Citations

Précis: In our study of the factors predictive of latanoprost response, we found that normotensive subjects with higher intraocular pressure, lower uveoscleral outflow, and higher body mass index had a greater response to 1-week treatment. Purpose: To evaluate relationships between variable intraocular pressure (IOP) responses to latanoprost and participant characteristics, baseline values and changes in aqueous humor dynamics (AHD) parameters. Methods: We assessed 226 eyes from 113 healthy participants. AHD parameters measured at baseline and after 1-week treatment with latanoprost included: IOP by pneumatonometry, episcleral venous pressure (EVP) by venomanometry, aqueous humor flow rate by fluorophotometry, outflow facility by 2-minute pneumatonography, and uveoscleral outflow calculated using the modified Goldmann equation. IOP responses were categorized into 4 groups: nonresponders (<10% reduction), all-responders (≥10% reduction), medium-responders (10%–20% reduction), and high-responders (≥20% reduction). Generalized estimating equation models were used to analyze treatment effects and compare groups. Results: Baseline IOP was higher in high-responders than medium-responders and nonresponders ( P =0.007 and P <0.001, respectively). Body mass index (BMI) was significantly higher in high-responders and all-responders compared with nonresponders ( P =0.02 and P =0.03, respectively). Responders had lower baseline uveoscleral outflow ( P =0.03). There were no significant differences in other baseline characteristics including EVP, outflow facility, and aqueous flow rate between the 4 groups. IOP decreased while outflow facility and uveoscleral outflow increased after latanoprost treatment in all responder groups but did not change in nonresponders. EVP and aqueous flow rate did not change significantly in any group. The change in uveoscleral outflow was greater in high-responders than in nonresponders ( P =0.004). Conclusions: In healthy subjects, higher baseline IOP, lower uveoscleral outflow and higher BMI are predictors of a greater IOP reduction by latanoprost. A greater increase in uveoscleral outflow is responsible for this larger response.

OBJECTIVE Chiari malformation type 1 (CM1) is the most common neurological disorder of the craniocervical junction. CM1 is characterized by cerebellar tonsillar herniation below the foramen magnum, causing CSF obstruction and neural compression. Patients with CM1 suffer from highly variable symptoms, progression, comorbidities, and outcomes, partly due to poor understanding of CM1 pathogenesis. In this paper, the authors present the only familial CM1 cohort study to statistically assess intrafamilial clinical phenotypes to date. METHODS Comprehensive medical, surgical, and family histories and neuroimaging were collected from families with multiple CM1-affected family members. Univariate analysis was performed for each symptom, comorbidity, or surgery to compare observed versus expected frequencies of affected patients with another CM1-affected family member with the same clinical characteristic. RESULTS Twenty-four new familial CM1 cases (totaling 57 patients with CM1) are presented. Intrafamilial similarities were identified for age of onset, symptoms such as headaches (p = 0.007) and neck pain (p = 0.018), neurological comorbidities such as syringomyelia (p = 0.003) and hydrocephalus (p = 0.0001), neurodevelopmental conditions such as dyslexia (p < 0.0001), and connective tissue disorders (CTDs) such as Ehlers-Danlos syndrome (p < 0.0001). CONCLUSIONS These results suggest that CM1 and its associated clinical phenotypes, including age of onset, clinical symptoms, neurological comorbidities, neurodevelopmental conditions, and CTDs, are genetically influenced. Whole-exome sequencing of CM1 patient-parent trios has the potential to identify the genetic determinants of CM1, with implications for neurosurgical management.

