Probability density and information entropy of machine learning derived intracranial pressure predictions.

Even with the powerful statistical parameters derived from the Extreme Gradient Boost (XGB) algorithm, it would be advantageous to define the predicted accuracy to the level of a specific case, particularly when the model output is used to guide clinical decision-making. The probability density function (PDF) of the derived intracranial pressure predictions enables the computation of a definite integral around a point estimate, representing the event's probability within a range of values. Seven hold-out test cases used for the external validation of an XGB model underwent retinal vascular pulse and intracranial pressure measurement using modified photoplethysmography and lumbar puncture, respectively. The definite integral ±1 cm water from the median (DIICP) demonstrated a negative and highly significant correlation (-0.5213±0.17, p< 0.004) with the absolute difference between the measured and predicted median intracranial pressure (DiffICPmd). The concordance between the arterial and venous probability density functions was estimated using the two-sample Kolmogorov-Smirnov statistic, extending the distribution agreement across all data points. This parameter showed a statistically significant and positive correlation (0.4942±0.18, p< 0.001) with DiffICPmd. Two cautionary subset cases (Case 8 and Case 9), where disagreement was observed between measured and predicted intracranial pressure, were compared to the seven hold-out test cases. Arterial predictions from both cautionary subset cases converged on a uniform distribution in contrast to all other cases where distributions converged on either log-normal or closely related skewed distributions (gamma, logistic, beta). The mean±standard error of the arterial DIICP from cases 8 and 9 (3.83±0.56%) was lower compared to that of the hold-out test cases (14.14±1.07%) the between group difference was statistically significant (p<0.03). Although the sample size in this analysis was limited, these results support a dual and complementary analysis approach from independently derived retinal arterial and venous non-invasive intracranial pressure predictions. Results suggest that plotting the PDF and calculating the lower order moments, arterial DIICP, and the two sample Kolmogorov-Smirnov statistic may provide individualized predictive accuracy parameters.

A possible association between intraocular pressure changes and pigment epithelial detachment in central serous chorioretinopathy.

Central serous chorioretinopathy (CSC) is a frequently occurring chorioretinal disease, that is commonly associated with subretinal fluid accumulation in a generally young population. Even though choroidal abnormalities have been found to be of importance, the exact pathogenesis of CSC is still being learned. The origin of pigment epithelial detachments, seen in many CSC patients, is also unclear. Based on the follow-up of a CSC patient for more than 5 years, we hypothesize that intraocular pressure and, by extension, the pressure gradient across the Bruch's membrane, may be one factor in the pathogenesis of pigment epithelial detachments in CSC, which might very well have implications for the occurrence of and possible ways to prevent subretinal fluid in CSC.

Posture-Induced Changes in Intraocular, Orbital, Cranial, Jugular Vein, and Arterial Pressures in a Porcine Model.

Purpose: The purpose of this study was to determine posture-induced changes in arterial blood pressure (ABP), intraocular pressure (IOP), orbital pressure (Porb), intracranial pressure (ICP), and jugular vein pressure (JVP) at various tilt angles in an in vivo pig. Methods: Anesthetized and ventilated pigs (n = 8) were placed prone on a tiltable operating table. ABP, IOP, Porb, ICP, and JVP were monitored while the table was tilted at various angles between 15 degrees head up tilt (HUT) and 25 degrees head down tilt (HDT) either in stepwise changes (5 degrees per step) or continuously. The mean pressure was calculated from digitized pressure waveforms from each compartment. For stepwise changes in tilt angle the pressures were plotted as a function of tilt angle. For continuous tilt changes, the pressures were plotted as a function of time. Results: In the case of stepwise changes, ABP remained relatively stable whilst IOP, Porb, ICP, and JVP demonstrated significant differences between most angles (typically P < 0.0001). The difference was greatest for IOP (P < 0.0001) where the average IOP increased from 13.1 ± 1.23 mm Hg at 15 degrees HUT to 46.3 ± 2.03 mm Hg at 25 degrees HDT. The relationship between pressure and tilt angle was almost linear for ICP and JVP, and sigmoidal for IOP and Porb. Interestingly, the effect of changes in tilt angle occurred very rapidly, within a few seconds. Conclusions: Our results in a pig model demonstrate that changes in posture (tilt angle) induce rapid changes in IOP, Porb, ICP, and JVP, with IOP affected most severely.

