Autonomous Artificial Intelligence Increases Access and Health Equity in Underserved Populations with Diabetes.

Diabetic eye disease (DED) is a leading cause of blindness in the world. Early detection and treatment of DED have been shown to be both sight-saving and cost-effective. As such, annual testing for DED is recommended for adults with diabetes and is a Healthcare Effectiveness Data and Information Set (HEDIS) measure. However, adherence to this guideline has historically been low, and access to this sight-saving intervention has particularly been limited for specific populations, such as Black or African American patients. In 2018, the US Food and Drug Agency (FDA) De Novo cleared autonomous artificial intelligence (AI) for diagnosing DED in a primary care setting. In 2020, Johns Hopkins Medicine (JHM), an integrated healthcare system with over 30 primary care sites, began deploying autonomous AI for DED testing in some of its primary care clinics. In this retrospective study, we aimed to determine whether autonomous AI implementation was associated with increased adherence to annual DED testing, and whether this was different for specific populations. JHM primary care sites were categorized as "non-AI" sites (sites with no autonomous AI deployment over the study period and where patients are referred to eyecare for DED testing) or "AI-switched" sites (sites that did not have autonomous AI testing in 2019 but did by 2021). We conducted a difference-in-difference analysis using a logistic regression model to compare change in adherence rates from 2019 to 2021 between non-AI and AI-switched sites. Our study included all adult patients with diabetes managed within our health system (17,674 patients for the 2019 cohort and 17,590 patients for the 2021 cohort) and has three major findings. First, after controlling for a wide range of potential confounders, our regression analysis demonstrated that the odds ratio of adherence at AI-switched sites was 36% higher than that of non-AI sites, suggesting that there was a higher increase in DED testing between 2019 and 2021 at AI-switched sites than at non-AI sites. Second, our data suggested autonomous AI improved access for historically disadvantaged populations. The adherence rate for Black/African Americans increased by 11.9% within AI-switched sites whereas it decreased by 1.2% within non-AI sites over the same time frame. Third, the data suggest that autonomous AI improved health equity by closing care gaps. For example, in 2019, a large adherence rate gap existed between Asian Americans and Black/African Americans (61.1% vs. 45.5%). This 15.6% gap shrank to 3.5% by 2021. In summary, our real-world deployment results in a large integrated healthcare system suggest that autonomous AI improves adherence to a HEDIS measure, patient access, and health equity for patients with diabetes - particularly in historically disadvantaged patient groups. While our findings are encouraging, they will need to be replicated and validated in a prospective manner across more diverse settings.

Tandem Mass Tag LC-MS/MS of Aqueous Humor From Individuals With Type 2 Diabetes Without Retinopathy Reveals Early Dysregulation of Synaptic Proteins.

Purpose: An early neurodegenerative component of diabetic retinal disease (DRD) that precedes the vascular findings of clinically diagnosed diabetic retinopathy (DR) is increasingly being recognized. However, the relevant molecular mechanisms and biomarkers for early DRD are poorly defined. The purpose of this study was to uncover novel potential mediators of early diabetic retinal neuronal dysfunction through analysis of the aqueous fluid proteome in preclinical DR. Methods: Aqueous fluid was collected from subjects with type 2 diabetes mellitus (DM) but no clinical DR and from nondiabetic controls undergoing routine cataract surgery. Preoperative spectral-domain optical coherence tomography of the macula was obtained. Tandem mass tag LC-MS/MS was performed to identify proteins differentially present in diabetic and control aqueous fluid, and proteins with >50% change and P < 0.05 were considered significant. Selected results were validated with western blot of human aqueous fluid samples. Results: We identified decreased levels of proteins implicated in neuronal synapse formation and increased levels of inflammatory proteins in the aqueous fluid from patients with type 2 DM but no DR compared with controls. Of the differentially present synaptic proteins that we identified and confirmed with western blot, the majority have not previously been linked with DRD. Conclusions: The proteomic profile of aqueous fluid from individuals with type 2 DM but no DR suggests that retinal neuronal dysfunction and inflammation represent very early events in the pathophysiology of DRD. These findings support the concept that diabetic retinal neurodegeneration precedes vascular pathology and reveal novel potential mediators and/or biomarkers warranting further investigation.

Factors Associated With Receipt of Crosslinking for Keratoconus.

