Vascular resistance indices are higher in the superior than inferior optic nerve head and retina.

Retinal vascular resistance is of interest in glaucoma research, as a potential link between retinal ganglion cell loss and observed phenomena including disrupted vascular autoregulation, altered biomechanical stiffness, and impaired neurovascular coupling. It can now be assessed in vivo, using laser speckle flowgraphy. However, continued progress in the field requires better understanding of its physiology. In this study, we test the hypothesis of homogeneity of vascular resistance indices between regions of the retina: specifically, between superior and inferior hemifields. The resistivity index (maximum flow minus minimum flow, as a proportion of the maximum) and pulsatility index (maximum minus minimum, as a proportion of the mean) were measured in major vessels within the optic nerve head, in the remaining tissue within the optic nerve head, and in peripapillary branch retinal arteries, separated in each case into superior and inferior quadrants. This was performed in 378 eyes of 189 participants with suspected, early or moderate glaucoma; and in 99 eyes of 50 participants without any ocular pathology. In the glaucoma cohort, the resistivity index was on average 9% higher superiorly than inferiorly in vessels within the optic nerve head; 8% higher superiorly in remaining tissue; and 8% higher superiorly in peripapillary vessels (all p < 0.001). The pulsatility index was on average 11% higher superiorly in all three locations (all p < 0.001). Average flow was slightly higher superiorly in major vessels in the nerve head, but higher inferiorly elsewhere. In the healthy control cohort, resistivity index was higher superiorly by 10% in vessels and 8% in tissue within the optic nerve head; pulsatility index was 12% and 10% higher superiorly respectively (all p < 0.001). The fact that these differences were similar between the two cohorts suggests that they are not caused by the disease process. However, it is notable that glaucomatous loss most frequently occurs first in the superior visual field, corresponding with the inferior retina. The finding that vascular resistance indices are consistently higher in the superior retina warrants further investigation, both for its causes and consequences.

Quality of Life and Primary Open-Angle Glaucoma in the Ocular Hypertension Treatment Study.

Importance: If preperimetric glaucoma reduces patient-reported vision-related quality of life (VRQoL), clinicians might consider earlier and more aggressive treatment of some patients with ocular hypertension and early glaucoma. Objective: To determine the impact of preperimetric glaucoma and early glaucomatous visual field (VF) loss on participants' VRQoL compared with participants who did not develop glaucoma in the Ocular Hypertension Treatment Study (OHTS). Design, Setting, and Participants: This cross-sectional study used data from participants enrolled in the OHTS from 1994 to 1996 who completed 20-year examination follow-up and VRQoL surveys from January 7, 2016, to November 19, 2019. Diagnosis of primary open-angle glaucoma (POAG) required reproducible changes in VFs or optic discs as determined by reading centers and attributed to glaucoma by a masked end point committee. Data analysis was performed from June 27, 2023 to March 7, 2024. Exposure: Ocular hypertension and glaucoma. Main Outcomes and Measures: Cross-sectional analysis of Rasch-calibrated total scores of the National Eye Institute Visual Function Questionnaire (VFQ) and the Glaucoma Quality of Life (GQL) survey was performed. Total scores were standardized from 0 (poor) to 100 (good). The main outcomes were differences in total VRQoL scores between participants who did not develop POAG (control) and 4 mutually exclusive POAG groups: unilateral or bilateral disc POAG with no glaucomatous VF loss in either eye and unilateral or bilateral VF POAG with or without disc changes. Differences in total VRQoL scores were analyzed using univariate and multivariate linear regression models. Results: Of 1636 participants originally enrolled in the OHTS, 679 (42%) completed the 20-year examination and VRQoL surveys. Of those participants completing 20-year follow-up, mean (SD) participant age at follow-up was 73.8 (7.7) years, and 412 of 679 participants (60.7%) self-reported as female. The mean (SD) Rasch-calibrated total VFQ scores were 72.5 (13.4) in the no POAG group (control) vs 72.7 (13.8) in the unilateral disc POAG group (difference, 0.17; 95% CI, -3.17 to 3.41; P = .92), 73.4 (14.0) in the bilateral disc POAG group (difference, 0.92; 95% CI, -2.93 to 4.77; P = .64), 69.2 (14.5) in the unilateral VF POAG group (difference, 3.33; 95% CI, -6.38 to -0.27; P = .03), and 58.5 (16.9) in the bilateral VF POAG group (difference, -13.96; 95% CI, -17.73 to -10.19; P<.001). Similar results were found for the GQL questionnaire. Conclusions and Relevance: In this cross-sectional study, among the surviving participants of OHTS who completed the 20-year follow-up examination, those participants who developed preperimetric POAG but no glaucomatous VF loss did not report lower VFQoL compared with participants who did not develop POAG. This finding should allow clinicians and patients the time to determine the frequency of examinations and whether the initiation of treatment is appropriate.

