Diverse Research Teams and Underrepresented Groups in Clinical Studies.

Importance: Several ophthalmic diseases disproportionately affect racial and ethnic minority patients, yet most clinical trials struggle to enroll cohorts that are demographically representative of disease burden; some barriers to recruitment include time and transportation, language and cultural differences, and fear and mistrust of research due to historical abuses. Incorporating diversity within the research team has been proposed as a method to increase trust and improve engagement among potential study participants. Objective: To examine how demographic factors of potential research participants and personnel may be associated with patient consent rates to participate in prospective ophthalmic clinical studies. Design, Setting, and Participants: This retrospective cohort study included patients from an urban, academic hospital who were approached for consent to participate in prospective ophthalmic clinical studies conducted between January 2015 and December 2021. Main Outcomes and Measures: Multivariable logistic regression assessing associations between patient and research personnel demographics and rates of affirmative consent to participate was used. Results: In total, 1380 patients (mean [SD] age, 58.6 [14.9] years; 50.3% male) who were approached for consent to participate in 10 prospective ophthalmic clinical studies were included. Of prospective patients, 566 (43.5%) were Black; 327 (25.1%), Hispanic or Latino; 373 (28.6%), White; 36 (2.8%), other race and ethnicity; and 78 (5.8%) declined to answer. Black patients (odds ratio [OR], 0.32; 95% CI, 0.24-0.44; P < .001) and Hispanic or Latino patients (OR, 0.31; 95% CI, 0.20-0.47; P < .001) were less likely to consent compared with White patients. Patients with lower socioeconomic status were less likely to consent than patients with higher socioeconomic status (OR, 0.43; 95% CI, 0.33-0.53; P < .001). Concordance between patient and research staff race and ethnicity was associated with increased odds of affirmative consent (OR, 2.72; 95% CI, 1.99-3.73; P < .001). Conclusions and Relevance: In this cohort study, patients from underrepresented racial and ethnic groups and those with lower socioeconomic status were less likely to participate in ophthalmic clinical studies. Concordance of race and ethnicity between patients and research staff was associated with improved participant enrollment. These findings underscore the importance of increasing diversity in clinical research teams to improve racial and ethnic representation in clinical studies.

Macular Oxygen Saturation in Glaucoma Using Retinal Oximetry of Visible Light Optical Coherence Tomography.

Purpose: Oxygen saturation (sO2) plays a critical role in retinal pathophysiology, especially at the macula, which undergoes significant energy consumption. While macular damage has been suggested to be involved in early-stage glaucoma, there has been no report to date on non-invasive macular sO2 in glaucoma. Therefore, we conducted this study to compare macular sO2 associated with other clinical measurements between normal and glaucoma subjects and evaluate whether there are significant differences. Method: This is a cross-sectional study. We used visible light optical coherence tomography (VIS-OCT) for retinal oximetry in perifoveal vessels. The subjects from groups of normal, suspect/pre-perimetric glaucoma (GS/PPG) and perimetric glaucoma (PG) were scanned using VIS-OCT in the macular region with a sampling density of 512×256 in an area of 5×5 mm2. 48 eyes (16 normal, 17 GS/PPG and 15 PG) were included for the analysis. For each eye, we measured the sO2 of arterioles (AsO2), venules (VsO2), and calculated the difference between arterioles and venules (A-V sO2=AsO2-VsO2), oxygen extraction (OE=(AsO2-VsO2)/AsO2 ×100%). Additionally, we included Zeiss Cirrus OCT scans and 24-2 visual field test (VFT) for clinical benchmark. One-way ANOVA was used to compare the differences among the three groups. Spearman correlation tests were used for correlation sO2 markers to standard metrics including the thickness of ganglion cell layer and inner plexiform layer (GCL+IPL), circumpapillary retinal nerve fiber layer (cpRNFL) and mean deviation (MD) in VFT. Result: Significant differences were found among three groups for all VIS-OCT, Zeiss OCT, and VFT variables. Macular AsO2, A-V sO2, OE decreased, and VsO2 increased along with severity. Macular AsO2 and A-V sO2 were statistically correlated with GCL+IPL and cpRNFL in all eyes, as well as only PG eyes. Within PG eyes, the correlation between AsO2 and GCL+IPL is dominant in more damaged lower hemifield. Conclusion: The GS/PPG and PG subjects had significantly higher macular VsO2, lower A-V sO2 and OE indicating less oxygen consumption. The sO2 measured by retinal oximetry of VIS-OCT can be a potential metric for the early diagnosis of glaucoma.