PURPOSE: The aim of this study was to identify factors associated with receipt of standard fluence epithelium-off crosslinking (CXL) for keratoconus (KCN). METHODS: This retrospective, cross-sectional study reviewed electronic health records of treatment-naive patients with KCN seen at the Wilmer Eye Institute between January 2017 and September 2020. Tomographic data were derived from Pentacam (Oculus, Wetzlar, Germany) devices. Multivariable population-average model using generalized estimating equations adjusting for age, sex, race, national area deprivation index, vision correction method, and disease severity was used to identify factors associated with receipt of CXL. RESULTS: From 583 patients with KCN, 97 (16.6%) underwent CXL for KCN. Patients who received CXL in at least 1 eye were significantly younger (mean 24.0 ± 7.8 years) than patients who had never undergone CXL (33.4 ± 9.3 years) ( P < 0.001). In multivariable analysis, Black patients had 63% lower odds of receiving CXL for KCN (OR: 0.37, 95% CI, 0.18-0.79) versus White patients, and older age was protective against receipt of CXL (OR: 0.89 per 1-year increase, 95% CI, 0.86-0.93). Comparison of characteristics by race demonstrated that Black patients presented with significantly worse vision, higher keratometric indices (K1, K2, and Kmax), and thinner corneal pachymetry at baseline versus White or Asian patients. CONCLUSIONS: In this clinical cohort of patients with KCN from a tertiary referral center, Black patients were less likely to receive CXL presumably because of more advanced disease at presentation. Earlier active population screening may be indicated to identify and treat these patients before they become ineligible for treatment and develop irreversible vision loss. Such strategies may improve health equity in KCN management.

Risk Factors for Nondiagnostic Imaging in a Real-World Deployment of Artificial Intelligence Diabetic Retinal Examinations in an Integrated Healthcare System: Maximizing Workflow Efficiency Through Predictive Dilation.

OBJECTIVE: In the pivotal clinical trial that led to Food and Drug Administration De Novo "approval" of the first fully autonomous artificial intelligence (AI) diabetic retinal disease diagnostic system, a reflexive dilation protocol was used. Using real-world deployment data before implementation of reflexive dilation, we identified factors associated with nondiagnostic results. These factors allow a novel predictive dilation workflow, where patients most likely to benefit from pharmacologic dilation are dilated a priori to maximize efficiency and patient satisfaction. METHODS: Retrospective review of patients who were assessed with autonomous AI at Johns Hopkins Medicine (8/2020 to 5/2021). We constructed a multivariable logistic regression model for nondiagnostic results to compare characteristics of patients with and without diagnostic results, using adjusted odds ratio (aOR). P < .05 was considered statistically significant. RESULTS: Of 241 patients (59% female; median age = 59), 123 (51%) had nondiagnostic results. In multivariable analysis, type 1 diabetes (T1D, aOR = 5.82, 95% confidence interval [CI]: 1.45-23.40, P = .01), smoking (aOR = 2.86, 95% CI: 1.36-5.99, P = .005), and age (every 10-year increase, aOR = 2.12, 95% CI: 1.62-2.77, P < .001) were associated with nondiagnostic results. Following feature elimination, a predictive model was created using T1D, smoking, age, race, sex, and hypertension as inputs. The model showed an area under the receiver-operator characteristics curve of 0.76 in five-fold cross-validation. CONCLUSIONS: We used factors associated with nondiagnostic results to design a novel, predictive dilation workflow, where patients most likely to benefit from pharmacologic dilation are dilated a priori. This new workflow has the potential to be more efficient than reflexive dilation, thus maximizing the number of at-risk patients receiving their diabetic retinal examinations.

Racial Variation in Visual Impairment of Patients With Keratoconus at Presentation.

PURPOSE: This study aimed to investigate racial disparities in the severity of keratoconus (KCN) at presentation, their intersection with socioeconomic variables, and other factors associated with visual impairment. METHODS: This retrospective cohort study examined medical records of 1989 patients (3978 treatment-naive eyes) with a diagnosis of KCN seen at Wilmer Eye Institute between 2013 and 2020. A multivariable regression model adjusting for age, sex, race, insurance type, KCN family history, atopy, smoking status, and vision correction method examined factors associated with visual impairment, defined as a best available visual acuity of worse than 20/40 in the better eye. RESULTS: Demographically, Asian patients were the youngest (33.4 ± 14.0 years) ( P < 0.001), and Black patients had the highest median area deprivation index (ADI) of 37.0 [interquartile range (IQR): 21.0-60.5] ( P < 0.001). Multivariable analysis showed a higher risk of visual impairment for Black (OR 2.25, 95% CI, 1.71-2.95) versus White patients. Medicaid (OR 2.59, 95% CI, 1.75-3.83) and Medicare (OR 2.48, 95% CI, 1.51-4.07) were also associated with a higher odds of visual impairment compared with private insurance, and active smokers were more likely to have visual impairment than those with no prior smoking history (OR 2.17, 95% CI, 1.42-3.30). Eyes of Black patients had the highest maximum keratometry (Kmax) (56.0 ± 11.0D) ( P = 0.003) and the lowest thinnest pachymetry (463.2 ± 62.5 µm) ( P = 0.006) compared with eyes of other races. CONCLUSIONS: Black race, government-funded insurance, and active smoking were significantly associated with increased odds of visual impairment in adjusted analyses. Black race was also associated with higher Kmax and lower thinnest pachymetry, suggesting that Black patients have more severe disease at presentation.

