Morphometric, hemodynamic, and biomechanical factors influencing blood flow and oxygen concentration in the human lamina cribrosa

Purpose: We developed a combined biomechanical and hemodynamic model of the human eye to estimate blood flow and oxygen concentration within the lamina cribrosa (LC) and rank the factors that influence LC oxygen concentration. Methods: We generated 5000 finite-element eye models with detailed microcapillary networks of the LC and computed the oxygen concentration of the lamina retinal ganglion cell axons. For each model, we varied the intraocular pressure (IOP) from 10 mm Hg to 55 mm Hg in 5-mm Hg increments, the cerebrospinal fluid pressure (13 ± 2 mm Hg), cup depth (0.2 ± 0.1 mm), scleral stiffness (±20% of the mean values), LC stiffness (0.41 ± 0.2 MPa), LC radius (1.2 ± 0.12 mm), average LC pore size (5400 ± 2400 µm2), the microcapillary arrangement (radial, isotropic, or circumferential), and perfusion pressure (50 ± 9 mm Hg). Blood flow was assumed to originate from the LC periphery and drain via the central retinal vein. Finally, we performed linear regressions to rank the influence of each factor on the LC tissue oxygen concentration. Results: LC radius and perfusion pressure were the most important factors in influencing the oxygen concentration of the LC. IOP was another important parameter, and eyes with higher IOP had higher compressive strain and slightly lower oxygen concentration. In general, superior–inferior regions of the LC had significantly lower oxygen concentration than the nasal–temporal regions, resulting in an hourglass pattern of oxygen deficiency. Conclusions: To the best of our knowledge, this study is the first to implement a comprehensive hemodynamical model of the eye that accounts for the biomechanical forces and morphological parameters of the LC. The results provide further insight into the possible relationship of biomechanical and vascular pathways leading to ischemia-induced optic neuropathy

Effect of changing heart rate on the ocular pulse and dynamic biomechanical behavior of the optic nerve head

Purpose: To study the effect of changing heart rate on the ocular pulse and the dynamic biomechanical behavior of the optic nerve head (ONH) using a comprehensive mathematical model. Methods: In a finite element model of a healthy eye, a biphasic choroid consisted of a solid phase with connective tissues and a fluid phase with blood, and the lamina cribrosa (LC) was viscoelastic as characterized by a stress-relaxation test. We applied arterial pressures at 18 ocular entry sites (posterior ciliary arteries), and venous pressures at four exit sites (vortex veins). In the model, the heart rate was varied from 60 to 120 bpm (increment: 20 bpm). We assessed the ocular pulse amplitude (OPA), pulse volume, ONH deformations, and the dynamic modulus of the LC at different heart rates. Results: With an increasing heart rate, the OPA decreased by 0.04 mm Hg for every 10 bpm increase in heart rate. The ocular pulse volume decreased linearly by 0.13 µL for every 10 bpm increase in heart rate. The storage modulus and the loss modulus of the LC increased by 0.014 and 0.04 MPa, respectively, for every 10 bpm increase in heart rate. Conclusions: In our model, the OPA, pulse volume, and ONH deformations decreased with an increasing heart rate, whereas the LC became stiffer. The effects of blood pressure/heart rate changes on ONH stiffening may be of interest for glaucoma pathology

DeshadowGAN: a deep learning approach to remove shadows from optical coherence tomography images

Purpose: To remove blood vessel shadows from optical coherence tomography (OCT) images of the optic nerve head (ONH). Methods: Volume scans consisting of 97 horizontal B-scans were acquired through the center of the ONH using a commercial OCT device for both eyes of 13 subjects. A custom generative adversarial network (named DeshadowGAN) was designed and trained with 2328 B-scans in order to remove blood vessel shadows in unseen B-scans. Image quality was assessed qualitatively (for artifacts) and quantitatively using the intralayer contrast—a measure of shadow visibility ranging from 0 (shadow-free) to 1 (strong shadow). This was computed in the retinal nerve fiber layer (RNFL), the inner plexiform layer (IPL), the photoreceptor (PR) layer, and the retinal pigment epithelium (RPE) layer. The performance of DeshadowGAN was also compared with that of compensation, the standard for shadow removal. Results: DeshadowGAN decreased the intralayer contrast in all tissue layers. On average, the intralayer contrast decreased by 33.7 ± 6.81%, 28.8 ± 10.4%, 35.9 ± 13.0%, and 43.0 ± 19.5% for the RNFL, IPL, PR layer, and RPE layer, respectively, indicating successful shadow removal across all depths. Output images were also free from artifacts commonly observed with compensation. Conclusions: DeshadowGAN significantly corrected blood vessel shadows in OCT images of the ONH. Our algorithm may be considered as a preprocessing step to improve the performance of a wide range of algorithms including those currently being used for OCT segmentation, denoising, and classification. Translational Relevance: DeshadowGAN could be integrated to existing OCT devices to improve the diagnosis and prognosis of ocular pathologies