Differences in Systemic Pulse Waveform Between Individuals With Glaucoma, Glaucoma Suspects, and Healthy Controls.

Purpose: It has been hypothesized that compromised ocular circulation in glaucoma may be concomitant of systemic changes. The purpose of this study is to test whether systemic blood flow pulse waveform patterns differ between individuals with glaucoma (GL), glaucoma suspects (GLS), and normal healthy controls (HC). Methods: The study included 35 bilateral GL, 67 bilateral GLS, 29 individuals with unilateral GL who were considered GLS in the other eye, and 44 healthy controls. Systemic pulsatile blood pressure waveforms were recorded using a finger cuff. A continuous 200 Hz plethysmography recording is made to obtain a pulse waveform. Waveform parameters were extracted using custom software from an average of eight pulse cycles. These were compared between GL, GLS, and HC groups on a per-eye basis, using generalized estimating equation models to account for intereye correlations; and plotted against disease severity by visual field linearized mean deviation (MDlin) and retinal nerve fiber layer thickness (RNFLT). Results: Averaged blood pressure was significantly lower in the HC group (mean ± standard deviation 91.7 ±11.7 mm Hg) than the GLS (102.4 ± 13.9) or GL (102.8 ± 13.7) groups, with P < 0.0001 (generalized estimating equation regression). Waveform parameters representing vascular resistance were higher in both GLS and GL groups than the HC group; and were correlated with RNFLT and MDlin (P ≤ 0.05). Conclusions: The shape of the systemic pulsatile waveform differs in individuals with GL/GLS suspects, compared to HC eyes. Blood pressure changes more rapidly in individuals with GL, which suggests higher arterial stiffness.

Assessment of Time Lag Between Blood Flow, Retinal Nerve Fiber Layer Thickness and Visual Field Sensitivity Changes in Glaucoma.

Purpose: This study investigates the temporal relationship between blood flow changes and alterations in retinal nerve fiber layer thickness (RNFLT) and mean deviation (MD) in individuals with glaucoma. Methods: Blood flow, measured by mean blur rate in optic nerve head vessels (MBRv) and tissues (MBRt) using laser speckle flowgraphy (LSFG)-NAVI, was analyzed using structural equation models (SEMs). SEMs assessed whether the previous rate of one parameter predicted the current rate of the other parameter, adjusted for its own rate in the previous time interval. Data from 345 eyes of 174 participants were gathered from visits every six months. Results: Rates of change of both MBRv and MBRt were significantly predicted by their own rate in the previous time interval and by the rate of change of MD in the previous time interval (P < 0.001 and P = 0.043, respectively), but not by the rate of MD in the concurrent interval (P = 0.947 and P = 0.549), implying that changes in MD precede changes in blood flow. Rates of change of RNFLT were predicted by their own previous rate and the rate of change of MBRv and MBRt in either the previous interval (P = 0.002 and P = 0.008) or the concurrent interval (P = 0.001 and P = 0.018), suggesting that MBR may change before RNFLT. Conclusions: The evidence supports a temporal sequence where MD changes precede blood flow changes, which, in turn, may precede alterations in RNFLT.

The Temporal Relation Between Rates of Retinal Nerve Fiber Layer and Minimum Rim Width Changes in Glaucoma.

Purpose: This study aims to determine whether OCT-derived rates of change in minimum rim width (MRW) are associated with and can potentially predict corresponding alterations in retinal nerve fiber layer thickness (RNFLT) in people with glaucoma. Methods: The rates of change between six-monthly visits were taken from 568 eyes of 278 participants in the P3 Study. Structural equation models (SEM) assessed whether one parameter was predicted by the concurrent or previous rate of the other parameter, after adjusting for its own rate in the previous time interval. Root mean square error of approximation (RMSEA, with 90% confidence intervals [CI]), Tucker Lewis index (TLI) and the comparative fit index (CFI) assessed goodness of fit. Results: Models without a time lag provided a better fit for the data (RMSEA = 0.101 [CI, 0.089, 0.113]), compared to a model featuring a time lag in RNFLT (RMSEA = 0.114 [CI, 0.102, 0.126]) or MRW (RMSEA = 0.114 [CI, 0.102, 0.127]). The SEMs indicated that rates for both MRW and RNFLT were predicted by their own rate in the previous time interval and by the other measure's change in the concurrent time interval (P > 0.001 for all). No evidence of a clinically significant time lag for either parameter was determined. Conclusions: MRW and RNFLT exhibit concurrent changes over time in patients with glaucoma, with no clinically significant time lag determined. Translational Relevance: RNFLT may be more useful than MRW in early glaucoma assessment because of its previously reported lower variability and reduced sensitivity to intraocular pressure changes.