Perspectives of Resident and Attending Ophthalmologists on Common Ethical Dilemmas in Research.

Purpose To assess how resident and attending ophthalmologists perceive and evaluate ethically controversial scenarios regarding mentorship, authorship, and ethics compliance that may occur during research involving residents. Methods An online survey was developed and contained 14 controversial vignettes based on common research scenarios that can occur when conducting research with trainees. The scenarios were designed to capture issues regarding three themes: mentorship, authorship, and compliance with ethical guidelines. Resident and attending ophthalmologists at eight military and civilian academic residency programs in the United States were invited to participate. Respondents used a Likert scale to assess the ethicality of the situations in addition to self-reported demographic characteristics. Results The response rate was 35.6% (77/216), consisting of 37.7% ( n = 29) residents and 62.3% ( n = 48) attendings. More attending ophthalmologists responded than residents ( p = 0.004). Many respondents identified controversies around compliance (67.3%) and authorship (57.1%) as unethical, whereas situations regarding mentorship were largely viewed as neutral to ethical (68.0%). Responses to two scenarios, one regarding mentorship and one regarding authorship, significantly differed between residents and attendings ( p = 0.001 and p = 0.022, respectively). Conclusion Academic ophthalmologists' perceptions of the ethicality of common research scenarios varied. There is a need for more prescriptive guidelines for authorship and mentorship ethics at all training levels to ensure consistency, fairness, and integrity of research.

Rates of Internal Hiring of Ophthalmology Faculty from their Institution of Training at Top Academic Medical Centers: A Cross-Sectional Study.

Background Throughout graduate and postgraduate education, trainees need to gauge the impact of training location on future institutions of practice. Objective We assessed rates of internal hiring of ophthalmology faculty at academic institutions from their same institution of training. Methods This was a cross-sectional study. We included 1,246 clinical ophthalmology faculty at the 13 top-ranked institutions listed in the 2021 U.S. News and World Report. Primary, emeritus, adjunct, and affiliate faculty were included. Publicly available information was collected from institutional websites and other online sources. Statistical analyses were conducted using t -tests or Mann-Whitney tests, chi-squared or Fisher's exact tests, and multivariate logistic regression. The main outcome measured was internal hires, defined as faculty who had completed residency and/or fellowship training at their current institution. Results In total, 47.3% of faculty were internal hires who completed residency or fellowship at the same institution. Among externally trained faculty, 27.7% completed residency and 56.0% completed fellowship at another top 13 programs. Internal hires were more frequently fellowship-trained, had a greater number of publications, and practiced in smaller departments ( p < 0.001, p < 0.001, and p = 0.002, respectively). A greater proportion of internal hires held leadership positions ( p = 0.012). Faculty practicing in the Midwest or West and with more years since residency graduation were less likely (odds ratio [OR], 0.29, 95% confidence interval [CI], 0.18-0.48; OR, 0.49, 95% CI, 0.31-0.78; OR, 0.98, 95% CI, 0.97-0.99, respectively) to be internal hires. Faculty with non-R01 National Institutes of Health funding were more likely to be internal hires (OR, 1.82, 95% CI: 1.12-2.96). Conclusions Training institution is key to determining the institution of practice. These results may be beneficial for trainees to consider when selecting a training program.

Disparities in Eye Care Utilization by Self-Reported Vision Difficulty and Diabetes Status in the United States.

