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Objectives: Physical activity (PA) may help maintain brain structure and function in aging. Since the intensity of PA needed to effect cognition and cerebrovascular health remains unknown, we examined associations between PA and cognition, regional white matter hyperintensities (WMH), and regional cerebral blood flow (CBF) in older adults. Method: Forty-three older adults without cognitive impairment underwent magnetic resonance imaging (MRI) and comprehensive neuropsychological assessment. Waist-worn accelerometers objectively measured PA for approximately one week. Results: Higher time spent in moderate to vigorous PA (MVPA) was uniquely associated with better memory and executive functioning after adjusting for all light PA. Higher MVPA was also uniquely associated with lower frontal WMH volume although the finding was no longer significant after additionally adjusting for age and accelerometer wear time. MVPA was not associated with CBF. Higher time spent in all light PA was uniquely associated with higher CBF but not with cognitive performance or WMH volume. Conclusions: Engaging in PA may be beneficial for cerebrovascular health, and MVPA in particular may help preserve memory and executive function in otherwise cognitively healthy older adults. There may be differential effects of engaging in lighter PA and MVPA on MRI markers of cerebrovascular health although this needs to be confirmed in future studies with larger samples. Future randomized controlled trials that increase PA are needed to elucidate cause-effect associations between PA and cerebrovascular health.

PURPOSE: The tri-folded, endothelium-in approach to Descemet membrane endothelial keratoplasty (DMEK) facilitates tissue insertion into the anterior chamber. We hypothesized that pre-loading tri-folded donor grafts in a cartridge for 48 hours prior to insertion would induce biomechanical changes that decrease their scrolling tendency, compared to tri-folded donor grafts loaded immediately before insertion. METHODS: Ten Descemet membrane donor grafts, peeled and cut to 8.0mm, were prepared by a single eye bank technician. Each graft was tri-folded and pulled into a DMEK cartridge and stored for 48 hours. They were then pulled with microforceps into a petri dish filled with balanced salt solution. A video was taken of the graft becoming a scroll over a 2-minute period. Each graft, serving as its own control, was then tri-folded, pulled into the cartridge, and the process repeated. Images from 1, 5, 10, 60, and 120 seconds were extracted from video recording of the procedures. Scroll width was analyzed by graders blinded to group assignment. A paired t-test was used to determine differences in scroll width at each time point between the 48-hour and instant tri-folding conditions. RESULTS: All grafts scrolled after removal from the cartridge into balanced salt solution. We measured a significant difference at all time points, through 120 seconds (4.02 preloaded vs. 2.91mm instant tri-fold, p=0.035). CONCLUSIONS: Preloading DMEK grafts in a tri-folded configuration for 48 hours reduces the scrolling tendency of Descemet membrane for at least two minutes.

Purpose To compare corneal endothelial damage associated with 2 techniques for preloaded Descemet membrane endothelial keratoplasty (DMEK): a tri-folded graft stored in a plastic cartridge designed for DMEK and a scrolled graft stored in a modified Jones Tube, at the time of preparation and after shipping. Methods DMEK grafts were prepared at the Rocky Mountain Lions Eye Bank. The grafts were either tri-folded and loaded in a plastic cartridge or scrolled and loaded into a modified Jones Tube. In each group, the grafts were then either immediately removed from the cartridges or shipped for 48 hours. The grafts were then stained with Calcein AM and imaged using a fluorescent microscope. Endothelial cell loss (ECL) was determined using trainable segmentation in Fiji by 2 graders. At each time point, rates of ECL loss were compared across the 2 groups. To explore the role of donor characteristics, a multivariable regression model was produced to account for method (tri-folding vs. scroll), donor age, donor gender, death-to-preservation time, death-to-preparation time, and shipping. Results A total of 40 grafts were prepared, processed, imaged, and analyzed. No significant difference in cell loss was seen between groups at either time point alone. In the multivariate model, no significant increase in cell loss was associated with either tri-folding (3.7% less ECL; P = 0.051) or shipping (4.3% less ECL; P = 0.049). Conclusions All techniques used resulted in clinically acceptable levels of ECL. Tri-folded tissue in a plastic cartridge did not result in ECL inferior to a scroll when prepared either immediately or preloaded for 48 hours.