Retrolaminar Demyelination of Structurally Intact Axons in Nonhuman Primate Experimental Glaucoma.

Purpose: To determine if structurally intact, retrolaminar optic nerve (RON) axons are demyelinated in nonhuman primate (NHP) experimental glaucoma (EG). Methods: Unilateral EG NHPs (n = 3) were perfusion fixed, EG and control eyes were enucleated, and foveal Bruch's membrane opening (FoBMO) 30° sectoral axon counts were estimated. Optic nerve heads were trephined; serial vibratome sections (VSs) were imaged and colocalized to a fundus photograph establishing their FoBMO location. The peripheral neural canal region within n = 5 EG versus control eye VS comparisons was targeted for scanning block-face electron microscopic reconstruction (SBEMR) using micro-computed tomographic reconstructions (µCTRs) of each VS. Posterior laminar beams within each µCTR were segmented, allowing a best-fit posterior laminar surface (PLS) to be colocalized into its respective SBEMR. Within each SBEMR, up to 300 axons were randomly traced until they ended (nonintact) or left the block (intact). For each intact axon, myelin onset was identified and myelin onset distance (MOD) was measured relative to the PLS. For each EG versus control SBEMR comparison, survival analyses compared EG and control MOD. Results: MOD calculations were successful in three EG and five control eye SBEMRs. Within each SBEMR comparison, EG versus control eye axon loss was -32.9%, -8.3%, and -15.2% (respectively), and MOD was increased in the EG versus control SBEMR (P < 0.0001 for each EG versus control SBEMR comparison). When data from all three EG eye SBEMRs were compared to all five control eye SBEMRs, MOD was increased within the EG eyes. Conclusions: Structurally intact, RON axons are demyelinated in NHP early to moderate EG. Studies to determine their functional status are indicated.

Optical Coherence Tomographic Optic Nerve Head Morphology in Myopia III: The Exposed Neural Canal Region in Healthy Eyes-Implications for High Myopia.

PURPOSE: To determine the prevalence and magnitude of optical coherence tomography (OCT) exposed neural canal (ENC), externally oblique choroidal border tissue (EOCBT), and exposed scleral flange (ESF) regions in 362 non-highly myopic (spherical equivalent -6.00 to 5.75 diopters) eyes of 362 healthy subjects. DESIGN: Cross-sectional study. METHODS: After OCT optic nerve head (ONH) imaging, Bruch membrane opening (BMO), the anterior scleral canal opening (ASCO), and the scleral flange opening (SFO) were manually segmented. BMO, ASCO, and SFO points were projected to the BMO reference plane. The direction and magnitude of BMO/ASCO offset as well as the magnitude of ENC, EOCBT, and ESF was calculated within 30° sectors relative to the foveal-BMO axis. Hi-ESF eyes demonstrated an ESF ≥100 µm in at least 1 sector. Sectoral peri-neural canal choroidal thickness (pNC-CT) was measured and correlations between the magnitude of sectoral ESF and proportional pNC-CT were assessed. RESULTS: Seventy-three Hi-ESF (20.2%) and 289 non-Hi-ESF eyes (79.8%) were identified. BMO/ASCO offset as well as ENC, EOCBT, and ESF prevalence and magnitude were greatest inferior temporally where the pNC-CT was thinnest. Among Hi-ESF eyes, the magnitude of each ENC region correlated with the BMO/ASCO offset magnitude, and the sectors with the longest ESF correlated with the sectors with proportionally thinnest pNC-CT. CONCLUSIONS: ONH BMO/ASCO offset, either as a cause or result of ONH neural canal remodeling, corresponds with the sectoral location of maximum ESF and minimum pNC-CT in non-highly myopic eyes. Longitudinal studies to characterize the development and clinical implications of ENC Hi-ESF regions in non-highly myopic and highly myopic eyes are indicated.