Visible Light Optical Coherence Tomography of Peripapillary Retinal Nerve Fiber Layer Reflectivity in Glaucoma.

Purpose: To evaluate the clinical utility of visible light optical coherence tomography (VIS-OCT) and to test whether VIS-OCT reflectivity and spectroscopy of peripapillary retinal nerve fiber layer (pRNFL) are correlated with severity of glaucoma, compared with standard-of-care OCT thickness measurements. Methods: In total 54 eyes (20 normal, 17 suspect/preperimetric glaucoma [GS/PPG], 17 perimetric glaucoma [PG]) were successfully imaged with complete datasets. All the eyes were scanned by a custom-designed dual-channel device that simultaneously acquired VIS-OCT and near-infrared OCT (NIR-OCT) images. A 5 × 5 mm2 scan was taken of the pRNFL. The pRNFL reflectivity was calculated for both channels and the spectroscopic marker was quantified by pVN, defined as the ratio of VIS-OCT to NIR-OCT pRNFL reflectivity. The results were compared with ophthalmic examinations and Zeiss Cirrus OCT. Results: VIS-OCT pRNFL reflectivity significantly, sequentially decreased from normal to GS/PPG to PG, as did NIR-OCT pRNFL reflectivity. The pVN had the same decreasing trend among three groups. Normal and GS/PPG eyes were significantly different in VIS-OCT pRNFL reflectivity (P = 0.002) and pVN (P < 0.001), but were not in NIR-OCT pRNFL reflectivity (P = 0.14), circumpapillary RNFL thickness (P = 0.17), or macular ganglion cell layer and inner plexiform layer thickness (P = 0.07) in a mixed linear regression model. Conclusions: VIS-OCT pRNFL reflectivity and pVN better distinguished GS/PPG from normal eyes than Cirrus OCT thickness measurements. Translational Relevance: VIS-OCT pRNFL reflectivity and pVN could be useful metrics in the early detection of glaucoma upon further longitudinal validation.

Oral Sedation is Non-Inferior to Intravenous Sedation for Cornea and Glaucoma Surgery: A Randomized Controlled Trial.

Purpose: To determine whether oral sedation is as safe and effective as IV sedation for ophthalmic surgeries other than cataract surgery, we tested whether patient satisfaction with oral triazolam was non-inferior to IV midazolam for cornea and glaucoma surgeries. Patients and Methods: Seventy-five cornea and 49 glaucoma surgery patients 18 years and older at Boston Medical Center (Boston, MA) were randomized within each study group (cornea or glaucoma) to receive oral triazolam + IV placebo, or oral placebo + IV midazolam before surgery in a double-masked fashion. Supplemental IV anesthesia was administered as needed during surgery. The primary outcome measure was patient satisfaction with anesthesia, compared between oral and IV sedation groups via t-test for non-inferiority, based on 70 cornea and 43 glaucoma subjects completing the study. Secondary outcome measures included surgeon and anesthesia provider satisfaction with anesthesia, rate of supplemental IV anesthesia, and incidence of adverse events and surgical complications. Results: Using an a priori non-inferiority margin of 0.5, initial oral sedation was non-inferior to initial IV sedation in cornea (n=70, p<0.001) and glaucoma (n=43, p=0.017) groups, even after excluding subjects administered supplemental IV anesthesia. There were no significant differences in anesthesia provider or surgeon satisfaction, intra-operative complications, adverse events, or supplemental anesthesia between groups, except for higher anesthesia provider satisfaction with oral sedation in an Ahmed or Baerveldt implant ± cataract surgery sub-group (p=0.04). Subjects receiving supplemental anesthesia included 6 oral (18.2%) and 5 IV (13.5%) in the cornea group (p=0.59), and 7 oral (29.2%) and 6 IV (31.6%) in the glaucoma group (p=0.50). Conclusion: Our results suggest that an initial dose of oral triazolam is equivalent to IV midazolam for non-cataract anterior segment surgeries. However, there was a relatively high need for supplemental IV anesthesia during some surgery types, particularly with glaucoma tube shunt implantation.