Abstract Background: Epidemiologic studies commonly obtain important exposure and outcome information from patient self-report although these may be influenced by imperfect understanding and/or faulty recall. The Voyage Study is a large-scale, prospective cohort study of long-term health outcomes among participants with a valid multi-target stool DNA (mt-sDNA) test order (N=150, 047). The purpose of this analysis was to evaluate the validity of participant reported mt-sDNA tests, colorectal cancer (CRC), and/or aerodigestive cancers (ADC, including cancers of the head, neck, oral, esophageal, lung, liver, stomach, pancreas, anus) among respondents. Methods: Participants from across the Unites States enrolled in the study completing questionnaires at enrollment and 1 year. The year 1 questionnaire collected data on completion and outcome of their mt-sDNA test, follow up colonoscopies and other procedures as well as a diagnosis of CRC or ADC. The study team contacts those who reported either CRC or ADC for permission to obtain copies of medical records. Records are then reviewed by a trained nurse abstractor and evaluated for validity. Mt-sDNA test results were available from Exact Sciences. Results: At the time of this analysis, year 1 questionnaire data were available on 135, 035 participants. Abnormal mt-sDNA results (n=12, 928) were self-reported by 13, 420 participants with 96.3% accuracy. Of the 111, 556 self-reported normal results, 93.4% (n=104, 150) were reported correctly. The validation process for the Voyage Study is ongoing with 860 self-reported CRC and 318 self-reported aerodigestive cancer diagnoses to date. Complete data are available on 155 individuals with a self-report of a new CRC diagnosis and 63 individuals with a self-report of aerodigestive cancer. Abstraction confirmed 47% (n=73) of those reported as true CRC diagnoses. Participants were better at correctly reporting at least one aerodigestive cancer (73%, n=46). Discussion and Conclusions: Patient reported medical record validation poses a unique challenge in today’s world. The process of requesting participant authorization followed by institutional requests to release the medical records to the research team is slow and painstaking. We found that patients are able to correctly report their mt-sDNA tests but found a relatively low proportion of reported cancer diagnoses reported correctly. This underscores the need to continue to validate key outcomes rather than relying solely on participant responses. As the number of outcomes validated increases, the study team will look at a variety of social and economic factors to better understand what contributes to or hinders an accurate self-report. Citation Format: Emily J. Kirsch, Jessica A. Grimm, Shawn M. Stoddard, Winnie Z. Fan, Kandace A. Bohn, Kathleen J. Yost, Lila J. Finney Rutten, Janet E. Olson. Patient reported outcome validation within the Voyage Study cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7354.

ImportanceThe safety and effectiveness of combining surgical peripheral iridectomy (SPI) with goniosynechialysis (GSL) and goniotomy (GT) vs trabeculectomy for intraocular pressure (IOP) reduction remains unknown.ObjectiveTo investigate the safety and effectiveness at 1 year of SPI + GSL + GT vs trabeculectomy in advanced primary angle-closure glaucoma (PACG) without cataract.Design, Setting, and ParticipantsThis noninferiority randomized clinical trial was conducted at 8 tertiary eye centers in China. A total of 88 Chinese patients (88 eyes) with advanced PACG without cataract were enrolled from January 2022 to July 2023. Data were analyzed from August 2024 to September 2024. Mean (SD) patient age was 60.3 (7.3) years, and 52 patients (59.1%) were female. Forty-three patients were randomized to SPI + GSL + GT and 45 were randomized to trabeculectomy; 86 patients (97.7%) completed the 12-month follow-up.InterventionsParticipants were randomized 1:1 to receive SPI + GSL + GT or trabeculectomy.Main Outcomes and MeasuresThe primary outcome was IOP at 12 months (noninferior margin: 4 mm Hg). Secondary outcomes included surgical success (IOP: 5-18 mm Hg, ≥20% reduction from baseline, with or without antiglaucoma medications); postoperative complications and interventions, including bleb massage, suture lysis, or releasable sutures; and number of antiglaucomatous medications prescribed.ResultsAt 12 months, the SPI + GSL + GT group had a mean (SD) IOP of 15.6 (4.0) mm Hg vs 14.9 (4.2) mm Hg in the trabeculectomy group (difference, 0.5 mm Hg; 95% CI, −1.2 to 2.2; P = .55), which was within the 4-mm Hg noninferiority margin. Qualified success rates were 38 of 43 participants (88.4%) for SPI + GSL + GT and 42 of 45 participants (93.3%) for trabeculectomy (difference, −5.0%; 95% CI, −19.6% to 8.5%; P = .48). However, complete success rates were lower in the SPI + GSL + GT group (26 participants [60.5%]) vs the trabeculectomy group (37 participants [82.2%]; difference, −21.8%; 95% CI, −40.2% to −2.4%; P = .03). Postoperative complications were present for 8 participants (18.6%) in the SPI + GSL + GT group vs 9 participants (20.0%) in the trabeculectomy group (difference, −1.4%; 95% CI, −17.9% to 15.1%; P = .71). Postoperative interventions were lower in the SPI + GSL + GT group (3 participants [7.0%] vs 25 participants [55.6%]; difference, 48.6%; 95% CI, 32.2%-65.0%; P &amp;lt; .001). Median (IQR) numbers of medications used decreased from 2 (0-3) to 0 (0-1) in the SPI + GSL + GT group and from 2 (2-3) to 0 (0-0) in the trabeculectomy group (difference, −0.81; 95% CI, −1.36 to −0.26; P = .004).Conclusions and RelevanceIn this randomized clinical trial among patients with advanced PACG without cataract, SPI + GSL + GT demonstrated noninferiority (4-mm Hg margin) to trabeculectomy for IOP at 12 months, with fewer interventions (including bleb massage, suture lysis, or releasable sutures) but no difference in postoperative medication use. This suggests SPI + GSL + GT as a potential alternative to trabeculectomy for similar cases, pending validation in larger sample sizes with smaller noninferiority margins.Trial RegistrationClinicalTrials.gov Identifier: NCT05163951