OCT Segmentation Errors with Bruch's Membrane Opening-Minimum Rim Width as Compared with Retinal Nerve Fiber Layer Thickness.

OBJECTIVE: To compare the magnitude and location of automated segmentation errors of the Bruch's membrane opening-minimum rim width (BMO-MRW) and retinal nerve fiber layer thickness (RNFLT). DESIGN: Cross-sectional study. PARTICIPANTS: We included 162 glaucoma suspect or open-angle glaucoma eyes from 162 participants. METHODS: We used spectral-domain optic coherence tomography (Spectralis 870 nm, Heidelberg Engineering) to image the optic nerve with 24 radial optic nerve head B-scans and a 12-degree peripapillary circle scan, and exported the native "automated segmentation only" results for BMO-MRW and RNFLT. We also exported the results after "manual refinement" of the measurements. MAIN OUTCOME MEASURES: We calculated the absolute and proportional error globally and within the 12 30-degree sectors of the optic disc. We determined whether the glaucoma classifications were different between BMO-MRW and RNFLT as a result of manual and automatic segmentation. RESULTS: The absolute error mean was larger for BMO-MRW than for RNFLT (10.8 µm vs. 3.58 µm, P < 0.001). However, the proportional errors were similar (4.3% vs. 4.4%, P = 0.47). In a multivariable regression model, errors in BMO-MRW were not significantly associated with age, location, magnitude, or severity of glaucoma loss (all P ≥ 0.05). However, larger RNFLT errors were associated with the superior and inferior sector location, thicker nerve fiber layer, and worse visual field (all P < 0.05). Errors in BMO-MRW and RNFLT were not likely to occur in the same sector location (R2 = 0.001; P = 0.15). With manual refinement, the glaucoma classification changed in 7.8% and 6.2% of eyes with BMO-MRW and RNFLT, respectively. CONCLUSIONS: Both BMO-MRW and RNFLT measurements included segmentation errors, which did not seem to have a common location, and may result in differences in glaucoma classification. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Displacement of the Lamina Cribrosa With Acute Intraocular Pressure Increase in Brain-Dead Organ Donors.

Purpose: To examine deformations of the optic nerve head (ONH) deep tissues in response to acute elevation of intraocular pressure (IOP). Methods: Research-consented brain-dead organ donors underwent imaging by spectral domain optical coherence tomography (OCT). OCT imaging was repeated while the eye was sequentially maintained at manometric pressures of 10, 30, and 50 mm Hg. Radial scans of the ONH were automatically segmented by deep learning and quantified in three dimensions by a custom algorithm. Change in lamina cribrosa (LC) depth and choroidal thickness was correlated with IOP and age by linear mixed-effect models. LC depth was computed against commonly utilized reference planes. Results: Twenty-six eyes from 20 brain-dead organ donors (age range, 22-62 years; median age, 43 years) were imaged and quantified. LC depth measured against a reference plane based on Bruch's membrane (BM), BM opening, and an anterior sclera canal opening plane showed both a reduction and an increase in LC depth with IOP elevation. LC depth universally increased in depth when measured against a sclera reference plane. Choroidal (-0.5222 µm/mm Hg, P < 0.001) and retinal nerve fiber layer thickness (-0.0717 µm/mm Hg, P < 0.001) significantly thinned with increasing IOP. The magnitude of LC depth change with IOP was significantly smaller with increasing age (P < 0.03 for all reference planes). Conclusions: LC depth changes with IOP reduce with age and are significantly affected by the reference plane of choice, which highlights a need for standardizing LC metrics to properly follow progressive remodeling of the loadbearing tissues of the ONH by OCT imaging and for the definition of a reference database.

Detectability of Visual Field Defects in Glaucoma Using Moving Versus Static Stimuli for Perimetry.

Purpose: We have previously shown that using moving, instead of static, stimuli extends the effective dynamic range of automated perimetry in glaucoma. In this study, we further investigate the effect of using moving stimuli on the detectability of functional loss. Methods: We used two experimental perimetry paradigms to test 155 subjects with a diagnosis of glaucoma or glaucoma suspect, and 34 healthy control subjects. One test used stimuli moving parallel to the average nerve fiber bundle orientation at each location; the other used static stimuli. Algorithms were otherwise identical. Sensitivities to moving stimuli were transformed to the equivalent values for static stimuli based on a Bland-Altman plot. The proportions of locations outside age-corrected normative limits were compared, and test-retest variability was compared against defect depth for each stimulus type. Results: More tested locations were below the fifth percentile of the normative range for that location using static stimuli. However, among locations abnormal according to standard clinical perimetry on the same day, 19.2% were abnormal using static stimuli, versus 20.5% using moving stimuli (P = 0.372). Test-retest variability was 44% lower for moving stimuli across the range of defect depths. Conclusions: When compared with static automated perimetry and expressed on a common scale, moving stimuli extend the effective dynamic range and decrease variability, without decreasing the detectability of known functional defects. Translational Relevance: Moving stimuli provide a method to improve known problems of current clinical perimetry.