PURPOSE: To assess differences in eye care utilization by vision difficulty (VD), diabetes status, and sociodemographic characteristics for American adults. METHODS: The analysis pooled cross-sectional data from the National Health Interview Survey (2010-2018) from US adults ≥ 18 years. The outcome measure was eye care utilization in the past year. The primary independent variable included four groups: no VD or diabetes, only diabetes, only VD, and diabetes and VD. VD was defined as self-reported difficulty seeing even with glasses or contacts. Diabetic status was defined as ever receiving this diagnosis by a health professional. Multivariable logistic regression analyses examined associations between eye care utilization, VD, diabetic status, and sociodemographic characteristics. RESULTS: Of the 284,599 adults included in this study, the majority were female (55%), White (73%), and non-Hispanic (84%). In regression analysis, as compared to adults without diabetes or VD, adults with both diabetes and VD had the greatest utilization (OR = 2.49, 99% CI = 2.18-2.85). Females had higher utilization than men (OR = 1.45, 99% CI = 1.41-1.50). Higher levels of education was associated with greater utilization (OR = 1.82, 99% CI = 1.72-1.92). White and American Indian adults without diabetes had higher utilization compared to other races (OR = 1.17, 99% CI = 1.12-1.24, 0.98-1.39). CONCLUSION: While adults with VD and diabetes are better connected to eye care, significant eye care disparities persist for marginalized groups in the U.S. Identifying and understanding these disparities and eliminating barriers to care is critical to better support all patient populations.

The Impact of Social Determinants of Health on Eye Care Utilization in a National Sample of People with Diabetes.

PURPOSE: To evaluate the association of social determinants of health (SDoH) with eye care utilization among people with diabetes mellitus using the 2013-2017 National Health Interview Survey (NHIS). DESIGN: Retrospective cross-sectional study. PARTICIPANTS: Participants ≥ 18 years of age with self-reported diabetes. METHODS: The SDoH in the following domains were used: (1) economic stability; (2) neighborhood, physical environment, and social cohesion; (3) community and social context; (4) food environment; (5) education; and (6) health care system. An aggregate SDoH score was calculated and divided into quartiles, with Q4 representing those with the highest adverse SDoH burden. Survey-weighted multivariable logistic regression models evaluated the association of SDoH quartile with eye care utilization in the preceding 12 months. A linear trend test was conducted. Domain-specific mean SDoH scores were calculated, and the performance of domain-specific models was compared using area under the curve (AUC). MAIN OUTCOME MEASURE: Eye care utilization in the preceding 12 months. RESULTS: Of 20 807 adults with diabetes, 43% had not used eye care. Greater adverse SDoH burden was associated with decrements in odds of eye care utilization (P < 0.001 for trend). Participants in the highest quartile of adverse SDoH burden (Q4) had a 58% lower odds (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.37-0.47) of eye care utilization than those in Q1. The domain-specific model using economic stability had the highest performing AUC (0.63; 95% CI, 0.62-0.64). CONCLUSIONS: Among a national sample of people with diabetes, adverse SDoH were associated with decreased eye care utilization. Evaluating and intervening upon the effects of adverse SDoH may be a means by which to improve eye care utilization and prevent vision loss. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Development and Validation of the Hospital-to-Home-Health Transition Quality (H3TQ) Index: A Novel Measure to Engage Patients and Home Health Providers in Evaluating Hospital-to-Home Care Transition Quality.

BACKGROUND: Patients requiring skilled home health care (HH) after hospitalization are at high risk of adverse events. Human factors engineering (HFE) approaches can be useful for measure development to optimize hospital-to-home transitions. OBJECTIVE: To describe the development, initial psychometric validation, and feasibility of the Hospital-to-Home-Health-Transition Quality (H3TQ) Index to identify patient safety risks. METHODS: Development: A multisite, mixed-methods study at 5 HH agencies in rural and urban sites across the United States. Testing: Prospective H3TQ implementation on older adults' hospital-to-HH transitions. Populations Studied: Older adults and caregivers receiving HH services after hospital discharge, and their HH providers (nurses and rehabilitation therapists). RESULTS: The H3TQ is a 12-item count of hospital-to-HH transitions best practices for safety that we developed through more than 180 hours of observations and more than 80 hours of interviews. The H3TQ demonstrated feasibility of use, stability, construct validity, and concurrent validity when tested on 75 transitions. The vast majority (70%) of hospital-to-HH transitions had at least one safety issue, and HH providers identified more patient safety threats than did patients/caregivers. The most frequently identified issues were unsafe home environments (32%), medication issues (29%), incomplete information (27%), and patients' lack of general understanding of care plans (27%). CONCLUSIONS: The H3TQ is a novel measure to assess the quality of hospital-to-HH transitions and proactively identify transitions issues. Patients, caregivers, and HH providers offered valuable perspectives and should be included in safety reporting. Study findings can guide the design of interventions to optimize quality during the high-risk hospital-to-HH transition.

Corneal Culture and Antibiotic Susceptibility Results for Microbial Keratitis in the Mid-Atlantic Region of the United States, 2016 to 2020.

