Citations

Précis: Glaucoma patients with significant visual field defects show poorer driving performance, higher collision risks, and a greater likelihood of driving cessation. They face difficulties with lane maintenance, slower hazard responses, and self-regulation while driving. Purpose: Glaucoma is a chronic, progressive optic neuropathy associated with visual field (VF) defects, which in advanced disease has been shown to affect patients’ activities of daily living. This systematic review qualitatively analyzes existing literature that explores the impact of glaucomatous VF loss on the driving performance of glaucoma patients, the extent of driving limitation and cessation, as well as the risk of motor vehicle collisions (MVCs). Methods: A literature search of MEDLINE and Embase (via Ovid), PubMed, Cochrane Library, and Web of Science databases was performed for studies published from 2003 to 2023, with the terms “glaucoma,” “visual field defect/disorder,” and “driving,” followed by selective vetting based on inclusion criteria. Within studies, data pertaining to study design, subject demographics, VF defect characteristics, driving performance and related outcomes were extracted. Results: Initial search yielded 835 studies, with 20 studies selected. Three more studies were included through hand-searching, with a total of 23 studies included for final review. Moderate to severe VF defects resulted in poorer driving performance, with slower response times to road hazards, decreased ability for lane maintenance, and increased difficulty driving at night. Patients with more severe VF defects and with bilateral glaucoma were more likely to limit or cease driving compared with those with milder and unilateral glaucoma. A greater severity of VF loss was associated with a higher risk of MVCs. Conclusion: More severe glaucomatous VF and bilateral glaucoma is associated with worse driving performances and a higher risk of MVCs, in both simulator and real-world settings.

Background/Objectives: Coronavirus disease 2019 (COVID-19) is associated with gastrointestinal (GI) symptoms. Small intestinal bacterial overgrowth (SIBO) is emerging as a significant GI sequela post-COVID-19 infection. This study aimed to evaluate the prevalence and incidence of SIBO post-COVID-19 infection across different age groups and to identify associated risk factors in a global cohort. Methods: A retrospective study utilized the TriNetX database and included adult patients (≥18 years) diagnosed with SIBO following COVID-19 infection (1 January 2022–30 May 2024). A propensity score matching (1:1) was used to adjust for demographics and SIBO risk factors. Kaplan–Meier survival analysis assessed the SIBO incidence within 12 months. Results: Among 1,660,092 COVID-19 patients and 42,322,017 controls, SIBO was diagnosed in 353 COVID-19 patients without hydrogen breath tests (BT) and 78 with BT, compared to 3368 controls without BT and 871 with BT. Age-specific analysis demonstrated a clear, progressive increase in the SIBO incidence, becoming distinctly significant by 6 months and highest at 12 months post-infection. The highest risks were noted in ages 60–69 (0.011% vs. 0.004%, OR 2.6, p = 0.0003) and 70–79 (0.011% vs. 0.005%, OR 2.0, p = 0.0004), with younger age groups (30–49 years) also showing significantly increased risks. The medication analysis revealed strong associations with chronic opioid, proton pump inhibitor, and antidiarrheal medication. Conclusions: COVID-19 significantly increased the risk of SIBO, particularly within the first 12 months post-infection, across various age groups and, notably, in association with certain chronic medications. Clinical vigilance and targeted management strategies are recommended to mitigate long-term GI consequences.

A systematic review was conducted of studies published up to 30 August 2024. Studies comparing conventional visual field (VF) indices, ability to detect central visual field defects (CVFDs), structure–function (S-F) concordance, and test characteristics across the HVF 24-2C SITA-Faster, 24-2 SITA-Standard/Faster, and 10-2 SITA-Standard/Fast tests were included. Eight studies with 1239 subjects (49.1% male; mean age, 54.8–66.9 years) were analyzed. The 24-2C produced similar global VF indices compared to the 10-2 and 24-2 (Standard/Faster) (ICC = 0.95 and 0.80, p < 0.001), detected more VF defects and CVFD clusters, and demonstrated greater S-F concordance than the 24-2 (Standard/Faster). Although the 10-2 (Standard/Fast) detected significantly more CVFDs and had a greater S-F concordance, the agreement between the 24-2C and 10-2 grids was substantial (ĸ = 0.488 to 0.708). The 24-2C was also faster compared to the 24-2 Standard and 10-2 (Standard/Fast), with comparable false positives, higher false negatives, and fewer fixation losses than the 24-2 Standard. In conclusion, the HVF 24-2C is quicker and identifies more CVFDs than the 24-2 grid, demonstrates high agreement with the 10-2 grid, and aids in CVFD screening.

