Late diagnosis of Cutibacterium acnes (formerly Proprionibacterium acnes) endophthalmitis and the importance of dual testing with bacterial culture and polymerase chain reaction.

PURPOSE: To describe two cases of C. acnes endophthalmitis that reinforce the importance of performing both bacterial culture and 16s polymerase chain reaction when the causative pathogen is unclear or difficult to culture, such as C. acnes. A case of C. acnes endophthalmitis complicated by sub-buckle scleral perforation is illustrated with intraoperative photography. METHODS: Two-case series. RESULTS: Case 1 describes a case of C. acnes endophthalmitis in a longstanding pseudophakic patient following multiple vitrectomies for recurrent retinal detachment, complicated by sub-buckle scleral perforation. Bacterial culture revealed C. acnes while 16s PCR was negative. Conversely, Case 2 demonstrates a case of chronic endophthalmitis diagnosed one year following cataract surgery. PCR (with repeat tap for confirmation) revealed C. acnes with a negative culture. CONCLUSION: When the causative pathogen of endophthalmitis is unclear, dual testing of microbial culture and C. acnes 16s PCR improves the diagnostic yield of investigations for fastidious pathogens. C. acnes can present as an indolent or virulent endophthalmitis.

Prevalence of persistent avascular retina in untreated children with a history of retinopathy of prematurity screening.

Persistent avascular retina (PAR) in prematurely born individuals may be a risk factor for late sequelae of retinopathy of prematurity (ROP), including retinal detachment in older childhood and adulthood. Although PAR has been associated with use of vascular endothelial growth factor antagonist therapy for treatment-requiring ROP, the prevalence of this finding in patients without prior ROP treatment is unknown. We performed a cross-sectional study to determine the prevalence of PAR in a cohort of patients 4-8 years of age who were screened for ROP in the neonatal intensive care unit and did not receive treatment. Patients were recruited from an existing population-based cohort and underwent ultra-widefield fluorescein angiography (UWFFA). UWFFA images of 43 eyes of 23 patients were evaluated. Average age at time of evaluation was 6.2 years. PAR was observed in 21 patients (91%). Thirteen eyes (30%) had PAR in zone II; 23 (53%), in zone III. Six eyes (14%) had abnormal vessels without clear PAR. These findings indicate a high prevalence of PAR in patients with a history of ROP screening without treatment.

Artificial intelligence for retinopathy of prematurity.

PURPOSE OF REVIEW: In this article, we review the current state of artificial intelligence applications in retinopathy of prematurity (ROP) and provide insight on challenges as well as strategies for bringing these algorithms to the bedside. RECENT FINDINGS: In the past few years, there has been a dramatic shift from machine learning approaches based on feature extraction to 'deep' convolutional neural networks for artificial intelligence applications. Several artificial intelligence for ROP approaches have demonstrated adequate proof-of-concept performance in research studies. The next steps are to determine whether these algorithms are robust to variable clinical and technical parameters in practice. Integration of artificial intelligence into ROP screening and treatment is limited by generalizability of the algorithms to maintain performance on unseen data and integration of artificial intelligence technology into new or existing clinical workflows. SUMMARY: Real-world implementation of artificial intelligence for ROP diagnosis will require massive efforts targeted at developing standards for data acquisition, true external validation, and demonstration of feasibility. We must now focus on ethical, technical, clinical, regulatory, and financial considerations to bring this technology to the infant bedside to realize the promise offered by this technology to reduce preventable blindness from ROP.

Fluorescence Lifetime Imaging Ophthalmoscopy: A Novel Way to Assess Macular Telangiectasia Type 2.

PURPOSE: Macular Telangiectasia Type 2 (MacTel) is an uncommon, late-onset complex retinal disease that leads to central vision loss. No causative gene(s) have been identified so far, resulting in a challenging clinical diagnostic dilemma because retinal changes of early stages are often subtle. The objective of this study was to investigate the benefit of fluorescence lifetime imaging ophthalmoscopy (FLIO) for retinal imaging in patients with MacTel. DESIGN: Cross-sectional study from a tertiary-care retinal referral practice. SUBJECTS AND CONTROLS: 42 eyes of 21 patients (mean age 60.5±13.3 years) with MacTel as well as an age-matched healthy control group (42 eyes of 25 subjects, mean age 60.8±13.4 years). METHODS: A 30° retinal field centered at the fovea was investigated using FLIO. This camera is based on a Heidelberg Engineering Spectralis system. Fundus autofluorescence (FAF) decays were detected in short (498-560 nm, SSC) and long (560-720 nm, LSC) spectral channels. The mean fluorescence lifetime, τm, was calculated from a 3-exponential approximation of the FAF decays. For MacTel patients, macular pigment (MP), OCT, blue light reflectance, fluorescein angiography, as well as fundus photography, were also recorded. MAIN OUTCOME MEASURES: Mean FAF lifetime (τm) images. RESULTS: FLIO of MacTel patients shows a unique pattern of prolonged τm at the temporal side of the fovea in patients with MacTel in the "MacTel area" within 5-6° of the foveal center. In early stages, this region appears crescent-shaped, while advanced stages show a ring-like pattern. This pattern corresponds well with other imaging modalities and gives an especially high contrast of the affected region even in minimally affected individuals. Additionally, FLIO provides a novel means to monitor the abnormal MP distribution. In one case, FLIO showed changes suggestive of MacTel within a clinically normal parent of two MacTel patients. CONCLUSIONS: FLIO detects retinal changes in patients with MacTel with high contrast, presenting a distinctive signature that is a characteristic finding of the disease. The non-invasive properties of this novel imaging modality provide a valuable addition to clinical assessment of early changes in the disease that could lead to more accurate diagnosis of MacTel.