Retinal Vessel Pulsatile Characteristics Associated With Vascular Stiffness Can Predict the Rate of Functional Progression in Glaucoma Suspects.

Purpose: Tissue stiffening and alterations in retinal blood flow have both been suggested as causative mechanisms of glaucomatous damage. We tested the hypothesis that retinal blood vessels also stiffen, using laser speckle flowgraphy (LSFG) to characterize vascular resistance. Methods: In the longitudinal Portland Progression Project, 231 eyes of 124 subjects received LSFG scans of the optic nerve head (ONH) and automated perimetry every 6 months for six visits. Eyes were classified as either "glaucoma suspect" or "glaucoma" eyes based on the presence of functional loss on the first visit. Vascular resistance was quantified using the mean values of several instrument-defined parameterizations of the pulsatile waveform measured by LSFG, either in major vessels within the ONH (serving the retina) or in capillaries within ONH tissue, and age-adjusted using a separate group of 127 healthy eyes of 63 individuals. Parameters were compared against the severity and rate of change of functional loss using mean deviation (MD) over the six visits, within the two groups. Results: Among 118 "glaucoma suspect" eyes (average MD, -0.4 dB; rate, -0.45 dB/y), higher vascular resistance was related to faster functional loss, but not current severity of loss. Parameters measured in major vessels were stronger predictors of rate than parameters measured in tissue. Among 113 "glaucoma" eyes (average MD, -4.3 dB; rate, -0.53 dB/y), higher vascular resistance was related to more severe current loss but not rate of loss. Conclusions: Higher retinal vascular resistance and, by likely implication, stiffer retinal vessels were associated with more rapid functional loss in eyes without significant existing loss at baseline.

Patients with Low Vision Struggle with Placing Eye Drops and Benefit from an Eye Drop Aid.

PURPOSE: To evaluate eye drop self-administration in a low-vision patient population and test whether a nose-pivoted drop delivery device (NPDD, GentleDrop) can improve eye drop delivery in these patients. DESIGN: Repeated-measures case series. PARTICIPANTS: Thirty subjects (58 eyes) with low vision, defined as best-corrected visual acuity worse than 20/60 or visual field worse than 20° in the better-seeing eye. METHODS: We video-recorded subjects while self-administering eye drops using their own traditional delivery at baseline, after a standardized teaching, and with an NPDD. Two masked graders independently reviewed each drop delivery. Primary success was defined as the drop reaching the eye without the bottle touching the eye or eyelids. Subjects rated ease-of-use (1-10 scale, 10 = easiest) after each drop delivery and completed a satisfaction survey, which included asking whether subjects could place drops independently (1-5 scale, 5 = most independent). MAIN OUTCOME MEASURES: Logistic-transformed generalized estimating equation regression to compare technique satisfaction, ease-of-use, independence, no contact, and success. RESULTS: Primary success was observed in 30 (52%) of 58 eyes at baseline and increased to 44 eyes (76%) with an NPDD (P = 0.013). Bottle tip contact occurred in 23 (40%) of 58 eyes at baseline and 8 eyes (14%) with an NPDD (P = 0.004). Mean ease-of-use scores were 6.7 ± 3.1 at baseline and 8.3 ± 1.8 (P < 0.001) with an NPDD. Likewise, the NPDD improved success, bottle tip contact, and ease-of-use compared with post-teaching traditional delivery (P < 0.01). Twenty-two (73%) of 30 subjects preferred the NPDD to traditional delivery. Twenty-nine (97%) thought the NPDD was comfortable to use, and all would recommend the device. A subgroup analysis was performed on 16 subjects that self-reported difficulty instilling drops at baseline. The NPDD showed similar results, and it increased confidence in placing drops independently (4.6 ± 0.9) compared with baseline (2.7 ± 1.6, P < 0.001). Fifteen (94%) subjects in this subgroup preferred the NPDD. CONCLUSIONS: Low-vision subjects struggled to self-administer eye drops. An NPDD can improve bottle tip contact, ease-of-use, satisfaction, and independence. Eye care providers could consider screening low-vision patients about difficulty with eye drop self-administration and recommending eye drop aids. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Eye Drop Adherence With an Eye Drop Bottle Cap Monitor.