ImportanceIntraocular pressure (IOP) reduction with phacogoniotomy (phacoemulsification plus goniosynechialysis plus goniotomy) was not less than that of phacotrabeculectomy for advanced primary angle-closure glaucoma (PACG) with cataract at 1-year follow-up, but longer-term outcomes are needed.ObjectiveTo investigate if phacogoniotomy is noninferior to phacotrabeculectomy for advanced PACG with cataract at 2 years.Design, Setting, and ParticipantsThis multicenter, noninferiority, randomized clinical trial took place in 7 ophthalmology centers in China. The trial started May 31, 2021, and 2-year follow-up ended May 31, 2024. Included in this analysis were patients with advanced PACG and cataract. Study data were analyzed from September 2024 to January 2025.InterventionsRandom assignment (1:1) to phacogoniotomy or phacotrabeculectomy.Main Outcomes and MeasuresThe primary outcome measure was reduction in IOP from baseline to the 2-year visit with a noninferiority margin of 4 mm Hg.ResultsA total of 124 participants (124 eyes) were randomized (mean [SD] age, 66.4 [8.6] years; 67 female [54.0%]), 65 (52.4%) to the phacogoniotomy group and 59 (47.6%) to the phacotrabeculectomy group. A total of 59 patients (90.7%) in the phacogoniotomy group and 52 patients (88.1%) in the phacotrabeculectomy group completed 2-year visits. All participants were Chinese. Mean (SD) IOP reduction was −25.6 (10.2) mm Hg and −24.7 (9.4) mm Hg in the phacogoniotomy and phacotrabeculectomy groups, respectively, and the upper boundary of the CI for difference in change between groups was lower than the 4-mm Hg noninferiority margin (mean difference, −0.5 mm Hg; 97.5% CI, −1.7 mm Hg to 0.8 mm Hg; P = .42). The mean difference for complete success for phacogoniotomy vs phacotrabeculectomy was −6.7% (95% CI, −21.4% to 8.8%; P = .47) and for qualified success was 1.4% (95% CI, −11.0% to 14.3%, P = .30). Median (IQR) number of antiglaucomatous medication was 0 (0) vs 0 (0; Hodges-Lehmann estimate of location shift, 0; 95% CI, 0; P =.12) with phacogoniotomy vs phacotrabeculectomy, respectively (mean difference, 0.13; 95% CI, −0.36 to 0.63; P = .60).Conclusions and RelevanceMean IOP reduction with phacogoniotomy was noninferior to phacotrabeculectomy for advanced PACG and cataract at 2-year follow-up with no differences detected in complete or qualified success or mean number of antiglaucomatous medications. These findings support phacogoniotomy as an alternative to phacotrabeculectomy for patients with advanced PACG and cataract.Trial registrationClinicalTrials.gov Identifier: NCT04878458

ABSTRACT The rare human neuroendocrine tumors pheochromocytoma and paraganglioma (PPGL) can result from loss of mitochondrial succinate dehydrogenase. The resulting succinate accumulation is tumorigenic in certain neuroendocrine cells. Here, we explore two theoretical approaches to mitigate tumorigenic succinate accumulation in a cell culture model of PPGL. We first study a gene replacement strategy using transposition technology, and conclude that many of the changes in mitochondrial morphology, oxidative cell metabolism and succinate accumulation can be reversed by this process. We then investigate whether riboflavin supplementation has the potential to rescue succinate dehydrogenase activity in the intact SDHA catalytic subunit to suppress succinate accumulation even in the absence of SDHB. We show that this latter strategy is not successful.