OBJECTIVE: To examine the microbial distribution and antimicrobial susceptibility of culture-positive microbial keratitis at a large tertiary referral center in the mid-Atlantic region of the United States. METHODS: Retrospective review of culture-positive microbial keratitis cases at the Wilmer Eye Institute from 2016 through 2020. RESULTS: Of the 474 culture-positive microbial keratitis cases, most were bacterial (N=450, 94.9%), followed by fungal (N=48, 10.1%) and Acanthamoeba keratitis (N=15, 3.1%). Of the 450 bacterial isolates, 284 (69.5%) were gram-positive organisms, whereas 157 (28.4%) were gram-negative organisms. The most common bacterial species isolated was coagulase-negative Staphylococcus spp (N=154, 24.8%), and the most common gram-negative isolate was Pseudomonas aeruginosa (N=76, 12.3%). Among fungi, the most common isolates were Candida (N=25, 45.4%), whereas Fusarium (N=6, 10.9%) and Aspergillus (N=3, 5.5%) were less common. Of the 217 bacterial isolates tested for erythromycin susceptibility, 121 (55.7%; ∼60% of coagulase-negative staphylococci and corynebacteria tested) showed resistance to erythromycin. CONCLUSIONS: Microbial keratitis in the Baltimore Mid-Atlantic region of the United States is most commonly caused by bacteria, with fungi and acanthamoeba being less common. Gram-positive bacterial infections predominate. Among fungal keratitis cases, Candida species are more commonly encountered than are filamentous species. Use of erythromycin as infection prophylaxis should be reexamined. Findings from our study may guide empiric treatment in this geographic region.

The lncRNA OIP5-AS1/miR-4500 axis targeting ARG2 modulates oxidative stress-induced premature senescence in endothelial cells: implications for vascular aging.

BACKGROUND: Endothelial senescence due to increased age or oxidative stress can cause endothelial dysfunction, which is strongly associated with the pathogenesis of cardiovascular diseases (CVDs). RESEARCH DESIGN AND METHODS: Hydrogen peroxide (H2O2) was used to induced human umbilical vein endothelial cells (HUVECs) senescence model. Cell senescence and cell proliferation were assessed by SA-ß-gal staining and PCNA staining. Nitric oxide (NO) and reactive oxygen species (ROS) levels were detected by DAF-2 DA and DCFH-DA. Inflammatory indicators were quantified by qPCR. Meanwhile, western blot was used to examine the ARG2 protein. Finally, an aging mice model induced by H2O2 was established to confirm the role of OIP5-AS1/miR-4500/ARG2 in endothelial dysfunction in vivo. RESULTS: ARG2 was upregulated and miR-4500 was reduced in H2O2-induced HUVECs. MiR-4500 negatively regulates ARG2 expression, meanwhile ameliorating H2O2-induced ECs senescence and dysfunction. Targeted interactions among OIP5-AS1, miR-4500, and ARG2 were confirmed by dual-luciferase reporter assays. OIP5-AS1 as miR4500 sponge negatively mediates miR-4500 expression, and is upregulated upon H2O2 stimulation in HUVECs. OIP5-AS1 depletion shows the protective effects on H2O2-induced ECs senescence, dysfunction, and SASP. In vivo, a higher expression of OIP5-AS1 and ARG2 in the aortas of aged mice. CONCLUSIONS: We disclosed a regulatory mechanism for OIP5-AS1/miR-4500/ARG2 in the regulation of oxidative stress-related ECs senescence and vascular aging.

Barriers in Ophthalmology Residency Applications for Students Identifying as Underrepresented in Medicine: A San Francisco Match Analysis.

OBJECTIVE: There is a significant lack of ophthalmologists who self-identify as underrepresented in medicine (URiM) in the physician workforce. Prior literature has revealed bias in traditional metrics for selection relied on by resident programs such as United States Medical Licensing Examination (USMLE) scores, letters of recommendation (LOR), and induction into medical honors societies such as Alpha Omega Alpha (AOA). The purpose of this study was to elucidate race-based differences in word usage within ophthalmology residency letters of recommendation that may disproportionately affect URiM applicants. DESIGN: This was a retrospective, cohort study. SETTING: This was a multicenter study across the Wilmer Eye Institute at Johns Hopkins, the University of California San Francisco, and the University of North Carolina at Chapel Hill. PARTICIPANTS: San Francisco (SF) Match applications submitted to three ophthalmology residency programs between 2018 and 2020 were reviewed. URiM status, USMLE Step 1 score, and AOA membership were recorded. Letters of recommendation were analyzed using text analysis software. T-tests and chi-squared or Fisher's exact tests were used to compare continuous and categorical variables, respectively. Frequency of word/summary term usage in letters of recommendation were the main outcome measures. RESULTS: Relative to non-URiM applicants, URiM applicants had lower USMLE Step 1 scores (mean difference=7.0; p<0.001). Non-URiM letters of recommendation were more likely to describe applicants as "dependable" (p=0.009) and highlight "research" (p=0.046). URiM letters were more likely to describe applicants as "warm" (p=0.02) and "caring" (p=0.02). CONCLUSIONS: This study identified potential barriers for URiM ophthalmology residency applicants which can help guide future interventions to increase workforce diversity.