A Baseline Study of Oxygen Saturation in Parafoveal Vessels Using Visible Light Optical Coherence Tomography.

The retinal macula is at the center of our visual field, and thus pathological damage in the macula significantly impacts an individual's quality of life. The parafoveal vessels form the inner retina provide oxygen perfusion, and the measurement of parafoveal oxygen saturation (sO2) can evaluate macular metabolism and provide pathophysiological insight. In this paper, for the first time, we present a baseline study of microvascular oxygen saturation (sO2) in perifoveal macular region using visible light optical coherence tomography (VIS-OCT) on normal eyes. The arterial and venous sO2 from all eyes was 92.1 ± 7.1 (vol %) and 48.4 ± 5.0 (vol %) (mean ± SD), respectively. Arteriovenous sO2 difference was 43.8 ± 9.5 (vol %). Marginal correlation was found between venous sO2 and intraocular pressure (IOP) among eyes. No significant correlation was found between sO2 and vessel topological features, including length, diameter, and distance to fovea. This baseline study could serve as a benchmark for the future sO2 investigation of retinal macular pathologies.

Poor Correlation of Provider and Patient Satisfaction with Anesthesia in Ophthalmic Surgeries: A Secondary Analysis of a Clinical Trial.

Purpose: This secondary analysis of a clinical trial that measured surgeon, anesthesiologist, and patient satisfaction following ophthalmic surgery under monitored anesthesia care (MAC) with a benzodiazepine investigates the degree of association between patient satisfaction with anesthesia compared to surgeon and anesthesiologist satisfaction with anesthesia. Patients and Methods: Data from analogous 6-point surgeon satisfaction surveys and anesthesiologist satisfaction surveys were compared to data from a 6-point validated patient satisfaction survey collected from a clinical trial investigating satisfaction with different forms of benzodiazepine for patients undergoing cataract, retina, cornea, or glaucoma surgery. Relationships between measures were analyzed using Pearson's correlation coefficient, with further subgroup analysis based on language groups and single-question measures of satisfaction. Results: A total of 283 ophthalmic surgical cases were analyzed. Mean surgeon satisfaction was 5.27 (range, 1.33-6.00), mean anesthesiologist satisfaction was 5.12 (range, 1.17-6.00), and mean patient satisfaction was 5.28 (range, 2.58-6.00). The correlation between surgeon and patient satisfaction was 0.333 (p = 9.06e-9), while the correlation between anesthesiologist and patient satisfaction was 0.319 (p = 4.28e-8). There was no difference between English and non-English speaking patients in correlation between surgeon and patient satisfaction (p = 0.08) and anesthesiologist and patient satisfaction (p = 0.47). Conclusion: The data demonstrate a low level of association between patient satisfaction with anesthesia and provider satisfaction, even when patient language is taken into consideration. This suggests that providers are poor predictors of patient satisfaction with anesthesia and are unreliable judges of patient comfort perioperatively.

Patient Satisfaction With Oral vs Intravenous Sedation for Vitrectomy Surgery: A Randomized, Noninferiority Clinical Trial.