Complete genome of Aedes japonicus narnavirus from wild caught mosquitoes collected in Ohio, USA.

Narnaviruses infect several genera of mosquitoes including Culex and Aedes . The narnavirus genome is a positive, single stranded RNA encoding an RNA-dependent RNA polymerase gene. The partial genome of a narnavirus identified in wild Aedes japonicus mosquitoes collected in Wooster, Ohio, USA was obtained using metagenomic analyses. Rapid amplification of 5'-cDNA ends (RACE) and Sanger sequencing were used to obtain the remaining genomic sequence of this strain. The complete genome is composed of 3153 nucleotides and has 98.4% and 99.1% nucleotide sequence identity with Aedes japonicus narnavirus genomes identified in Netherlands and Japan.

Complete resolution of focal-on-diffuse myocardial activity pattern on FDG PET-CT by prolonging the dietary preparation protocol in cardiac sarcoidosis.

Patient preparation is crucial for reliable interpretation of cardiac inflammation FDG PET. We share our experience of improved reporting confidence and propose a simple approach of prolonging preparation (from 24 to 48 hours) with the high-fat, no-carbohydrate, and protein-permitted diet followed by fasting in cardiac sarcoidosis in cases with diffuse or focal-on-diffuse myocardial FDG uptake.

Genetic predisposition to ocular surface disorders and opportunities for gene-based therapies.

The ocular surface, comprised of the corneal and conjunctival epithelium, innervation system, immune components, and tear-film apparatus, plays a key role in ocular integrity as well as comfort and vision. Gene defects may result in congenital ocular or systemic disorders with prominent ocular surface involvement. Examples include epithelial corneal dystrophies, aniridia, ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome, xeroderma pigmentosum (XP), and hereditary sensory and autonomic neuropathy. In addition, genetic factors may interact with environmental risk factors in the development of several multifactorial ocular surface disorders (OSDs) such as autoimmune disorders, allergies, neoplasms, and dry eye disease. Advanced gene-based technologies have already been introduced in disease modelling and proof-of-concept gene therapies for monogenic OSDs. For instance, patient-derived induced pluripotent stem cells have been used for modelling aniridia-associated keratopathy (AAK), XP, and EEC syndrome. Moreover, CRISPR/Cas9 genome editing has been used for disease modelling and/or gene therapy for AAK and Meesmann's epithelial corneal dystrophy. A better understanding of the role of genetic factors in OSDs may be helpful in designing personalized disease models and treatment approaches. Gene-based approaches in monogenic OSDs and genetic predisposition to multifactorial OSDs such as immune-mediated disorders and neoplasms with known or possible genetic risk factors has been seldom reviewed. In this narrative review, we discuss the role of genetic factors in monogenic and multifactorial OSDs and potential opportunities for gene therapy.

A Review of Smartphone Adapters Capable of Imaging the Anterior Segment in Ophthalmology.

Teleophthalmology is a widely recognised way to provide health care to patients living in rural and remote regions by leveraging limited clinician availability and resources. This is most important in low socioeconomic areas, where the disparity between prevalence of preventable blindness and practicing ophthalmologists is greatest. The ubiquity and accessibility of smartphones allow them to be utilised in a clinical setting and facilitate teleophthalmology. While the current market of smartphone adapters capable of imaging ocular pathology is expanding, few focus on the anterior segment and operate independently of the slit-lamp microscope. This article reviews the available smartphone adapters capable of imaging anterior segment pathology.

Decontamination and Annotation of the Draft Genome Sequence of the Oomycete Lagenidium giganteum ARSEF 373.

Scaffolds of a previously published Lagenidium giganteum ARSEF 373 genome assembly found at GenBank were filtered to remove contaminating sequences. Genome annotation of the 437 scaffolds (total length, 56.2 MB; GC content, 58.8%) with confirmed L. giganteum sequences identified 13,069 potential protein-coding genes, encoding at least 737 predicted secreted proteins and >100 putative translocated effectors.