PRCIS: An eye drop bottle cap monitor with audio and visual alarms measured eye drop adherence in 50 subjects with glaucoma. Baseline adherence rates were too high to test if the alarms could improve adherence. PURPOSE: To determine if an eye drop bottle cap monitor can measure and improve adherence. MATERIALS AND METHODS: The Devers Drop Device (D3, Universal Adherence LLC) was designed to measure eye drop adherence by detecting bottle cap removal and replacement, and it can provide text, visual and audio alerts when a medication is due. In Stage 1, we determined baseline adherence for 50 subjects using a nightly eye drop over a 25-day period. Subjects with less than 90% baseline adherence were eligible for Stage 2. In Stage 2, we randomized subjects to receive either no reminder or automated D3 alerts for their nightly eye drop over a subsequent 25-day period. We defined adherence as the proportion of drops administered within 3 hours of the subjects' scheduled dosing time. Subjects completed 3 questions regarding satisfaction with the device and willingness to pay. RESULTS: The D3 monitor remained attached to the eye drop bottle cap for the duration of the study and collected adherence data in all 50 patients. In Stage 1, the mean adherence rate was 90 ± 18% (range 32-100%). Forty (80%) subjects had an adherence rate greater than 90%. Adherence rates were too high in Stage 1 to adequately test the effects of reminders in Stage 2. Ninety-eight percent (49/50) and 96% (48/50) of subjects agreed "the device always stayed attached to the bottle cap" and "I was able to use the device to take the drops", respectively. Patients would pay $61±83 (range $0-400) for a similar device to improve adherence. CONCLUSIONS: The D3 can measure eye drop adherence. Research subjects reported high satisfaction and willingness to pay for an eye drop bottle cap monitor. Glaucoma patients have high adherence when they are being monitored, and future studies with research subjects screened for poor adherence may further determine the benefit of electronic monitoring of adherence with and without electronic reminders.

Delayed adjuvant endocrine therapy is associated with decreased recurrence-free survival following neoadjuvant chemotherapy for breast cancer.

BACKGROUND: In hormone receptor-positive breast cancer (HRPBC), endocrine therapy is often initiated after adjuvant radiotherapy given concerns of radiation fibrosis. No studies have investigated how this may impact outcomes in high-risk patients undergoing neoadjuvant chemotherapy (NAC). METHODS: Females with nonmetastatic HRPBC receiving NAC from 2011 to 2017 were identified from our multi-institutional database. Interval from surgery to endocrine therapy (ISET) was calculated in weeks. Recurrence-free survival (RFS) and overall survival (OS) were evaluated with Kaplan-Meier and Cox proportional hazards modeling. RESULTS: Of 280 patients, 179 (64%) received adjuvant radiotherapy; all deaths (n = 25) and 90% (n = 27) of recurrences occurred in this group, which was the focus of subsequent analysis. Median follow-up was 49 months. Recurrences were predominantly distant metastases (n = 21, 81%). Median ISET was 12 weeks (range 0-55 weeks). On multivariable analysis, ISET >14 weeks was independently associated with worse RFS (HR 3.20, 95% C.I. 1.22-8.40, P = 0.02) but not OS (HR 2.15, 95% C.I. 0.75-6.15, P = 0.15). CONCLUSION: In patients with HRPBC treated with NAC and adjuvant radiation, increasing ISET is associated with adverse oncologic outcomes.

Longitudinal Signal-to-Noise Ratio of Perimetry at Different Severities of Glaucoma.

