TxR melanoma xenografts in mice and induced necrosis, anti-angiogenesis, and apoptosis in tumors. Moreover, SB226 treatment significantly inhibited spontaneous axillary lymph node, lung, and liver metastases originating from subcutaneous tumors in mice without any obvious toxicity to the animals' major organs, demonstrating the therapeutic potential of SB226 as a novel anticancer agent for cancer therapy., Competing Interests: Declaration of competing interest W.L. and D.D.M. report receiving a sponsored research agreement grant from Veru, Inc. However, Veru, Inc. had no input or influence in the experimental design, data collection, and data analysis in this manuscript. Other authors did not disclose potential conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Defatted green microalgae Nannochloropsis oceanica (DGM) is a rich source of bioavailable iron. However, its use in foods results in unacceptable color and taste development. Therefore, the purpose of this study was to investigate strategies to enhance the use of DGM in foods. DGM and inulin were encapsulated (EC) in an oil-in-water emulsion using high-pressure homogenization. To confirm iron bioavailability, C57BL/6 mice were fed an iron-deficient diet (ID) for 2 weeks. The mice were then fed one of the four diets: ID, ID + DGM (DGM), ID + EC (EC50 or EC100) for 4 weeks. To test the stability of DGM as an iron fortificant at two different fortification rates of 17.5 mg Fe/kg (50%) or 35 mg Fe/kg (100%), whole (DGM50/DGM100), encapsulated (EC50/EC100) and color-masked (CM50/CM100) DGM were added to wheat flour (WF) at two different temperatures: 20 °C and 45 °C and were examined for 30 days. Acceptability studies were conducted to determine sensory differences between rotis (Indian flat bread) prepared from WF/EC50/CM50/EC100. The mice consuming EC50/EC100 diets showed comparable iron status to DGM-fed mice, suggesting that encapsulation did not negatively impact iron bioavailability. Addition of EC to wheat flour resulted in the lowest Fe 2+ oxidation and color change amongst treatments, when stored for 30 days. There were no differences in the overall liking and product acceptance of rotis amongst treatments at both day 0 and day 21 samples. Our results suggest that EC50 can be effectively used as an iron fortificant in WF to deliver highly bioavailable iron without experiencing any stability or sensory defects, at least until 30 days of storage.

Introduction: The clinical course of schizophrenia is often characterized by recurrent relapses. Blood inflammatory markers are altered in acute psychosis, and may be state markers for illness relapse in schizophrenia. Few studies have investigated longitudinal, intra-individual changes in inflammatory markers as a predictor of relapse. In the present study, we explored this association in a relapse prevention trial in patients with schizophrenia., Methods: We analyzed blood inflammatory markers in 200 subjects, with a mean 11 samples per subject, during the 30 month Preventing Relapse in schizophrenia: Oral Antipsychotics Compared to Injectable: eValuating Efficacy (PROACTIVE) trial. Associations between longitudinal changes in inflammatory markers and relapse were analyzed using a within-subjects design., Results: 70 (35 %) of subjects relapsed during the study period. There were no significant differences in mean inflammatory marker levels based on relapse status (yes/no). Baseline levels of inflammatory markers did not predict incident relapse. Among subjects who relapsed, there was a significant decrease in mean blood IL-6 (n = 38, p = 0.019) and IFN-γ (n = 44, p = 0.012) levels from the visit before the relapse to the visit after relapse., Conclusion: Although there was some evidence for inflammation as a potential state marker for acute psychosis, we did not find significant evidence for its utility as a relapse-predictive marker., Competing Interests: Declaration of competing interest Dr. B. Miller served as PI on the associated National Institute of Mental Health grant. In the past 12 months, Dr. Miller received research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute; and Honoraria from Atheneum, Carlat Psychiatry, Clearview, and Psychiatric Times. Dr. Lemos declares no financial interests or potential conflicts of interest related directly or indirectly to this work. Dr. Schooler declares no financial interests or potential conflicts of interest related directly or indirectly to this work. Dr. Goff declares no financial interests or potential conflicts of interest related directly or indirectly to this work. Dr. Kopelowicz declares no financial