Empirical retinal venous pulse wave velocity using modified photoplethysmography.

OBJECTIVE: Using the novel imaging method of high-speed modified photoplethysmography we measured the retinal venous pulse wave velocity in a single case. RESULTS: A healthy 30-year-old subject underwent high-speed modified photoplethysmography (120 frames per second) with simultaneous ophthalmodynamometry at 26 Meditron units. A video of the optic nerve was analyzed using custom software. A harmonic regression model was fitted to each pixel in the time series and used to quantify the retinal vascular pulse wave parameters. Retinal venous pulsation at the optic disc was observed as a complex dynamic wall motion, whereas contraction commenced at a point in the vein at the center of the optic disc, and progressed centrifugally. The empirically estimated retinal venous pulse wave velocity at this segment was approximately 22.24694 mm/s. This measurement provides an estimate for future studies in the field.

Optimal Calculation of Mean Pressure From Pulse Pressure.

BACKGROUND: There are six different formulae for estimating mean arterial pressure (MAP) from systolic and diastolic pressure readings. This study is to determine the optimum formula for calculating MAP when compared to the gold standard approach, which is the area under the curve of an invasively measured pulse waveform divided by the cardiac cycle duration. METHODS: Eight live pigs were used as the experimental model for the invasive measurement of femoral artery pressure (AP) by a fluid filled catheter connected with a pressure transducer. In addition, intraocular pressure (IOP) and jugular vein pressure (JVP) were also recorded. The mean pressure (MP) was calculated from digital waveforms sampled at 1,000 points per second with the six formulae and area method for AP, IOP and JVP. RESULTS: The absolute mean difference between the area MAP and each formula's MAP ranged from 0.98 to 3.23 mm Hg. Our study also found that even under physiological conditions, area MAP can vary between successive pulses by up to 5 mm Hg. For mean IOP and JVP, the mean difference between a formula's MP and the area method's was less than 1 mm Hg for most formulae. With the pooled data, there was excellent agreement amongst all formulae for MAP with the intra-class correlation coefficient (ICC) ranging from 0.97 to 0.99, while the ICC of most formulae for IOP and JVP was 1.0. CONCLUSIONS: Our study suggests that all current formulae are adequate for estimating MAP, though some formulae are not suitable for mean IOP and JVP.

Spontaneous Closure of a Coronary Artery Bypass Graft Pseudoaneurysm Embedded in a Mediastinal Hematoma.

Coronary artery bypass graft (CABG) pseudoaneurysms are a rare but often unrecognized clinical entity. They are prone to rupture and hemodynamic compromise and should therefore be on the differential in the appropriate patient. We present a case of a gentleman with a recent CABG surgery who presented with acute onset dyspnea and a large pleural effusion. Imaging revealed a saphenous vein graft pseudoaneurysm embedded in a mediastinal hematoma. Four weeks later, prior to planned stenting, the pseudoaneurysm had spontaneously closed. This case highlights an unusual acute presentation of a CABG pseudoaneurysm and a multidisciplinary approach to its management.

Vessel Pulse Amplitude Mapping in Eyes With Central and Hemi Retinal Venous Occlusion.