Reduction of the Lamina Cribrosa Curvature After Trabeculectomy in Glaucoma

PURPOSE. To investigate whether the lamina cribrosa (LC) curvature is decreased after trabeculectomy. METHODS. Thirty-nine eyes of 39 patients with primary open-angle glaucoma who underwent trabeculectomy were included. Optic nerves were scanned by using enhanced-depth-imaging spectral-domain optical coherence tomography before and after trabeculectomy. The LC curvature was assessed by measuring the LC curvature index (LCCI) in seven horizontal Bscan images in each eye. RESULTS. The LCCI was significantly smaller at postoperative 6 months than at the preoperative level in all seven planes (all P < 0.001). Preoperative LCCI was associated with younger age at superior midperiphery, midhorizontal plane, inferior midperiphery (all P 0.005) and higher preoperative intraocular pressure (IOP) at superior and inferior midperiphery (both P ¼ 0.039). Younger age and larger preoperative LCCI were associated with a larger reduction of the LCCI at all three locations (P ¼ 0.003 and 0.031 at superior midperiphery, P ¼ 0.011 and 0.001 at midhorizontal plane, and P ¼ 0.014 and 0.005 at inferior midperiphery, respectively), whereas the percentage IOP lowering was associated at superior and inferior midperiphery (P ¼ 0.017 and 0.047, respectively). CONCLUSIONS. Lamina cribrosa curvature was reduced after trabeculectomy. This finding suggests that LC curvature may have value as a parameter relevant to optic nerve head biomechanics

OCT-GAN: single step shadow and noise removal from optical coherence tomography images of the human optic nerve head

Speckle noise and retinal shadows within OCT B-scans occlude important edges, fine textures and deep tissues, preventing accurate and robust diagnosis by algorithms and clinicians. We developed a single process that successfully removed both noise and retinal shadows from unseen single-frame B-scans within 10.4ms. Mean average gradient magnitude (AGM) for the proposed algorithm was 57.2% higher than current state-of-the-art, while mean peak signal to noise ratio (PSNR), contrast to noise ratio (CNR), and structural similarity index metric (SSIM) increased by 11.1%, 154% and 187% respectively compared to single-frame B-scans. Mean intralayer contrast (ILC) improvement for the retinal nerve fiber layer (RNFL), photoreceptor layer (PR) and retinal pigment epithelium (RPE) layers decreased from 0.362 ± 0.133 to 0.142 ± 0.102, 0.449 ± 0.116 to 0.0904 ± 0.0769, 0.381 ± 0.100 to 0.0590 ± 0.0451 respectively. The proposed algorithm reduces the necessity for long image acquisition times, minimizes expensive hardware requirements and reduces motion artifacts in OCT images

A multi-site campaign to measure solar-like oscillations in Procyon. II. Mode frequencies

We have analyzed data from a multi-site campaign to observe oscillations in the F5 star Procyon. The data consist of high-precision velocities that we obtained over more than three weeks with eleven telescopes. A new method for adjusting the data weights allows us to suppress the sidelobes in the power spectrum. Stacking the power spectrum in a so-called echelle diagram reveals two clear ridges that we identify with even and odd values of the angular degree (l=0 and 2, and l=1 and 3, respectively). We interpret a strong, narrow peak at 446 muHz that lies close to the l=1 ridge as a mode with mixed character. We show that the frequencies of the ridge centroids and their separations are useful diagnostics for asteroseismology. In particular, variations in the large separation appear to indicate a glitch in the sound-speed profile at an acoustic depth of about 1000 s. We list frequencies for 55 modes extracted from the data spanning 20 radial orders, a range comparable to the best solar data, which will provide valuable constraints for theoretical models. A preliminary comparison with published models shows that the offset between observed and calculated frequencies for the radial modes is very different for Procyon than for the Sun and other cool stars. We find the mean lifetime of the modes in Procyon to be 1.29 +0.55/-0.49 days, which is significantly shorter than the 2-4 days seen in the Sun.Comment: accepted for publication in Ap

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Numerical stress analysis of the iris tissue induced by pupil expansion: Comparison of commercial devices

<div><p>Purpose</p><p>(1) To use finite element (FE) modelling to estimate local iris stresses (i.e. internal forces) as a result of mechanical pupil expansion; and to (2) compare such stresses as generated from several commercially available expanders (Iris hooks, APX dilator and Malyugin ring) to determine which design and deployment method are most likely to cause iris damage.</p><p>Methods</p><p>We used a biofidelic 3-part iris FE model that consisted of the stroma, sphincter and dilator muscles. Our FE model simulated expansion of the pupil from 3 mm to a maximum of 6 mm using the aforementioned pupil expanders, with uniform circular expansion used for baseline comparison. FE-derived stresses, resultant forces and area of final pupil opening were compared across devices for analysis.</p><p>Results</p><p>Our FE models demonstrated that the APX dilator generated the highest stresses on the sphincter muscles, (max: 6.446 MPa; average: 5.112 MPa), followed by the iris hooks (max: 5.680 MPa; average: 5.219 MPa), and the Malyugin ring (max: 2.144 MPa; average: 1.575 MPa). Uniform expansion generated the lowest stresses (max: 0.435MPa; average: 0.377 MPa). For pupil expansion, the APX dilator required the highest force (41.22 mN), followed by iris hooks (40.82 mN) and the Malyugin ring (18.56 mN).</p><p>Conclusion</p><p>Our study predicted that current pupil expanders exert significantly higher amount of stresses and forces than required during pupil expansion. Our work may serve as a guide for the development and design of next-generation pupil expanders.</p></div