Triple-negative breast cancer (TNBC) represents the most malignant subtype of breast cancer. The clinical application of PARP inhibitors (PARPi) is limited by the low frequency of BRCA1/2 mutations in TNBC. Here, we identified that MTAP deletion sensitized genotoxic agents in our clinical cohort of metastatic TNBC. Further study demonstrated that MTAP deficiency or inhibition rendered TNBC susceptibility to chemotherapeutic agents, particularly PARPi. Mechanistically, targeting MTAP that synergized with PARPi by disrupting the METTL16-MAT2A axis involved in methionine metabolism and depleting in vivo s-adenosylmethionine (SAM) levels. Exhausted SAM in turn impaired PARPi-induced DNA damage repair through attenuation of MRE11 recruitment and end resection by diminishing MRE11 methylation. Notably, brain metastatic TNBC markedly benefited from a lower dose of PARPi and MTAP deficiency/inhibition synergy due to the inherently limited methionine environment in the brain. Collectively, our findings revealed a feed-forward loop between methionine metabolism and DNA repair through SAM, highlighting a therapeutic strategy of PARPi combined with MTAP deficiency/inhibition for TNBC.

e15125 Background: Endometrial cancer (EC) is the most common gynecologic malignancy, with endometrioid being the most prevalent histology. Approximately 75% of high-grade endometrioid tumors are TP53 wild-type. During studies testing a novel combination of the PARP inhibitor rucaparib and TOP1 poison SN38 in high-risk primary patient serous and serous-like ECs, a subset of non-serous ECs with normal p53 expression showed unexpected synergy. This suggests broad efficacy in EC, warranting in vivo studies to assess tolerability and efficacy. Given potential overlapping toxicity, a novel formulation, pegylated SN38 (PLX038A), was tested. Methods: Primary patient tumors (n=4) were treated with rucaparib (0µM-25 µM) and SN38 (0µM-0.5 µM) in 3D cell culture experiments. RealTime Glo assessed viability after 3-5 days of drug exposure. Combination indices were determined using the Chou-Talalay method. Tolerability and efficacy were assessed in female SCID-beige mice (n=45) injected with intraperitoneal EC PDX tumors. Mice were randomized to controls, PLX038A (15 mmol/µmol IP, every 14 days), rucaparib (150 mg/kg daily gavage), or combination (same dose and schedule) for 8 weeks. Tolerability was assessed by daily animal weight and total condition score (TCS) from 1 (emaciated, non-ambulatory) to 13 (obese). Weight change more than -20% or TCS < 5 defined moribund criteria. Weekly ultrasound measurements assessed tumor response. Results: All four primary patient tumors exhibited synergy, with a combination index less than 1. Moribund criteria were not met in any mice across all cohorts. The average percent weight change and lowest TCS across cohorts were: rucaparib (-8.51%, min/max -19 to +14%; TCS 6.25, range 5-8, n=8), PLX038A (-3.97%, min/max -19 to +5%; TCS 6.8, range 6-9, n=10), the combination (-5.52%, min/max -15 to +1.8%; TCS 7.18, range 6-8, n=11), and control (+1.61%, range -6 to +8%; TCS 6.5, range 6-7, n=4). Scores were similar between groups, but the slightly lower TCS in the rucaparib cohort was associated with higher tumor burden from ineffective therapy. Tumors in the rucaparib monotherapy group grew similarly to controls. In contrast, the combination therapy cohort exhibited significant regression below baseline during treatment. Conclusions: These findings suggest that the combination of rucaparib and SN38 (PLX038A) is effective in EC primary patient tumor organoids and PDXs with wild-type TP53. No significant negative physiological effects on animal TCS and weight change were observed. No drug-related toxicity was observed in mice receiving combination treatment. Mice receiving combination treatment displayed significant tumor regression below baseline compared to both single agents and control. These data support future exploration of this combination therapy in ECs.