Purpose: Automated perimetry is relied on for functional assessment of patients with glaucoma, but questions remain about its effective dynamic range and its utility for quantifying rates of progression at different stages of the disease. This study aims to identify the bounds within which estimates of rate are most reliable. Methods: Pointwise longitudinal signal-to-noise ratios (LSNR), defined as the rate of change divided by the standard error of the trend line, were calculated for 542 eyes of 273 patients with glaucoma/suspects. The relations between the mean sensitivity within each series and lower percentiles of the distribution of LSNRs (representing progressing series) were analyzed by quantile regression, with 95% confidence intervals derived by bootstrapping. Results: The 5th and 10th percentiles of LSNRs reached a minimum at sensitivities 17 to 21 dB. Below this, estimates of rate became more variable, making LSNRs of progressing series less negative. A significant step change in these percentiles also occurred at approximately 31 dB, above which LSNRs of progressing locations became less negative. Conclusions: The lower bound of maximum utility for perimetry was ∼17 to 21dB, coinciding with previous results suggesting that below this point, retinal ganglion cell responses saturate and noise overwhelms remaining signal. The upper bound was ∼30 to 31 dB, coinciding with previous results suggesting that above this point, the size III stimulus used is larger than Ricco's area of complete spatial summation. Translational Relevance: These results quantify the impact of these two factors on the ability to monitor progression and provide quantifiable targets for attempts to improve perimetry.

Optic Nerve Head Myelin-Related Protein, GFAP, and Iba1 Alterations in Non-Human Primates With Early to Moderate Experimental Glaucoma.

Purpose: The purpose of this study was to test if optic nerve head (ONH) myelin basic protein (MBP), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), glial fibrillary acidic protein (GFAP), and ionized calcium binding adaptor molecule 1 (Iba1) proteins are altered in non-human primate (NHP) early/moderate experimental glaucoma (EG). Methods: Following paraformaldehyde perfusion, control and EG eye ONH tissues from four NHPs were paraffin embedded and serially (5 µm) vertically sectioned. Anti-MBP, CNPase, GFAP, Iba1, and nuclear dye-stained sections were imaged using sub-saturating light intensities. Whole-section images were segmented creating anatomically consistent laminar (L) and retrolaminar (RL) regions/sub-regions. EG versus control eye intensity/pixel-cluster density data within L and two RL regions (RL1 [1-250 µm]/RL2 [251-500 µm] from L) were compared using random effects models within the statistical program "R." Results: EG eye retinal nerve fiber loss ranged from 0% to 20%. EG eyes' MBP and CNPase intensity were decreased within the RL1 (MBP = 31.4%, P < 0.001; CNPase =62.3%, P < 0.001) and RL2 (MBP = 19.6%, P < 0.001; CNPase = 56.1%, P = 0.0004) regions. EG eye GFAP intensity was decreased in the L (41.6%, P < 0.001) and RL regions (26.7% for RL1, and 28.4% for RL2, both P < 0.001). Iba1+ and NucBlue pixel-cluster density were increased in the laminar (28.2%, P = 0.03 and 16.6%, P = 0.008) and both RL regions (RL1 = 37.3%, P = 0.01 and 23.7%, P = 0.0002; RL2 = 53.7%, P = 0.002 and 33.2%, P < 0.001). Conclusions: Retrolaminar myelin disruption occurs early in NHP EG and may be accompanied by laminar and retrolaminar decreases in astrocyte process labeling and increases in microglial/ macrophage density. The mechanistic and therapeutic implications of these findings warrant further study.

Moving Stimulus Perimetry: A New Functional Test for Glaucoma.

Purpose: Static pointwise perimetric sensitivities of less than approximately 19 dB are unreliable in glaucoma owing to excessive variability. We propose using moving stimuli to increase detectability, decrease variability, and hence increase this dynamic range. Methods: A moving stimulus was designed to travel parallel to the average nerve fiber bundle orientation at each location, and compared against an otherwise identical static stimulus. To assess dynamic range, psychometric functions were measured at 4 locations of each of 10 subjects. To assess clinically realistic test-retest variability, 34 locations of 94 subjects with glaucoma and glaucoma suspects were tested twice, 6 months apart. Pointwise sensitivity estimates were compared using generalized estimating equation regression models. The test-retest limits of agreement for each stimulus were assessed, adjusted for within-eye clustering. Results: Using static stimuli, 9 of the 40 psychometric functions had less than a 90% maximum response probability, suggesting being beyond the dynamic range. Eight of those locations had asymptotic maximum of more than 90% with moving stimuli. Sensitivities were higher for moving stimuli (P < 0.001); the difference increased as sensitivity decreased (P < 0.001). Test-retest limits of agreement were narrower for moving stimuli (-6.35 to +6.48 dB) than static stimuli (-12.7 to +7.81 dB). Sixty-two percent of subjects preferred using moving stimuli versus 19% who preferred static stimuli. Conclusions: Using a moving stimulus increases perimetric sensitivities in regions of glaucomatous loss. This extends the effective dynamic range, allowing reliable testing later into the disease. Results are more repeatable, and the test is preferred by most subjects. Translational Relevance: Moving stimuli allow reliable testing in patients with more severe glaucoma than currently possible.

