Faculty Bibliography

PURPOSE/OBJECTIVE:To investigate intravitreal anti-VEGF drug use among Medicare Fee-For-Service (FFS) and Medicare Advantage (MA) beneficiaries. DESIGN/METHODS:Retrospective, cross-sectional analysis of de-identified healthcare data from the American Academy of Ophthalmology's IRIS® Registry (Intelligent Research in Sight) for patient encounters between January 2017 to December 2022. PARTICIPANTS/METHODS:Medicare beneficiaries 65 years and older with FFS or MA coverage with continuous insurance enrollment for at least12 months. METHODS:Unique FFS and MA beneficiaries receiving intravitreal anti-VEGF were included. Patients were considered to be treated with a particular drug if more than 50% of their injections for at least 12 months were with that drug. For each anti-VEGF drug, we compared proportions of patients treated (more than 50% of their injections) with that drug between FFS and MA and calculated the difference in use between the two Medicare health care programs. MAIN OUTCOME MEASURES/METHODS:Differences in anti-VEGF drug utilization between FFS and MA. RESULTS:930,411 beneficiaries underwent 12,942,057 intravitreal injections. In the FFS group, aflibercept 2mg was used most frequently (43.8%; n = 4,271,050), followed by bevacizumab (34.7%; n = 3,382,439), ranibizumab (20.6%; n = 2,008,791), brolucizumab (0.6%; n = 56,728) and faricimab (0.4%; n = 40,729). In the MA group, bevacizumab was used most frequently (45.1%; n = 1,436,151), followed by aflibercept 2mg (37.8%; n = 1,201,311), ranibizumab (6.5%; n = 524,758), brolucizumab (0.4%; n = 13,406), and faricimab (0.2%; n = 6,694). Repackaged bevacizumab (lower cost) was more common in the MA group compared with the FFS group (60.0% vs. 47.0%; difference (diff) = 13.0%, 95% CI:12.8, 13.3%; P<.001). Higher cost drugs were used significantly less often among persons with MA compared with FFS, respectively (aflibercept 2mg (28.9 vs. 36.6%; diff = -7.7%; 95% CI -7.9%, -7.4%; P<.001), ranibizumab (11.9% vs. 16.8%; diff = -4.9%; 95% CI -5.03%, -4.7%; P<.001), faricimab (0.06% vs. 0.24%; diff = -0.18%; 95% CI -0.19%, -0.16%); P<.001, and brolucizumab (0.12% vs. 0.19%; diff = -0.07%; 95% CI -0.09%, -0.05%; P<.001). CONCLUSIONS:Beneficiaries enrolled in MA were less likely to receive higher cost, anti-VEGF drugs, raising concerns about reduced beneficiary access to newer more expensive anti-VEGF drugs in MA.

PURPOSE/OBJECTIVE:The dependence of the long-time (tortuosity) limit of the extra-cellular diffusivity on the intra-cellular volume fraction is of fundamental importance for microstructure modeling. While such dependencies have been explored for the white matter, the tortuosity limit in gray matter is unknown due to complex cell composition and geometry. Here we rationalize and validate numerically the analytical relation between the extra-cellular diffusivity and intra-cellular fractions of cell bodies (somas) and neurites. METHODS:The tortuosity relation for extra-cellular diffusivity qualitatively follows from effective medium theory, coarse-grained by diffusion outside somas (spheres) and neurites (cylinders), respectively. This problem is equivalent to finding the overall conductivity in a medium of grains in a matrix, with methodology dating back to the 19th century. We extend the effective medium methodology to populations of impermeable spheres and randomly oriented cylinders with various volume fractions, yielding closed-form expressions corroborated by Monte Carlo simulations. RESULTS:We establish the power-law scaling of the extra-cellular diffusivity with the volume fractions of the extra-soma and extra-neurite spaces. We further evaluate the proposed framework using simulations in realistic tissue geometries, and by applying it to in vivo MRI data. CONCLUSION/CONCLUSIONS:Theory and simulations relate extra-cellular tortuosity to soma and neurite fractions, thereby offering a diffusion MRI protocol design optimized for in vivo assessment of soma size and soma/neurite fractions within clinical scan times. Such in vivo measurements can be used to study development, aging, and neurodegenerative disorders.