interests or potential conflicts of interest related directly or indirectly to this work. Dr. Lauriello declares no financial interests or potential conflicts of interest related directly or indirectly to this work. Dr. Manschreck declares no financial interests or potential conflicts of interest related directly or indirectly to this work. Dr. Mendelowitz declares no financial interests or potential conflicts of interest related directly or indirectly to this work. Dr. D. Miller declares no financial interests or potential conflicts of interest related directly or indirectly to this work. Ms. Severe declares no financial interests or potential conflicts of interest related directly or indirectly to this work. Dr. Wilson declares no financial interests or potential conflicts of interest related directly or indirectly to this work. Dr. Ames declares no financial interests or potential conflicts of interest related directly or indirectly to this work. Dr. Bustillo declares no financial interests or potential conflicts of interest related directly or indirectly to this work. Dr. Kane declares no financial interests or potential conflicts of interest related directly or indirectly to this work. Dr. Rapaport served as mentor on the associated National Institute of Mental Health grant. Dr. Buckley served as mentor on the associated National Institute of Mental Health grant., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Androgen receptor (AR) and its splice variants (AR-SVs) promote prostate cancer (PCa) growth by orchestrating transcriptional reprogramming. Mechanisms by which the low complexity and intrinsically disordered primary transactivation domain (AF-1) of AR and AR-SVs regulate transcriptional programming in PCa remains poorly defined. Using omics, live and fixed fluorescent microscopy of cells, and purified AF-1 and AR-V7 recombinant proteins we show here that AF-1 and the AR-V7 splice variant form molecular condensates by liquid-liquid phase separation (LLPS) that exhibit disorder characteristics such as rapid intracellular mobility, coactivator interaction, and euchromatin induction. The LLPS and other disorder characteristics were reversed by a class of small-molecule-selective AR-irreversible covalent antagonists (SARICA) represented herein by UT-143 that covalently and selectively bind to C406 and C327 in the AF-1 region. Interfering with LLPS formation with UT-143 or mutagenesis resulted in chromatin condensation and dissociation of AR-V7 interactome, all culminating in a transcriptionally incompetent complex. Biochemical studies suggest that C327 and C406 in the AF-1 region are critical for condensate formation, AR-V7 function, and UT-143's irreversible AR inhibition. Therapeutically, UT-143 possesses drug-like pharmacokinetics and metabolism properties and inhibits PCa cell proliferation and tumor growth. Our work provides critical information suggesting that clinically important AR-V7 forms transcriptionally competent molecular condensates and covalently engaging C327 and C406 in AF-1, dissolves the condensates, and inhibits its function. The work also identifies a library of AF-1-binding AR and AR-SV-selective covalent inhibitors for the treatment of PCa.

HER2+ breast cancer accounts for 15% of all breast cancer cases. Current frontline therapy for HER2+ metastatic breast cancer relies on targeted antibodies, trastuzumab and pertuzumab, combined with microtubule inhibitors in the taxane class (paclitaxel or docetaxel). It is well known that the clinical efficacy of taxanes is limited by the development of chemoresistance and hematological and neurotoxicities. The colchicine-binding site inhibitors (CBSIs) are a class of promising alternative agents to taxane therapy. Sabizabulin (formerly known as VERU-111) is a potent CBSI that overcomes P-gp-mediated taxane resistance, is orally bioavailable, and inhibits tumor growth and distant metastasis in triple negative breast cancer (TNBC). Herein, we demonstrate the efficacy of sabizabulin in HER2 + breast cancer. In vitro, sabizabulin inhibits the proliferation of HER2+ breast cancer cell lines with low nanomolar IC 50 values, inhibits clonogenicity, and induces apoptosis in a concentration-dependent manner. In vivo, sabizabulin inhibits breast tumor growth in the BT474 (ER+/PR+/HER2+) xenograft model and a HER2+ (ER-/PR-) metastatic patient-derived xenograft (PDX) model, HCI-12. We demonstrate that sabizabulin is a promising alternative agent to target tubulin in HER2+ breast cancer with similar anti-metastatic efficacy to paclitaxel, but with the advantage of oral bioavailability and lower toxicity than taxanes.