Histological Comparative Analysis of Bowman Layer Grafts Procured Using 3 Different Techniques.

PURPOSE: The objective of this study is to perform a histological analysis of Bowman layer (BL) grafts. METHODS: BL grafts were procured from 13 human cadaver corneal tissues using 3 different donor preparation techniques. Subsequently, the grafts were fixed in 10% buffered formalin phosphate and embedded in paraffin. Hematoxylin and eosin sections of BL grafts were obtained and analyzed under a light microscope. BL and full graft thickness were measured using an image-processing software. RESULTS: All 13 BL grafts contained residual anterior stromal tissue. BL stripping using Kelman-McPherson and Moorfield forceps (technique 3) achieved the thinnest graft thickness with a mean full graft thickness of 18.7 µm (95% confidence interval [CI], -9.8 to 47.2) at the thinnest point of the graft, whereas BL procurement using the Melles lamellar dissector (technique 2) led to the highest mean full graft thickness of 279.9 µm (95% CI, 251.4-308.5) even at the thinnest area of the graft. By contrast, BL dissection using a blunt dissector (technique 1) provided a mean full graft thickness of 70.2 µm (95% CI, 40.4-100.1) at the graft's thinnest point. Although peripheral graft tears occurred in 50%, 50%, and 100% of techniques 1, 2, and 3, respectively, intact 6.25-mm diameter BL grafts could be secured in 50%, 100%, and 80% of techniques 1, 2, and 3, respectively. CONCLUSIONS: None of the techniques used led to the procurement of pure BL grafts devoid of the anterior stroma. Peripheral scoring with a thin needle and tissue manipulation with Kelman-McPherson and Moorfield forceps led to the thinnest grafts in this study.

Correlation between hyperreflective foci and visual function testing in eyes with intermediate age-related macular degeneration.

BACKGROUND: To investigate the relationship between intraretinal hyperreflective foci (HRF) and visual function in intermediate age-related macular degeneration (iAMD). METHODS: Retrospective, cross-sectional study. iAMD patients underwent spectral domain optical coherence tomography (SD-OCT) imaging and vision function testing: normal luminance best corrected visual acuity (VA), low luminance VA (LLVA), quantitative contrast sensitivity function (qCSF), low luminance qCSF (LLqCSF), and mesopic microperimetry. Each OCT volume was graded for the presence and number of HRF. Each HRF was graded for: separation from the retinal pigment epithelium (RPE), above drusen, and shadowing. Central drusen volume was calculated by the built-in functionality of the commercial OCT software after manual segmentation of the RPE and Bruch's membrane. RESULTS: HRF group: 11 eyes; 9 patients; mean age 75.7 years. No-HRF group: 11 eyes; 10 patients; mean age 74.8 years. In linear mixed effect model adjusting for cube-root transformed drusen volume, HRF group showed statistically significant worse VA, LLVA, LLqCSF, and microperimetry. HRF group showed worse cone function, as measured by our pre-defined multicomponent endpoint, incorporating LLVA, LLqCSF and microperimetry (p = 0.018). For eyes with HRF, # of HRF did not correlate with any functional measures; however, % of HRF separated from RPE and # of HRF that created shadowing were statistically associated with low luminance deficit (LLD). CONCLUSIONS: The association between the presence of HRF and worse cone visual function supports the hypothesis that eyes with HRF have more advanced disease.

Alzheimer's disease genetic risk and cognitive reserve in relationship to long-term cognitive trajectories among cognitively normal individuals.