Purpose: The purpose of this study was to describe vessel pulse amplitude characteristics in eyes with central retinal vein occlusion (CRVO), hemiretinal vein occlusion (HVO), normal eyes (N1 N1), and the unaffected contralateral eyes of CRVO and HVO eyes (N1 CRVO and N1 HVO), as well as the unaffected hemivessels of HVO eyes (N2 HVO). Methods: Ophthalmodynamometry estimates of blood column pulse amplitudes with modified photoplethysmography were timed against cardiac cycles. Harmonic analysis was performed on the vessel reflectance within 0.25 to 1 mm from the disc center to construct pulse amplitude maps. Linear mixed modeling was used to examine variable effects upon the log harmonic pulse amplitude. Results: One hundred seven eyes were examined. Normal eyes had the highest mean venous pulse amplitude (2.08 ± 0.48 log u). CRVO had the lowest (0.99 ± 0.45 log u, P < 0.0001), followed by HVO (1.23 ± 0.46 log u, P = 0.0002) and N2 HVO (1.30 ± 0.59 log u, P = 0.0005). N1 CRVO (1.76 ± 0.34 log u, P = 0.52) and N1 HVO (1.33 ± 0.37 log u, P = 0.0101) had no significantly different mean amplitudes compared to N1 N1. Arterial amplitudes were lower than venous (P < 0.01) and reduced with venous occlusion (P < 0.01). Pulse amplitude versus amplitude over distance decreased along the N1 N1 vessels, with increasing slopes observed with CRVO (P < 0.01). Conclusions: Pulse amplitude reduction and attenuation characteristics of arteries and veins in venous occlusion can be measured and are consistent with reduced vessel wall compliance and pulse wave transmission. Translational Relevance: Retinal vascular pulse amplitudes can be measured, revealing occlusion induced changes, suggesting a role in evaluating the severity and progression of venous occlusion.

Endothelial contraction of retinal veins.

We have previously reported that porcine retinal veins can be contracted by vasoactive factors such as endothelin-1, but it is still unknown which cells play the major role in such contraction responses. This study seeks to confirm whether retinal vein endothelial cells play a significant role in the endothelin-1 induced contraction of porcine retinal veins. This is a novel study which provides confirmation of the endothelial cells' ability to contract retinal veins using a live vessel preparation. Retinal veins were isolated from porcine retina and cannulated for perfusion. The vessels were exposed to extraluminal delivery of endothelin-1 (10-8 M) and change in vessel diameter recorded automatically every 2 s. A phase contrast objective lens was also used to capture images of the endothelial cell morphometries. The length, width, area, and perimeter were assessed. In addition, vein histology and immuno-labeling for contractile proteins was performed. With 10-8 M endothelin-1 contractions to 63.6% of baseline were seen. The polygonal shape of the endothelial cells under normal tone became spindle-like after contraction. The area, width, perimeter and length were significantly reduced by 54.8%, 48.1%, 28.5% and 10.5% respectively. Three contractile proteins, myosin, calponin and alpha-SMA were found in retinal vein endothelial cells. Retinal vein endothelial cells contain contractile proteins and can be contracted by endothelin-1 administration. Such contractile capability may be important in regulating retinal perfusion but could also be a factor in the pathogenesis of retinal vascular diseases such as retinal vein occlusion. As far as we are aware, this is the first study on living isolated veins to confirm that endothelial cells contribute to the endothelin-1 induced contraction.

Topographic distribution and phenotypic heterogeneity of Schlemm's canal endothelium in human donor eyes.

Endothelium phenotype is known to be closely associated with flow shear stress. This study is to determine the topographic distribution of endothelial cells and the phenotype of different quadrants and regions of Schlemm's canal using human donor eyes. This study infers differences in flow dynamics based on cell shape and intracellular structure. The Schlemm's canal from 15 human donor eyes were either perfusion labelled using silver stain or dissected for float labeling with Phalloidin to enable visualization of endothelial cell border and intracellular structure. Data were acquired for endothelial cells from the outer and inner wall of Schlemm's canal and grouped according to quadrant of origin. Measurements included endothelial cell length, width, area, and aspect ratio and compared between quadrants. Endothelial cells are mostly spindle-shape and the cell size on the outer wall are larger and longer than those from the inner wall. Significant differences in endothelial cell size and shape were seen in different quadrants. The endothelial cells have varied shapes and orientations close to large ostia in the outer wall and remarkably long endothelial cells were found in the walls of collector channels. F-actin aggregation was found at all endothelial cell borders, and inside some of the endothelial cytoplasm. The presence of various spindle shapes, significant phenotype heterogeneity and F-actin aggregation of endothelial cells indicates aqueous humor flow likely creates variations in shear stress within Schlemm's canal. Further investigation of the relationship between the phenotype heterogeneity and hydrodynamics of aqueous flow may help us understand the mechanisms of outflow resistance changes in glaucoma.

Outcomes of 45 µm gelatin stent surgery over 24-month follow-up.