Within the aphasia literature, it is common to link location of lesioned brain tissue to specific patterns of language impairment. This has provided valuable insight into the relationship between brain structure and function, but it does not capture important underlying alterations in function of regions that remain structurally intact. Research has demonstrated that in the chronic stage of aphasia, variable patterns of reduced cerebral blood flow (CBF; hypoperfusion) in structurally intact regions of the brain contribute to persisting language impairments. However, one consistent issue in this literature is a lack of clear consensus on how to define hypoperfusion, which may lead to over- or underestimation of tissue functionality. In the current study, we conducted an exploratory analysis in six individuals with chronic aphasia (>1 year post-onset) using perfusion imaging to (1) suggest a new, individualized metric for defining hypoperfusion; (2) identify the extent of hypoperfused tissue in perilesional bands; and (3) explore the relationship between hypoperfusion and language impairment. Results indicated that our individualized metric for defining hypoperfusion provided greater precision when identifying functionally impaired tissue and its effects on language function in chronic aphasia. These results have important implications for intervention approaches that target intact (or impaired) brain tissue.

Importance Federal policy in the United States prohibits corneal donation by men who have had sex with another man (MSM) in the preceding 5 years, whereas Canada enforces a 12-month ban. The potential consequences of these policies on corneal donations should be evaluated. Objective To estimate the number of potential corneal donations associated with MSM deferral policies in the United States and Canada. Design, Setting, and Participants A nonvalidated telephone survey study was conducted of all 65 eye banks in the United States and Canada to investigate how many potential corneal donors were disqualified in 2018 because of federal MSM restrictions. Published demographic data were also used to arrive at a separate estimate. Survey data were gathered from May 2019 to February 2020. Main Outcomes and Measures Eye banks were asked if they keep records of referrals disqualified specifically because of the federal MSM restrictions and, if so, how many referrals they disqualified in 2018 owing to MSM status. Results Fifty-four of 65 eye banks (83%) responded to the survey, with 30 eye banks reporting they do not keep specific records of MSM deferrals. The remaining 24 eye banks reported disqualifying 360 referrals in 2018 because of MSM status, equating to 720 corneas. The 24 eye banks accounted for 46.2% of corneal donations in the United States and Canada in 2018, yielding an estimate of approximately 1558 corneas rejected that year because of MSM status. A separate estimate using published MSM demographic data indicates that up to 3217 potential corneal donations may have been disqualified in 2018 because of these federal policies. Conclusions and Relevance Findings suggest that between 1558 and 3217 corneal donations were disqualified in 2018 because of federal regulations prohibiting corneal donation by men who have had sex with another man in the preceding 5 years in the United States or 1 year in Canada. With modern virologic testing that is reliable within days of HIV exposure and given the global shortage of corneal tissue, these policies should be reevaluated using current scientific evidence to increase the availability of vision-restoring surgery worldwide.

PurposeIn multi-echo fMRI (ME-fMRI), various weighting schemes have been proposed for the combination of the data across echoes. Here we introduce a framework that facilitates a deeper understanding of the weight dependence of temporal SNR measures in ME-fMRI.Theory and MethodsWe examine two metrics that have been used to characterize ME-fMRI performance: temporal SNR (tSNR) and multi-echo temporal (metSNR). Both metrics can be described using the generalized Rayleigh quotient (GRQ) and are predicted to be relatively insensitive to the weights when there is a high degree of similarity between a metric-specific matrix in the GRQ numerator and a metricindependent covariance matrix in the GRQ denominator. The application of the GRQ framework to experimental data is demonstrated using a resting-state fMRI dataset acquired with a multi-echo multi-band EPI sequence.ResultsIn the example dataset, similarities between the covariance matrix and the metSNR and tSNR numerator matrices are highest in grey matter (GM) and cerebrospinal fluid (CSF) voxels, respectively. For representative GM and CSF voxels that exhibit high matrix similarity values, the metSNR and tSNR values, respectively, are both within 4% of their optimal values across a range of weighting schemes. However, there is a fundamental tradeoff, with a high degree of weight sensitivity in the tSNR and metSNR metrics for the representative GM and CSF voxels, respectively. Geometric insight into the observed weight dependencies is provided through a graphical interpretation of the GRQ.ConclusionA GRQ framework can provide insight into the factors that determine the weight sensitivity of tSNR and metSNR measures in ME-fMRI.