BACKGROUND:Emerging evidence suggests endocrine disrupting chemicals, including bisphenols and phthalates, may affect behavioral development in children and adolescents. Risk behavior constitutes a potentially sex hormone sensitive behavioral construct. Here, we examined longitudinal associations of phthalate and bisphenol exposure with performance-based tasks and self-reported risk-taking behaviors. METHODS:Within a population-based birth cohort in the Netherlands, urinary bisphenols and phthalate metabolite concentrations were measured in women during pregnancy (three times, n = 1379) and in children (once at 6 years, n = 775). At 10 years, child risk-taking behavior was assessed with the computerized experimental Columbia Card Task (CCT). At 14 years, adolescents completed a computerized self-assessment of real-life risk-taking behaviors. Linear regression and hurdle models adjusted for confounders were applied in the whole sample and stratified by sex at birth. RESULTS:After multiple testing correction, no associations in all children or in boys were found for prenatal or childhood phthalate exposure with the average CCT-score. In girls, prenatal mono-isobutyl phthalate was associated with a higher average CCT-score, indicting more risk-taking (B per 10-fold increase in creatinine-adjusted average prenatal levels = 2.10, 95% CI: 0.69,3.52). No associations were observed for bisphenol exposure nor for self-reported risk-taking. CONCLUSIONS:Prenatal phthalate exposure was associated with more risk-taking in an experimental task at 10 years-of-age in girls only. The task reflects risky decision-making, which may be a hormonally sensitive construct. Risky decision making potentially precedes real-life risk-taking, which was captured by the self-reported measure and was limited in this young sample.

BACKGROUND/UNASSIGNED:Racial and ethnic disparities are a concern in lung cancer screening. OBJECTIVE/UNASSIGNED:To investigate the performance of risk prediction models to define screening eligibility across 4 U.S. racial and ethnic groups. DESIGN/UNASSIGNED:Cohort study. SETTING/UNASSIGNED:United States, Lung Cancer Cohort Consortium. PARTICIPANTS/UNASSIGNED:641 830 participants aged 50 to 80 years with a smoking history from 12 U.S. cohorts, including 6390 Asian, 9781 Hispanic, 39 872 non-Hispanic Black, and 585 787 non-Hispanic White participants. MEASUREMENTS/UNASSIGNED:Calibration and discrimination were quantified for 16 lung cancer prediction models. Then, screening-related metrics were calculated after applying model thresholds to select the same number of eligible participants as the 2021 criteria from the U.S. Preventive Services Task Force (USPSTF-2021). These included eligibility, sensitivity, and efficiency measured as estimated number needed to screen (NNS; the ratio between participants and lung cancer cases) for each strategy or prediction model in each racial and ethnic group. RESULTS/UNASSIGNED:General patterns across the 16 models included substantial underestimation of lung cancer risk in non-Hispanic Black participants (expected-observed ratio < 0.75 for 11 of 16 models), lower discrimination in Asian participants than all other groups (13 of 16 models), and lower discrimination in non-Hispanic Black than non-Hispanic White participants (15 of 16 models). When a same-sized screening-eligible population as USPSTF-2021 (38.0%) was enforced, all risk-based strategies achieved better average estimated screening efficiency and reduced racial and ethnic differences in efficiency compared with USPSTF-2021. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Model 2012 (PLCOm2012) and Life Years gained From Screening-Computed Tomography model (LYFS-CT) performed best (mean estimated NNS, 36.5 [SD, 8.8] and 40.1 [SD, 8.2], respectively). However, no strategy could simultaneously optimize eligibility, sensitivity, and efficiency while also reducing racial and ethnic differences. LIMITATION/UNASSIGNED:Smaller sample for Asian and Hispanic participants. CONCLUSION/UNASSIGNED:To optimize efficiency and minimize its variation across racial and ethnic groups, risk-based strategies were superior to USPSTF criteria. Further optimization of prediction models for the diverse U.S. population is needed. PRIMARY FUNDING SOURCE/UNASSIGNED:U.S. National Cancer Institute, Lung Cancer Research Foundation, and Cancer Research UK.