BACKGROUND: The main objectives of this study were to determine whether known risk factors for trabeculectomy failure similarly influence gelatin stent outcomes and to identify surgical factors which may optimise success. METHODS: A retrospective, observational study was conducted at a single centre in Perth, Western Australia over 24 months. Two-hundred and sixty-two eyes of 207 patients underwent XEN-45 stent surgery with various forms of glaucoma. Surgical and postoperative data on subjects undergoing XEN-45 stent surgery was collated. Intraocular pressure (IOP) reduction success was determined using three criteria: 1; IOP <18 mm Hg, 2: IOP <15 mm Hg and 3: >25% IOP reduction from baseline. Kaplan-Meier, mixed effects Cox Proportional hazard model and Chi-Square test were used to measure survival of functioning stents. RESULTS: The success rates at a maximum of 2 years after surgery by criteria 1, 2 and 3 were 61.3%, 26.2% and 28.9% in primary open angle glaucoma (n = 243), 18.8%, 16.9%, 21.4% in angle closure glaucoma (n = 11), 0%, 0%, 66.7% in congenital glaucoma (n = 5) and 0% in uveitic glaucoma (n = 3). No significant reduction in success was found in those eyes that had prior ocular surgery (all p > 0.07). CONCLUSIONS: Prior cataract or trabeculectomy surgery does not appear to adversely affect gelatin stent outcomes over 2 years follow up. Gelatin stent surgery appears to have less IOP reduction effect compared to trabeculectomy at 2 years.

Single-cell transcriptomic profiling reveals specific maturation signatures in human cardiomyocytes derived from LMNB2-inactivated induced pluripotent stem cells.

Mammalian cardiomyocyte maturation entails phenotypic and functional optimization during the late fetal and postnatal phases of heart development, both processes driven and coordinated by complex gene regulatory networks. Cardiomyocytes derived from human induced pluripotent stem cells (iPSCs) are heterogenous and immature, barely resembling their adult in vivo counterparts. To characterize relevant developmental programs and maturation states during human iPSC-cardiomyocyte differentiation, we performed single-cell transcriptomic sequencing, which revealed six cardiomyocyte subpopulations, whose heterogeneity was defined by cell cycle and maturation states. Two of those subpopulations were characterized by a mature, non-proliferative transcriptional profile. To further investigate the proliferation-maturation transition in cardiomyocytes, we induced loss-of-function of LMNB2, which represses cell cycle progression in primary cardiomyocytes in vivo. This resulted in increased maturation in LMNB2-inactivated cardiomyocytes, characterized by transcriptional profiles related to myofibril structure and energy metabolism. Furthermore, we identified maturation signatures and maturational trajectories unique for control and LMNB2-inactivated cardiomyocytes. By comparing these datasets with single-cell transcriptomes of human fetal hearts, we were able to define spatiotemporal maturation states in human iPSC-cardiomyocytes. Our results provide an integrated approach for comparing in vitro-differentiated cardiomyocytes with their in vivo counterparts and suggest a strategy to promote cardiomyocyte maturation.

MSGANet-RAV: A multiscale guided attention network for artery-vein segmentation and classification from optic disc and retinal images.

BACKGROUND: Retinal and optic disc images are used to assess changes in the retinal vasculature. These can be changes associated with diseases such as diabetic retinopathy and glaucoma or induced using ophthalmodynamometry to measure arterial and venous pressure. Key steps toward automating the assessment of these changes are the segmentation and classification of the veins and arteries. However, such segmentation and classification are still required to be manually labelled by experts. Such automated labelling is challenging because of the complex morphology, anatomical variations, alterations due to disease and scarcity of labelled data for algorithm development. We present a deep machine learning solution called the multiscale guided attention network for retinal artery and vein segmentation and classification (MSGANet-RAV). METHODS: MSGANet-RAV was developed and tested on 383 colour clinical optic disc images from LEI-CENTRAL, constructed in-house and 40 colour fundus images from the AV-DRIVE public dataset. The datasets have a mean optic disc occupancy per image of 60.6% and 2.18%, respectively. MSGANet-RAV is a U-shaped encoder-decoder network, where the encoder extracts multiscale features, and the decoder includes a sequence of self-attention modules. The self-attention modules explore, guide and incorporate vessel-specific structural and contextual feature information to segment and classify central optic disc and retinal vessel pixels. RESULTS: MSGANet-RAV achieved a pixel classification accuracy of 93.15%, sensitivity of 92.19%, and specificity of 94.13% on LEI-CENTRAL, outperforming several reference models. It similarly performed highly on AV-DRIVE with an accuracy, sensitivity and specificity of 95.48%, 93.59% and 97.27%, respectively. CONCLUSION: The results show the efficacy of MSGANet-RAV for identifying central optic disc and retinal arteries and veins. The method can be used in automated systems designed to assess vascular changes in retinal and optic disc images quantitatively.