Purpose: To identify reasons for variable intraocular pressure (IOP) responses to latanoprost and timolol in healthy volunteers and to generate the control group as part of Eye Dynamics and Engineering Network. Methods: In this multicenter, randomized, crossover study (NCT01677507), both eyes of 106 healthy subjects (212 eyes) were treated with latanoprost or timolol for 7 days, with a 6-week washout between treatments. Ocular biometrics, tonometry, and aqueous humor dynamics (AHD) were assessed at baseline and day 8 of each treatment. Subjects were divided into responders and nonresponders using cutoffs of >15% or >10% IOP reduction. Treatment effects and correlations were analyzed with paired t-tests. Results: More subjects responded to latanoprost (54%) than timolol (27%) at >15% cutoff ( p < 0.01). Responders had higher mean baseline IOP than nonresponders for both drugs at both cutoffs ( p < 0.01). Among timolol nonresponders ( n = 56), 39% responded to latanoprost in both eyes, 20% in one eye, and 41% in neither. Among latanoprost nonresponders ( n = 31), 13% responded to timolol in both eyes, 13% in one eye, and 74% in neither. Latanoprost increased uveoscleral outflow, while timolol reduced aqueous flow and outflow facility. Low baseline uveoscleral outflow was associated with latanoprost response. Conclusions: Higher baseline IOP predicted better responses to both drugs. Higher baseline uveoscleral outflow predicted nonresponse to latanoprost. No AHD differences were linked to the timolol response. Timolol nonresponders were often responsive to latanoprost, but not vice versa.

Abstract Studies have identified genetic and epidemiologic factors associated with mammographic density (MD) phenotypes. However, MD-associated genetic variants only account for a small proportion of the total estimated heritability. Interrogating interactions between genetic and epidemiologic factors could potentially identify additional MD-associated loci, expand our understanding of the genetic basis of MD phenotypes, and clarify how epidemiologic factors modulate relationships between genetic variants and MD. We conducted six separate genome-wide, gene–environment (GxE) interaction analyses, applying 2 degrees of freedom (df) and 1df interaction tests, for each of three MD phenotypes (percent density, dense area (DA), and nondense area (NDA)). The six epidemiologic factors considered were height, ever parous, parity, ever menopausal hormone therapy, ever breastfeeding, and months of breastfeeding. We included European ancestry participants from multiple studies within the Markers of Density consortium and the Breast Cancer Association Consortium (n = 4895-16 218 depending on specific analyses). We identified 11 loci with genome-wide significant (P &lt; 5 × 10−8) interaction tests including two novel common genetic signals interacting with parity (8p21.2) and ever breastfeeding (19p13.2) for NDA. Our results suggest that epidemiologic risk factors might influence relationships between common genetic variants and MD phenotypes at particular genomic loci.

Objectives/Goals: Identifying and indexing rare disease studies is labor intensive, especially in research centers with a large number of trials. To address this gap, we applied natural language processing (NLP) and visualization techniques to develop an efficient pipeline and user-friendly web interface. Our goal is to offer the rare disease study identification (RDSI) tool for adoption by other sites. Methods/Study Population: The RDSI retrieves study information (short and long titles, study abstract) from the IRB system. These descriptive fields are then processed by the MetaMap Lite NLP program for identifying disease terms and standardizing them to UMLS concepts. By terminology identifier mapping, the diseases intersecting with concepts in rare disease databases (Genetic and Rare Disease program and Orphanet) are further scored to pinpoint studies that focus on a rare disease. The web interface displays a scatter bubble chart as an overview of all the rare diseases, with each bubble size proportional to the number of studies for that disease. In addition to the visual navigation, users can search studies by disease name, PI, or IRB number. Search results contain detailed study information as well as the evidence used by algorithms of the pipeline. Results/Anticipated Results: The RDSI identification results and functions were verified manually and spot-checked by several study investigators. The web interface is a self-contained solution available to our staff for various use cases like reporting or environment scan. We have built in a versioning mechanism that logs the date of each major result in the process. Therefore, even as the rare disease data sources evolve over time, we will be able to preserve any historical context or perform updates as needed. The RDSI outputs are replicated to Mayo Clinic’s enterprise data warehouse daily, allowing tech-savvy users to leverage any useful intermediate results at the backend. We anticipate the performance of the rare disease identification to be further enhanced by employing the advancements in AI technology. Discussion/Significance of Impact: The RDSI represents an informatics solution that offers efficiency in identifying and navigating rare disease clinical studies. It features the use of public databases and open-source tools, manifesting return on investment from the broad translational science ecosystem. These considerations are informative and adoptable by other institutions.