BACKGROUND:This study evaluated differences in surgical and clinical outcomes among patients who have identical versus different implant sizes in sequential total knee arthroplasty (TKA) surgeries. METHODS:We retrospectively reviewed patients who underwent primary, elective, staged, bilateral, same-surgeon, same-prosthesis TKA between 2011 and 2024 at a large academic health system. Patients were grouped by femoral and tibial implant size consistency: same femoral and tibial (SS), different femoral, same tibial, different tibial, same femoral, and different femoral and tibial (DD). RESULTS:A total of 4,536 TKAs were performed in 2,268 patients. The SS had the shortest length of stay compared to DD (51.8 versus 58.2 hours, P < 0.001). The majority had the same femoral (75.6%) and tibial (76.6%) sizes in both knees, whereas polyethylene thickness varied. Undergoing contralateral surgery within one year was associated with receiving the same implant sizes (P < 0.001). The DD were more common in manual surgery, and the SS were more common using navigation assistance (P < 0.001). Different assistance modalities between surgeries increased different femoral, same tibial and DD, whereas the same navigation assistance increased SS (P < 0.001). Complication and revision rates were not significantly different between the groups. All groups showed improvement in their Knee injury and Osteoarthritis Outcome Score for Joint Replacement and Patient-Reported Outcomes Measurement Information System Pain Intensity and Interference scores with no significant intergroup differences (P > 0.05). CONCLUSIONS:Over one-third of patients (37.3%) undergoing staged, bilateral TKA received different implant sizes for at least one component, and over half had different polyethylene thicknesses. Although implant size consistency was influenced by factors such as time between surgeries and assistance modality, these variations did not significantly affect length of stay, complications, or patient-reported outcomes. Surgeons should be aware that minor implant size differences between knees are common, even when using the same prosthesis.

OBJECTIVE:Socioeconomic factors, including insurance status, have been implicated in disparities in surgical outcomes. This study evaluates whether insurance status influences urgency of presentation and postoperative outcomes following endovascular aneurysm repair (EVAR) for infrarenal abdominal aortic aneurysms (AAA). METHODS:Patients undergoing infrarenal EVAR for AAA were identified from the prospectively maintained Vascular Quality Initiative database encompassing centers across the United States and Canada, between January 2003 and February 2024. Patients were categorized by insurance status: Medicare, commercial, Medicaid, or uninsured, and stratified by intact versus ruptured AAA (rAAA). Subgroup analyses were performed for patients aged < 65 and ≥ 65 years. The primary outcome was in-hospital mortality. Secondary outcomes included in-hospital major adverse cardiac events and unplanned reoperation. Multivariable logistic regression assessed the association of insurance status with acuity of presentation and postoperative outcomes. RESULTS:Of 76,806 patients undergoing EVAR, 44,555 (58.0%) had Medicare, 21,782 (28.4%) commercial insurance, 9,708 (12.6%) Medicaid, and 761 (1.0%) were uninsured. Uninsured patients presented with larger aneurysms (mean ± standard deviation: 6.2 ± 1.7 cm vs 5.7 ± 1.3 cm; p<.001) and rupture (25.4% vs 5.9% Medicare, 6.3% commercial insurance, and 7.0% Medicaid; p<.001). After risk adjustment, both uninsured (odds ratio [OR], 2.70; 95% confidence interval [CI]: 2.05-3.18; p < .001) and Medicaid patients (OR, 1.12; 95% CI: 1.01-1.24; p = .030) were associated with significantly higher odds of rAAA presentation compared with Medicare beneficiaries. For intact AAA, insurance status was not associated with adverse perioperative outcomes in all age groups. In 4,869 patients presenting with rAAA, uninsured status was associated with higher in-hospital mortality across all age groups (age < 65 years: OR, 4.24; 95% CI: 1.95-9.23; p<.001; age ≥ 65 years: OR, 2.46; 95% CI: 1.27-4.75; p=.008). Among patients ≥ 65 years, Medicaid was also associated with increased mortality compared with Medicare (OR, 1.42; 95% CI: 1.10-1.82; p=.007). CONCLUSION/CONCLUSIONS:Among patients undergoing EVAR, uninsured and Medicaid patients were more likely to present with rAAA, while uninsured and older Medicaid patients were more likely to suffer from higher perioperative mortality after EVAR for rAAA. These disparities may reflect delayed detection and barriers to surveillance. Expanding AAA screening programs, improving insurance coverage, and enhancing perioperative management strategies are critical to addressing inequities and reducing preventable AAA-related deaths.

Bacterial keratitis (BK) is a common subtype of infectious keratitis, the most common cause of corneal blindness globally. While antibiotics are the mainstay of treatment for BK, numerous nonantibiotic treatments and adjuncts have emerged in recent years. These include, but are not limited to, collagen cross-linking, phototherapy, immunomodulators, and various forms of transplantation. The purpose of this work is to provide a comprehensive summary of the current literature, highlight promising areas of progress, and identify gaps and areas for further work in the management of BK. With rising resistance to antibiotics, this review echoes and emphasizes the call to study and establish alternative and adjunctive strategies for BK treatment.