A machine learning approach in the non-invasive prediction of intracranial pressure using Modified Photoplethysmography.

The ideal Intracranial pressure (ICP) estimation method should be accurate, reliable, cost-effective, compact, and associated with minimal morbidity/mortality. To this end several described non-invasive methods in ICP estimation have yielded promising results, however the reliability of these techniques have yet to supersede invasive methods of ICP measurement. Over several publications, we described a novel imaging method of Modified Photoplethysmography in the evaluation of the retinal vascular pulse parameters decomposed in the Fourier domain, which enables computationally efficient information filtering of the retinal vascular pulse wave. We applied this method in a population of 21 subjects undergoing lumbar puncture manometry. A regression model was derived by applying an Extreme Gradient Boost (XGB) machine learning algorithm using retinal vascular pulse harmonic regression waveform amplitude (HRWa), first and second harmonic cosine and sine coefficients (an1,2, bn1,2) among other features. Gain and SHapley Additive exPlanation (SHAP) values ranked feature importance in the model. Agreement between the predicted ICP mean, median and peak density with measured ICP was assessed using Bland-Altman bias±standard error. Feature gain of intraocular pressure (IOPi) (arterial = 0.6092, venous = 0.5476), and of the Fourier coefficients, an1 (arterial = 0.1000, venous = 0.1024) ranked highest in the XGB model for both vascular systems. The arterial model SHAP values demonstrated the importance of the laterality of the tested eye (1.2477), which was less prominent in the venous model (0.8710). External validation was achieved using seven hold-out test cases, where the median venous predicted ICP showed better agreement with measured ICP. Although the Bland-Altman bias from the venous model (0.034±1.8013 cm water (p<0.99)) was lower compared to that of the arterial model (0.139±1.6545 cm water (p<0.94)), the arterial model provided a potential avenue for internal validation of the prediction. This approach can potentially be integrated into a neurological clinical decision algorithm to evaluate the indication for lumbar puncture.

Near infra-red reflectance videography in the evaluation of retinal artery macroaneurysm pulsatility.

Purpose: To describe pulsations of the retinal arteries detected in the course of evaluation of an exudative non-pulsatile retinal arterial macroaneurysm using near infra-red reflectance videography. Observations: A 68-year-old patient underwent slit lamp examination, color retinal imaging, optical coherence tomography, fluorescein videography, short wave-length and near infrared fundus autofluorescence of the left, and near infrared reflectance videography of both eyes. A 1309.3 × 955.1 µm exudative lesion with intraretinal hemorrhage and retinal edema secondary to a retinal arterial macroaneurysm was observed along the superior temporal arcade between the retinal artery and vein. Bilateral serpentine and expansile spontaneous retinal artery pulsations were detected along the retinal vascular tree and imaged using near infrared reflectance videography. Fluorescein video-angiography showed an irregular filling defect of the lesion with minimal angiographic leakage. Whereas pulsations of the retinal arteries were visualized, no pulsations of the retinal arterial macroaneurysm were detected with either dynamic imaging modality, therefore observation was recommended. Significant spontaneous lesion regression was observed at one month follow-up. Conclusionand Importance: Detection of spontaneous retinal artery pulsation and the assessment of exudative maculopathy due to an underlying retinal arterial macroaneurysm could be facilitated by near infrared reflectance videography. This imaging modality can aid in clinical decision-making where a non-pulsatile macroaneurysm would favor conservative management.