Retinitis pigmentosa (RP) and associated inherited retinal diseases (IRDs) are caused by rod photoreceptor degeneration, necessitating therapeutics promoting rod photoreceptor survival. To address this, we tested compounds for neuroprotective effects in zebrafish and mouse RP models, reasoning drugs effective across species may translate better clinically. We first performed a large-scale phenotypic drug screen using a larval zebrafish model of inducible RP. 2,934 compounds, mostly human-approved drugs, were tested across six concentrations. Statistically, 113 compounds achieved “hit” status. Secondary tests of 42 high-priority hits confirmed eleven lead compounds. Nine leads were then evaluated in mouse RP models, with six exhibiting neuroprotective effects. An analysis of potential mechanisms of action suggested complementary activities. Paired lead compound assays in zebrafish showed additive neuroprotective effects for the majority. These results highlight the value of cross-species phenotypic drug discovery and suggest combinatorial drug therapies may provide enhanced therapeutic benefits for patients with RP and IRDs.

Purpose Preloaded, trifolded grafts in Descemet membrane endothelial keratoplasty require transfer of the trifolding process from the corneal transplant surgeon to the eye bank technician. We sought to assess whether trifolding may be safely conducted by an eye bank technician with cell loss comparable to standard peeling and lifting. Methods A total of 10 grafts were stained, peeled, and transferred directly onto a bed of Calcein-AM and Amvisc Plus by an eye bank technician. Five grafts were removed and stained as a scroll, and 5 grafts were trifolded with the endothelium in before transfer. Photographs were acquired with an inverted fluorescence microscope, and image segmentation was performed. A t test was conducted to compare differences in endothelial cell loss across groups. Results Mean cell loss in the scroll group was 18.5% [95% confidence interval (CI): 15.2%-21.9%] compared with 7.6% of the trifolded group (95% CI: 1.7%-13.5%). A 2-tailed t test indicated decreased cell loss in the trifolded group (P = 0.013). Conclusions Despite additional manipulation of the graft, trifolding of Descemet membrane and endothelium may be performed by an eye bank technician without significantly increased cell loss relative to graft preparation as a scroll.

Purpose In Descemet membrane endothelial keratoplasty (DMEK), loading and positioning of tri-folded grafts into a cartridge is generally conducted with forceps or a hook, risking graft tear or trauma. We demonstrate the feasibility of loading tri-folded grafts into a cartridge with no touch to the endothelium required beyond the tri-folding process. Methods A corneoscleral rim with a prestripped DMEK graft is placed into a petri dish. After the graft is tri-folded with forceps and removed from its stromal attachment, the graft is gently wicked into the tip of a saline-filled Alcon B IOL cartridge connected to IV extension tubing and a 3 cc syringe, drawn into the cartridge by positioning it adjacent to the graft tip. The remainder of the graft is aspirated with the addition of saline. The cartridge orientation is reversed for graft injection. In this retrospective analysis, we analyzed surgical videos for preparation times, and assessed postoperative visual acuity, pachymetry, and endothelial cell density. Results Thirteen cases underwent this approach. Median preparation time from stain to cartridge eye contact was 8.5 minutes, and time from graft injection to final centration and bubbling was 2.9 minutes. Corneal thickness decreased from a median of 623 microns preoperatively to 566 μm at 1 month (P = 0.038). Visual acuity improved by 1 month by a median of 0.3 logarithm of the minimum angle of resolution (logMAR) (P = 0.016). Endothelial cell density decreased by 32.4% at 1 month compared with baseline. Conclusions Endothelium-in DMEK grafts may be loaded into a plastic cartridge using a skill set similar to aspiration of a scroll.