Purpose: This work aims to determine whether patient satisfaction with oral sedation is noninferior to intravenous (IV) sedation in vitrectomy surgery. Methods: This prospective, randomized, double-masked, noninferiority clinical trial measured patient satisfaction in 84 participants receiving oral or IV sedation during vitrectomy surgery under monitored anesthesia care. Patients were excluded if they were unable to receive benzodiazepines. Results: The primary outcome was patient satisfaction. Secondary outcomes included surgeon and anesthesia provider satisfaction, need for supplemental anesthesia, and surgical complications. Among the 84 patients (46 [54.8%] men; mean [SD] age, 57.0 [12.7 years]), mean patient satisfaction scores were 5.22 ± 0.81 (range, 3.08-6; scale 1-6) with oral and 5.25 ± 0.63 (range, 3.83-6; scale 1-6) with IV sedation. With an a priori noninferiority margin of 0.5 and a difference in mean scores between the groups of 0.03 (1-tailed 95% CI, infinity to 0.29), our results demonstrated the noninferiority of oral sedation (P = .002). There were no significant differences in surgeon or anesthesia satisfaction or major intraoperative complications. Five patients receiving oral (11.9%) and 3 receiving IV (7.1%) sedation required supplemental IV sedation (difference, 4.8%; P = .46). Conclusions: Patient satisfaction for oral sedation was noninferior to IV sedation for vitrectomy surgery.

A Comparison of Patient Acceptance of 3 Eye Drop Instillation Aids.

PRECIS: Patients can be quite amenable to using eye drop instillation aids. We should consider recommending these devices to patients who otherwise struggle with drop instillation and medication adherence. PURPOSE: The purpose of this study was to compare patient acceptance of 3 commercially available eye drop instillation aids in a diverse tertiary care population. METHODS: In this prospective, randomized controlled study, 39 patients being treated with topical antihypertensives were assigned to Arm A (no intervention) or Arm B (AutoDrop, AutoSqueeze, or SimplyTouch). Subjects in Arm B were instructed to administer their eye drop with the assigned drop aid at every use for ~6 weeks. Satisfaction surveys were administered at 3 and 6 weeks, where patients also reported the number of drops missed. RESULTS: Thirty-two of 39 subjects completed study participation and full data analysis. Within this total group, 24 subjects were randomized to drop aids (AutoDrop N=10, AutoSqueeze N=8, SimplyTouch N=6), and 8 were randomized to no drop aid. At the 3 and 6-week timepoints, patients found instillation easier with AutoDrop (70.0%, 60.0%) followed by the AutoSqueeze (62.5%, 75.0%), and lastly SimplyTouch (33.3%, 33.3%). For the AutoSqueeze, the mean number of drops missed with and without the drop aid were significantly different (P=0.015 at 3 wk, P=0.008 at 6 wk). There was no difference in the mean number of drops missed with the AutoDrop and SimplyTouch at either timepoint. CONCLUSIONS: For the AutoDrop and AutoSqueeze groups, over 60% of the patients found the devices helpful and would consider using them long-term. Our results suggest that patients would be amenable to using eye drop instillation aids, although more objective data is needed to determine whether these devices would improve medication compliance and clinical outcomes.

Cytokine Levels in Human Vitreous in Proliferative Diabetic Retinopathy.

In this study, we compare the vitreous cytokine profile in patients with proliferative diabetic retinopathy (PDR) to that of patients without PDR. The identification of novel cytokines involved in the pathogenesis of PDR provides candidate therapeutic targets that may stand alone or work synergistically with current therapies in the management of diabetic retinopathy. Undiluted vitreous humor specimens were collected from 74 patients undergoing vitrectomy for various vitreoretinal disorders. Quantitative immunoassay was performed for a panel of 36 neuroinflammatory cytokines in each specimen and assessed to identify differences between PDR (n = 35) and non-PDR (n = 39) patients. Levels of interleukin-8 (IL-8), IL-15, IL-16, vascular endothelial growth factor (VEGF), VEGF-D, c-reactive protein (CRP), serum amyloid-A (SAA), and intracellular adhesion molecule-1 (ICAM1) were significantly increased in the vitreous of PDR patients compared to non-PDR patients (p < 0.05). We report novel increases in IL-15 and IL-16, in addition to the expected VEGF, in the human vitreous humor of patients with PDR. Additionally, we confirm the elevation of ICAM-1, VCAM-1, SAA, IL-8 and CRP in the vitreous of patients with PDR, which has previously been described.

A Pilot Study of Automated Pupillometry in the Treatment of Opioid Use Disorder.