Geospatial analysis of blindness within rural and urban counties.

PURPOSE: To determine the associations of blindness within rural and urban counties using a registry of blind persons and geospatial analytics. METHODS: We used the Oregon Commission for the Blind registry to determine the number of persons who are legally blind, as well as licensure data to determine the density of eye care providers (optometrists and ophthalmologists) within each county of the State of Oregon. We used geospatial statistics, analysis of variance, and logistic regression to determine the explanatory variables associated with blindness within counties. RESULTS: We included 8350 individuals who are legally blind within the state of Oregon in the calendar year 2015. The mean observed prevalence of registered blindness was 0.21% and ranged almost 9-fold from 0.04% to 0.58% among counties (p < .001). In univariate models, higher blindness was associated with increasing median age (p = .027), minority race (p < .001), decreased median household income (p < .001), increased poverty within a county (p < .001), and higher density of ophthalmologists (p = .003). Density of optometrists was not associated with prevalence of blindness (p = .89). The final multivariable model showed higher blindness to be associated with lower median household income, higher proportion of black race, and lower proportion of Hispanic race (p < .001 for all). CONCLUSION: Geospatial analytics identified counties with higher and lower than expected proportions of blindness even when adjusted for sociodemographic factors. Clinicians and researchers may use the methods and results of this study to better understand the distribution of individuals with blindness and the associated factors to help design public health interventions.

Long- and Short-Term Variability of Perimetry in Glaucoma.

Purpose: Test-retest variability in perimetry consists of short-term and long-term components, both of which impede assessment of progression. By minimizing and quantifying the algorithm-dependent short-term variability, we can quantify the algorithm-independent long-term variability that reflects true fluctuations in sensitivity between visits. We do this at locations with sensitivity both < 28 dB (when the stimulus is smaller than Ricco's area and complete spatial summation can be assumed) and > 28 dB (when partial summation occurs). Methods: Frequency-of-seeing curves were measured at four locations of 35 participants with glaucoma. The standard deviation of cumulative Gaussian fits to those curves was modeled for a given sensitivity and used to simulate the expected short-term variability of a 30-presentation algorithm. A separate group of 137 participants was tested twice with that algorithm, 6 months apart. Long-term variance at different sensitivities was calculated as the LOESS fit of observed test-retest variance minus the LOESS fit of simulated short-term variance. Results: Below 28 dB, short-term variability increased approximately linearly with increasing loss. Long-term variability also increased with damage below this point, attaining a maximum standard deviation of 2.4 dB at sensitivity 21 dB, before decreasing due to the floor effect of the algorithm. Above 30 dB, the observed test-retest variance was slightly smaller than the simulated short-term variance. Conclusions: Long-term and short-term variability both increase with damage for perimetric stimuli smaller than Ricco's area. Above 28 dB, long-term variability constitutes a negligible proportion of test-retest variability. Translational Relevance: Fluctuations in true sensitivity increase in glaucoma, even after accounting for increased short-term variability. This long-term variability cannot be reduced by altering testing algorithms alone.

Variation in adoption of skin and nipple sparing mastectomy: An opportunity to enhance patient outcomes.

BACKGROUND: Nipple-sparing mastectomies (NSM) for breast cancer are under-utilized. We sought to investigate NSM utilization. METHODS: Females with nonmetastatic breast cancer undergoing mastectomy in the Legacy Health System from 2007 to 2020 were identified. Multivariable logistic regression was utilized to evaluate odds of receiving NSM. RESULTS: Three-thousand-four-hundred-seventeen mastectomies were performed with 772 undergoing NSM. On multivariable analysis, later year (OR 1.22/year, P < 0.001), neoadjuvant chemotherapy (OR 1.33, P = 0.04), HR+ (OR 1.61, P = 0.001) and surgeon volume (OR 1.16/10 yearly mastectomies, P < 0.001) were independently associated with increased odds of receiving a NSM while age (OR 0.94/year, P < 0.001), IDC (OR 0.58, P = 0.01), T3/T4 stage (OR 0.36, P = 0.009), and clinical node positivity (OR 0.63, P = 0.003) were independently associated with decreased odds. Surgeon volume was not associated with odds of receiving a non-NSM with reconstruction (OR 1.01 P = 0.48). CONCLUSION: NSM is under-utilized by low-volume breast surgeons. Understanding barriers to adoption is an is an opportunity to enhance patient-centered outcomes.