Précis: ASOCT features of greater bleb height, thicker bleb walls, and lower reflectivity are associated with trabeculectomy success, supporting the ASOCT’s utility in monitoring and predicting outcomes postsurgery through standardized imaging protocols. Purpose: To evaluate and quantify the relationship between bleb characteristics on ASOCT with surgical outcomes. Methods: A literature search was conducted across Medline, Embase, Cochrane, and Scopus for studies from the past 20 years, until 16 September 2024, on “glaucoma,” “trabeculectomy,” and “ASOCT.” Data collected included patient characteristics, each study’s definition of bleb success, clinical outcomes, as well as bleb characteristics. A literature review was conducted on studies that could not be used for meta-analysis. Results: Eleven studies, with a pooled total of 528 eyes in 517 patients, were included in the final meta-analysis. Successful blebs had significantly higher mean bleb height [mean difference (MD) 0.38 mm, 95% CI: 0.20-0.56 mm, P=0.002], greater maximum bleb wall thickness (MD: 0.21 mm, 95% CI: 0.07-0.35 mm, P=0.009), and decreased reflectivity (MD: −48.9%, 95% CI: −78.3 to −19.4%, P=0.010), compared with failed blebs. No significant differences were found in bleb fluid cavity height and bleb area. Narrative synthesis revealed that wider blebs, increased fluid-filled cavity height, increased number of microcysts, larger filtration opening widths, and multiform bleb walls were also associated with higher rates of bleb success. Early bleb parameters were statistically significant predictors of bleb success up to 12 months postoperatively. Conclusions: Greater bleb height, thicker bleb walls, and lower reflectivity on ASOCT are consistently associated with successful trabeculectomy outcomes. The ASOCT may be useful in predicting bleb success and in supplementing postoperative monitoring, hence guiding timely medical or procedural interventions, to ensure long-term bleb success.

AbstractINTRODUCTIONPhosphorylated ubiquitin (p‐S65‐Ub) is generated during PINK1‐PRKN mitophagy as a specific marker of mitochondrial damage. Despite the widespread deposition of p‐S65‐Ub in aged and diseased human brain, the genetic contribution to its accumulation remains unclear.METHODSTo identify novel mitophagy regulators, we performed a genome‐wide association study using p‐S65‐Ub level as a quantitative trait in 1012 autopsy‐confirmed Lewy body disease (LBD) samples.RESULTSWe identified a significant genome‐wide association with p‐S65‐Ub for rs429358 (apolipoprotein E ε4 [APOE4]) and a suggestive association for rs6480922 (ZMIZ1). APOE4 was associated with higher p‐S65‐Ub levels and greater neuropathological burden. Functional validation in mouse and human induced pluripotent stem cell (iPSC) models confirmed APOE4‐mediated mitophagy alterations. Intriguingly, ZMIZ1 rs6480922 was associated with lower p‐S65‐Ub levels, reduced neuropathological load, and increased brain weight, indicating a potential protective role.DISCUSSIONOur findings underscore the importance of mitochondrial quality control in LBD pathogenesis and nominate regulators that may contribute to disease risk or resilience.Highlights p‐S65‐Ub levels were used as a quantitative marker of mitochondrial damage. A GWAS identified two genetic variants that modify mitophagy in LBD autopsy brain. APOE4 was associated with increased p‐S65‐Ub accumulation and neuropathology. APOE4 altered mitophagy via pathology‐dependent and pathology‐independent mechanisms. ZMIZ1 was linked to reduced p‐S65‐Ub and neuropathology indicative of protection.

Abstract Cancer can recur when a subset of tumor cells, denoted here as persister cells, are able to survive therapy and re-enter the cell cycle. The precise mechanisms that confer the persister state and whether it is characteristic of a subgroup of cells or arises from multiple cellular lineages remain poorly understood. We hypothesize that an epigenetic signature underlies the drug-tolerant persister state, characterized by transcriptional and chromatin accessibility changes that promote survival of residual cancer following chemotherapy. To identify clinically relevant features of persister cells in untreated tumors and residual disease, we performed single-cell multiomic profiling (snRNA+snATAC) on a cohort of non-malignant fallopian tube, treatment-naïve, and neoadjuvant chemotherapy (NACT)-treated high-grade serous ovarian cancer (HGSOC) samples. We identified differences in gene expression and open chromatin between naïve and residual patient tumors following chemotherapy. Although only a small proportion of the differentially expressed genes enriched in residual HGSOC overlapped with established gene sets for chemo-response and patient prognosis, the epigenomic analysis revealed activity of several DNA-binding factors that are both enriched upon chemotherapy and also high in resistant tumors prior to treatment. From this analysis, we identified an epigenetic signature that precedes expression and defines the persister state. This epigenetic signature also correlated with chemotherapy sensitivity and resistance using patient-derived xenograft models of HGSOC. Gene regulatory networks driven by the persister signature are involved in the activation of oncogenic pathways, including changes to the cell cycle promoting quiescence and stress response. Further study of the persister cells identified by this epigenetic signature may increase understanding of the mechanisms underlying persister cell survival and reveal new vulnerabilities that could be exploited to delay or prevent cancer recurrence.