BACKGROUND: Both Alzheimer's disease (AD) genetic risk factors and indices of cognitive reserve (CR) influence risk of cognitive decline, but it remains unclear whether they interact. This study examined whether a CR index score modifies the relationship between AD genetic risk factors and long-term cognitive trajectories in a large sample of individuals with normal cognition. METHODS: Analyses used data from the Preclinical AD Consortium, including harmonized data from 5 longitudinal cohort studies. Participants were cognitively normal at baseline (M baseline age = 64 years, 59% female) and underwent 10 years of follow-up, on average. AD genetic risk was measured by (i) apolipoprotein-E (APOE) genetic status (APOE-ε2 and APOE-ε4 vs. APOE-ε3; N = 1819) and (ii) AD polygenic risk scores (AD-PRS; N = 1175). A CR index was calculated by combining years of education and literacy scores. Longitudinal cognitive performance was measured by harmonized factor scores for global cognition, episodic memory, and executive function. RESULTS: In mixed-effects models, higher CR index scores were associated with better baseline cognitive performance for all cognitive outcomes. APOE-ε4 genotype and AD-PRS that included the APOE region (AD-PRSAPOE) were associated with declines in all cognitive domains, whereas AD-PRS that excluded the APOE region (AD-PRSw/oAPOE) was associated with declines in executive function and global cognition, but not memory. There were significant 3-way CR index score × APOE-ε4 × time interactions for the global (p = 0.04, effect size = 0.16) and memory scores (p = 0.01, effect size = 0.22), indicating the negative effect of APOE-ε4 genotype on global and episodic memory score change was attenuated among individuals with higher CR index scores. In contrast, levels of CR did not attenuate APOE-ε4-related declines in executive function or declines associated with higher AD-PRS. APOE-ε2 genotype was unrelated to cognition. CONCLUSIONS: These results suggest that APOE-ε4 and non-APOE-ε4 AD polygenic risk are independently associated with global cognitive and executive function declines among individuals with normal cognition at baseline, but only APOE-ε4 is associated with declines in episodic memory. Importantly, higher levels of CR may mitigate APOE-ε4-related declines in some cognitive domains. Future research is needed to address study limitations, including generalizability due to cohort demographic characteristics.

The Impact of Social Determinants of Health on Vision Loss From Cataracts and Cataract Surgery Utilization in the United States-A National Health Interview Survey Analysis.

PURPOSE: To investigate the association of social determinants of health (SDOH) factors and cataract-related outcomes disparities. DESIGN: Cross-sectional, with a nationally representative sample. METHODS: We used publicly available data from the 2008, 2016, and 2017 National Health Interview Survey data sets. Outcome measures included self-reported prevalence for ever been diagnosed with cataract, vision loss secondary to cataracts, and the likelihood of undergoing cataract surgery. Survey-weighted, multivariable logistic regression models, adjusted for age, race and ethnicity, and other relevant covariates, were used to examine the association between SDOH factors and cataract-related outcomes. RESULTS: A total of 81,551 participants were included, who were predominantly between 18 and 44 years of age (49.6%), female (51.7%), and White (74.8%). Multivariable regression models with age as a covariate showed that individuals who were not working were more likely to report having cataracts than those who were working (P < .001). Those who needed but could not afford medical care in the past year were more likely to report vision loss secondary to cataracts than their counterparts (P < .001). Uninsured participants were less likely to report undergoing cataract surgery than those with private insurance (P = .03). Individuals with higher income (poverty-income ratio: 1.00-2.99 vs <1.00) were more likely to report undergoing cataract surgery (P = .04). CONCLUSIONS: Several SDOH factors were associated with disparities in rates of cataract-related outcomes. These findings highlight the importance of ophthalmologists screening for social risks in patients with cataract, as these social factors are important barriers for access to care.

Investigator-Determined Categories for Fever of Unknown Origin (FUO) Compared With International Classification of Diseases-10 Classification of Illness: A Systematic Review and Meta-analysis With a Proposal for Revised FUO Classification.

Background: Classifying fever of unknown origin (FUO) into categorical etiologies (ie, infections, noninfectious inflammatory, oncologic, miscellaneous, and undiagnosed disorders) remains unstandardized and subject to discrepancies. As some disease classifications change, a systematic review of studies would help physicians anticipate the frequency of illness types they may encounter that could influence care. Methods: We systematically reviewed prospective FUO studies published across the Medline (PubMed), Embase, Scopus, and Web of Science databases from January 1, 1997, to July 31, 2022. We performed a meta-analysis to estimate associated pooled proportions between the investigator-determined choice of disease category and those determined by the International Classification of Diseases, 10th edition (ICD-10), methodology. Results: The proportion of patients with a difference between the investigator and ICD-10-adjusted noninfectious inflammatory disorder category was 1.2% (95% CI, 0.005-0.021; P < .001), and the proportion was similar for the miscellaneous category at 1.5% (95% CI, 0.007-0.025; P < .001). The miscellaneous and noninfectious inflammatory disorders categories demonstrated significant across-study heterogeneity in the proportions of patients changing categories, with 52.7% (P = .007) and 51.0% (P = .010) I2 , respectively. Conclusions: Adjusting FUO-associated diagnoses by ICD-10 methodology was associated with a statistically significant risk of over- or underestimation of disease category frequency approximation when using a 5 FUO category system. An FUO diagnostic classification system that better reflects mechanistic understanding would assist future research and enhance comparability across heterogenous populations and different geographic regions. We propose an updated FUO classification scheme that streamlines categorizations, aligns with the current understanding of disease mechanisms, and should facilitate empirical decisions, if necessary.