INTRODUCTION/BACKGROUND: A rough, visual estimate of pupil size is used in grading the severity of opioid withdrawal. Few studies have examined the clinical utility of more precise automated pupillometry measurements. METHODS: This prospective cohort study enrolled 27 patients receiving opioid agonist therapy (OAT) to treat cravings or withdrawal during an acute hospitalization. Six sets of automated pupillometry measurements were obtained at regular intervals before and after administration of OAT. Clinical Opiate Withdrawal Scale measurements were performed pre and post OAT. Primary outcomes included pupil size in dark and bright illumination (mm). Latency of the pupillary light response (s), constriction and dilation velocity (mm/s), and percent constriction (%) were secondary outcomes. RESULTS: The mean predosing pupil size in dark and bright illumination was 4.33 ±â€Š1.40 mm and 2.96 ±â€Š0.79 mm, respectively. A significantly decreased mean pupil size was first detected at 15 minutes postdosing (4.01 ±â€Š1.34 mm, P = 0.0115 for dark illumination; 2.71 ±â€Š0.72 mm, P = 0.0003 for bright illumination) and this reduction in pupil size persisted at later postdosing timepoints. Those with Clinical Opiate Withdrawal Scale <5 after dosing had a greater decrease in dark pupil size (10.6% ±â€Š13.2 vs 3.2% ±â€Š3.2, P = 0.043). There was no significant change in the remaining pupil reactivity parameters. CONCLUSIONS: Automated pupillometry demonstrated a small but significant change in mean pupil size that occurred within 15 minutes of OAT dosing and was associated with low withdrawal scores. This pilot may inform future work to incorporate pupillometry measurement into OAT dosing assessments.

Neurofilament light chain in the vitreous humor of the eye.

BACKGROUND: Neurofilament light chain (NfL) is a promising biomarker of neurodegeneration in the cerebrospinal fluid and blood. This study investigated the presence of NfL in the vitreous humor and its associations with amyloid beta, tau, inflammatory cytokines and vascular proteins, apolipoprotein E (APOE) genotypes, Mini-Mental State Examination (MMSE) scores, systemic disease, and ophthalmic diseases. METHODS: This is a single-site, prospective, cross-sectional cohort study. Undiluted vitreous fluid (0.5-1.0 mL) was aspirated during vitrectomy, and whole blood was drawn for APOE genotyping. NfL, amyloid beta (Aß), total Tau (t-Tau), phosphorylated Tau (p-Tau181), inflammatory cytokines, chemokines, and vascular proteins in the vitreous were quantitatively measured by immunoassay. The main outcome measures were the detection of NfL levels in the vitreous humor and its associations with the aforementioned proteins. Linear regression was used to test the associations of NfL with other proteins, APOE genotypes, MMSE scores, and ophthalmic and systemic diseases after adjustment for age, sex, education level, and other eye diseases. RESULTS: NfL was detected in all 77 vitreous samples. NfL was not found to be associated with ophthalmic conditions, APOE genotypes, MMSE scores, or systemic disease (p > 0.05). NfL levels were positively associated with increased vitreous levels of Aß40 (p = 7.7 × 10-5), Aß42 (p = 2.8 × 10-4), and t-tau (p = 5.5 × 10-7), but not with p-tau181 (p = 0.53). NfL also had significant associations with inflammatory cytokines such as interleukin-15 (IL-15, p = 5.3 × 10-4), IL-16 (p = 2.2 × 10-4), monocyte chemoattractant protein-1 (MCP1, p = 4.1 × 10-4), and vascular proteins such as vascular endothelial growth factor receptor-1 (VEGFR1, p = 2.9 × 10-6), Vegf-C (p = 8.6 × 10-6), vascular cell adhesion molecule-1 (VCAM-1, p = 5.0 × 10-4), Tie-2 (p = 6.3 × 10-4), and intracellular adhesion molecular-1 (ICAM-1, p = 1.6 × 10-4). CONCLUSION: NfL is detectable in the vitreous humor of the eye and significantly associated with amyloid beta, t-tau, and select inflammatory and vascular proteins in the vitreous. Additionally, NfL was not associated with patients' clinical eye condition. Our results serve as a foundation for further investigation of NfL in the ocular fluids to inform us about the potential utility of its presence in the eye.