BACKGROUND:AQST-109 is an investigational epinephrine prodrug sublingual film for anaphylaxis treatment, with well-characterized pharmacokinetics (PK) and pharmacodynamics (PD) in healthy adults. It is unclear how oral symptoms during allergic reactions may affect absorption and these parameters. OBJECTIVE:To compare AQST-109's PK and PD in adults with oral allergy syndrome (OAS) undergoing oral allergen challenge (OAC) to elicit symptoms METHODS: This was a phase 2, two-part, open-label, randomized, fixed-sequence, stratified, crossover study to evaluate the PK and PD of single (12mg) and repeat doses (12mg × 2) of AQST-109 in adults with screening-confirmed OAS administered with and without OAC, to single (0.3mg) and repeat doses (0.3mg × 2) of manual IM epinephrine injection (IM-EPI) given without OAC. Geometric means for PK and PD parameters were analyzed for PK, PD, and safety subsets. RESULTS:During screening OAC, 94.4% of n=36 subjects experienced moderate or severe oral symptoms. Pharmacodynamics were not impacted by OAC following single- and repeat-dose of AQST-109 vs without OAC. AQST-109 PK values were similar with or without OAC. Single and repeat-dosing PD parameters were higher with AQST-109 after OAC vs IM-EPI without OAC, and were non-significantly higher for AQST-109 with vs without OAC. Almost all participants experienced a related mild treatment-emergent adverse event, with four considered moderate in severity, and no new safety signals identified compared to prior studies. CONCLUSION/CONCLUSIONS:AQST-109 PK and PD are not diminished with oral symptoms and changes, supporting reliable absorption in allergic reactions with such contexts.

IMPORTANCE:The relative efficacy and safety of oral P2Y purinergic receptor 12 (P2Y12) inhibitors (clopidogrel, ticagrelor, or prasugrel) after percutaneous coronary intervention (PCI) are not well defined. OBJECTIVE:To assess the efficacy and safety of oral P2Y12 inhibitors in patients who underwent PCI. DATA SOURCES AND STUDY SELECTION:PubMed and Embase were searched until November 15, 2025, for randomized clinical trials comparing at least 2 of the 3 agents. DATA EXTRACTION AND SYNTHESIS:Data were abstracted by 2 independent authors according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. Random-effects odds ratios (ORs) and 95% confidence intervals were calculated. Data were analyzed in December 2025. MAIN OUTCOMES AND MEASURES:The primary efficacy outcome was major adverse cardiovascular events (MACE), while the primary safety outcome was major bleeding. The primary analysis compared prasugrel and ticagrelor in reference to clopidogrel using a mixed treatment comparison meta-analysis. RESULTS:Data were analyzed from 15 randomized clinical trials that included 48 904 patients (mean [SD] age, 63.2 [4.21] years; 13 330 female patients [27.3%]). Compared with clopidogrel, there was a lower risk of MACE (OR, 0.80; 95% CI, 0.69-0.93) driven by lower myocardial infarction (OR, 0.71; 95% CI, 0.62-0.82) and stent thrombosis (OR, 0.48; 95% CI, 0.37-0.62) with prasugrel. MACE was not reduced with ticagrelor compared with clopidogrel, although there was lower stent thrombosis (OR, 0.73; 95% CI, 0.59-0.91). Furthermore, there was lower risk of MACE with prasugrel compared to ticagrelor (OR, 0.83; 95% CI, 0.70-0.98) driven by lower myocardial infarction (OR, 0.78; 95% CI, 0.65-0.94) and stent thrombosis (OR, 0.66; 95% CI, 0.49-0.88). There was a higher risk of major bleeding with ticagrelor vs clopidogrel (OR, 1.24; 95% CI, 1.01-1.52) driven by higher intracranial hemorrhage (OR, 1.89; 95% CI, 1.08-3.33). Prasugrel ranked first, followed by ticagrelor and clopidogrel, for MACE, myocardial infarction, and stent thrombosis. CONCLUSIONS AND RELEVANCE:In this systematic review and meta-analysis of 15 randomized clinical trials in patients who underwent PCI, prasugrel provided the optimal balance between efficacy and safety compared with ticagrelor and clopidogrel.