Cognitive impairment in chronic migraine compared to pseudotumor cerebri.

INTRODUCTION: We aimed to define the prevalence of objective cognitive impairment in a group of chronic migraineurs, and to define how migraineurs with cognitive impairment differed from those without impairment, and in doing so to compare cognitive impairment in chronic migraine to another chronic headache-related disorder already associated with cognitive impairment (i.e. pseudotumor cerebri syndrome). OBJECTIVES: Cognitive impairment in migraine, especially chronic migraine, has been too little studied. Only a few studies have been done, demonstrating that cognitive impairment exists in chronic migraineurs. It is not known how this compares to other headache-related conditions. MATERIAL AND METHODS: We administered a cognitive battery consisting of the National Adult Reading Test, Mini-Mental Status Examination, Digit Span, Boston Naming Test, Rey Auditory Verbal Learning Test, Trail Making Test, Controlled Oral Word Association, and Category Fluency. Cognitive impairment was defined as mild single-domain with one test score, and mild multi- -domain with two scores more than two standard deviations below the mean for age-, gender-, and education-adjusted norms. The data from this study was compared to our previously published population of patients with pseudotumor cerebri syndrome. RESULTS: One hundred prospectively recruited patients with chronic migraine were enrolled. Fifty-seven patients had normal cognitive profiles. Forty-three patients demonstrated mild cognitive impairment, and more than half (n = 24) showed impairment in multiple cognitive domains. Migraineurs with multi-domain impairment had higher pain intensity, shorter duration of disease, were taking narcotics, had more impaired vision-related mental health scores, and worse social health scores. We found an association between objective cognitive impairment and subjective perception of impairment only when controlling for pain. We found no associations with depression and topiramate use. The mean composite cognitive Z score was no different in chronic migraineurs and patients with pseudotumor cerebri. CONCLUSIONS AND CLINICAL IMPLICATIONS: Most chronic migraineurs have normal cognitive profiles, but a large proportion of them do experience mild cognitive impairment, especially in multiple domains. The impairment seen in migraine is similar to that in pseudotumor cerebri syndrome, which has already been associated with mild cognitive impairment. Cognitively impaired migraineurs are different from non-impaired/less impaired migraineurs in several ways, which may be an important factor in influencing their migraine treatment.

Risk of anaphylaxis in cluster vs standard subcutaneous multiallergen immunotherapy.

BACKGROUND: Cluster schedules for subcutaneous allergen immunotherapy (AIT) require significantly fewer injections, but there have been conflicting reports regarding the risk of systemic reactions (SR). OBJECTIVE: To compare the incidence of SRs during the build-up stages of multiallergen standard vs cluster immunotherapy. METHODS: Data on SRs were collected prospectively from 91 urban adult patients who underwent either standard or cluster AIT at the Johns Hopkins Allergy and Asthma Center from 2014 to 2022. The SRs were recorded during the build-up phase and compared for both protocols using Pearson's χ2, Fisher exact test, and multivariate logistic regression models. RESULTS: Overall, SR rates were 21% for patients in the standard schedule and 37% for patients in the cluster immunotherapy schedule, which was not statistically different (P = .08). However, the SR rate for each injection was 0.69% per injection in the standard protocol and 2.29% per injection in the cluster schedule (incident rate ratio = 3.3). All SRs (100%) in both groups occurred in the second half of the build-up phase. Multivariate regression revealed that the target prescription protein nitrogen units and the number of allergens in the treatment vial did not influence SR rates (odds ratio = 1.00 and 1.06, respectively). CONCLUSION: The overall incidence of SR was not statistically different for cluster and standard AIT protocols. However, because cluster patients received approximately half the number of injections, the risk for SR per individual injection is more than 3-fold higher than that of standard immunotherapy.