Upregulation of Lysyl Oxidase Expression in Vitreous of Diabetic Subjects: Implications for Diabetic Retinopathy.

Animal studies have shown diabetes-induced lysyl oxidase (LOX) upregulation promotes blood-retinal-barrier breakdown and retinal vascular cell loss associated with diabetic retinopathy (DR). However, it is unclear whether changes in LOX expression contribute to the development and progression of DR. To determine if vitreous LOX levels are altered in patients with DR, 31 vitreous specimens from subjects with advanced proliferative DR (PDR), and 27 from non-diabetics were examined. The two groups were age- and gender-matched (57 ± 12 yrs vs. 53 ± 18 yrs; 19 males and 12 females vs. 17 males and 10 females). Vitreous samples obtained during vitrectomy were assessed for LOX levels using ELISA. LOX was detected in a larger number of PDR subjects (58%) than in non-diabetic subjects (15%). Additionally, ELISA measurements showed a significant increase in LOX levels in the diabetic subjects with PDR, compared to those of non-diabetic subjects (68.3 ± 112 ng/mL vs. 2.1 ± 8.2 ng/mL; p < 0.01). No gender difference in vitreous LOX levels was observed in either the diabetic or non-diabetic groups. Findings support previous reports of increased LOX levels in retinas of diabetic animals and in retinal vascular cells in high glucose condition, raising the prospect of targeting LOX overexpression as a potential target for PDR treatment.

Patient Satisfaction with Oral versus Intravenous Sedation for Cataract Surgery: A Randomized Clinical Trial.

PURPOSE: To determine whether patient satisfaction with oral sedation is noninferior to intravenous sedation for cataract surgery. DESIGN: Prospective, randomized, double-masked clinical trial. PARTICIPANTS: A volunteer sample of patients 18 years or older from diverse backgrounds scheduled for cataract surgery. Patients who were allergic to benzodiazepines, older than 70 years with a failed delirium screening questionnaire, pregnant or nursing, using a medication inhibiting cytochrome 450 3A, or intoxicated on the day of surgery were excluded. METHODS: Patients were randomized to receive either oral triazolam with intravenous placebo or intravenous midazolam with oral placebo before surgery. MAIN OUTCOMES MEASURES: The primary outcome was patient satisfaction, measured by a survey administered on postoperative day 1. Secondary outcomes included surgeon and anesthesia provider satisfaction, need for supplemental anesthesia, and surgical complications. RESULTS: Among the 85 patients (42 men [49.4%]; mean age, 65.8 years; standard deviation, 9.5 years) completing the study, the mean satisfaction score was 5.34±0.63 (range, 3.75-6) in the oral sedation group and 5.40±0.52 (range, 4-6) in the intravenous group. With an a priori noninferiority margin of 0.5 and a difference in mean scores between the 2 groups of 0.06 (1-tailed 95% confidence interval [CI], -infinity to 0.27), our results demonstrate noninferiority of oral sedation with a P value of 0.0004. Surgeon and anesthesia provider satisfaction was similar between the 2 groups. Intraoperative complications occurred in 16.7% in the oral group and 9.3% in the intravenous group (difference, 7.4%; 95% CI, -6.9% to 21.6%; P = 0.31). The only major intraoperative complication-a posterior capsular tear-occurred in the intravenous group. Eight patients in the oral group (19.0%) and 3 in the intravenous group (7.0%) received supplemental intravenous sedation (difference, 12.1%; 95% CI, -2.0% to 26.2%; P = 0.097). CONCLUSIONS: The use of oral sedation in cataract surgery has been suggested as a cost- and space-saving measure, potentially allowing the transition of some patients from an operating to procedure room or office-based setting. We report the noninferiority of oral compared with intravenous sedation for cataract surgery in a diverse patient population in terms of patient satisfaction.