Patterns of Fundus Autofluorescence Lifetimes In Eyes of Individuals With Nonexudative Age-Related Macular Degeneration.

Purpose: To investigate fundus autofluorescence (FAF) lifetimes in patients with nonexudative AMD. Methods: A total of 150 eyes of 110 patients (mean age: 73.2 ± 10.7 years) with nonexudative AMD, as well as a healthy group of 57 eyes in 38 subjects (mean age: 66.5 ± 8.7 years), were included. Investigations were conducted at the University Eye Clinic in Jena, Germany, as well as the Moran Eye Center in Salt Lake City, Utah, USA, using the Heidelberg Engineering Spectralis-based fluorescence lifetime imaging ophthalmoscope (FLIO). A 30° retinal field centered at the fovea was investigated. FAF decays were detected in short (498-560 nm) and long (560-720 nm, LSC) spectral channels. The mean fluorescence lifetimes (τm) were calculated. Optical coherence tomography scans and fundus photographs were also recorded. Results: In patients with nonexudative AMD, FLIO shows a ring-shaped pattern of prolonged τm in the LSC. This pattern occurs in all patients with AMD (including very early stages) and in one-third of the healthy controls. FAF lifetimes were longer with more advanced stages. The presence of drusen is associated with prolonged τm when compared with the healthy fundus, but drusen identification is difficult with FLIO only. Conclusions: FLIO detects a clear pattern of changes within the fundus, which appears to be AMD-associated. These changes are already visible in early AMD stages and not masked by the presence of other coexisting retinal diseases. These findings may be useful for the early diagnosis of AMD and to distinguish AMD from other retinal diseases.

Fluorescence Lifetime Imaging Ophthalmoscopy (FLIO) of Macular Pigment.

Purpose: To describe different patterns of macular pigment (MP) seen in fluorescence lifetime imaging ophthalmoscopy (FLIO) and to analyze ex vivo fluorescence characteristics of carotenoids. Methods: A total of 31 eyes of young healthy subjects, 4 eyes from patients with albinism, 36 eyes with macular telangiectasia type 2 (MacTel), 24 eyes with retinitis pigmentosa, and 1 eye with a macular hole were included in this clinic-based, cross-sectional study. All subjects underwent Heidelberg Engineering FLIO and MP measurements (dual-wavelength autofluorescence). Fundus autofluorescence (FAF) lifetimes of a 30° retinal field were detected in two spectral channels (SSC: 498-560 nm; LSC: 560-720 nm), and amplitude-weighted mean fluorescence lifetimes (τm) were calculated. Additionally, autofluorescence lifetimes of known dilutions of lutein and zeaxanthin were measured in a cuvette in free- and protein-associated states. Results: MP shows a significant inverse correlation to foveal FAF lifetimes measured with FLIO (SSC: r = -0.608; P < 0.001). Different distribution patterns can be assigned to specific disease-related changes. Two patients with albinism, who did not have MP, were found to be missing short FAF lifetimes. In solvent, lutein and zeaxanthin show very short autofluorescence lifetimes (∼50-60 ps; SSC), as do their respective binding proteins (∼40-50 ps; SSC). When combining carotenoids with their specific binding proteins, the decay times shift to longer means (∼70-90 ps; SSC). Conclusions: This study expands upon previous findings of an impact of MP on short FAF lifetimes by describing ex vivo autofluorescence lifetimes of carotenoids and different in vivo autofluorescence patterns that can be associated with certain diseases.

Characterization of Retinitis Pigmentosa Using Fluorescence Lifetime Imaging Ophthalmoscopy (FLIO).

PURPOSE: We investigated fundus autofluorescence (FAF) lifetimes in patients with retinitis pigmentosa (RP) using fluorescence lifetime imaging ophthalmoscopy (FLIO). METHODS: A total of 33 patients (mean age, 40.0 ± 17.0 years) with RP and an age-matched healthy group were included. The Heidelberg FLIO was used to detect FAF decays in short (SSC; 498-560 nm) and long (LSC; 560-720 nm) spectral channels. We investigated a 30° retinal field and calculated the amplitude-weighted mean fluorescence lifetime (τm). Additionally, macular pigment measurements, macular optical coherence tomography (OCT) scans, fundus photographs, visual fields, and fluorescein angiograms were recorded. Genetic studies were performed on nearly all patients. RESULTS: In RP, FLIO shows a typical pattern of prolonged τm in atrophic regions in the outer macula (SSC, 419 ± 195 ps; LSC, 401 ± 111 ps). Within the relatively preserved retina in the macular region, ring-shaped patterns were found, most distinctive in patients with autosomal dominant RP inheritance. Mean FAF lifetimes were shortened in rings in the LSC. Central areas remained relatively unaffected. CONCLUSIONS: FLIO uniquely presents a distinct and specific signature in eyes affected with RP. The ring patterns show variations that indicate genetically determined pathologic processes. Shortening of FAF lifetimes in the LSC may indicate disease progression, as was previously demonstrated for Stargardt disease. Therefore, FLIO might be able to indicate disease progression in RP as well. TRANSLATIONAL RELEVANCE: Hyperfluorescent FLIO rings with short FAF lifetimes may provide insight into the pathophysiologic disease status of RP-affected retinas potentially providing a more detailed assessment of disease progression.

Short-duration transient visual evoked potentials and color reflectivity discretization analysis in glaucoma patients and suspects.

AIM: To evaluate the use of short-duration transient visual evoked potentials (VEP) and color reflectivity discretization analysis (CORDA) in glaucomatous eyes, eyes suspected of having glaucoma, and healthy eyes. METHODS: The study included 136 eyes from 136 subjects: 49 eyes with glaucoma, 45 glaucoma suspect eyes, and 42 healthy eyes. Subjects underwent Humphrey visual field (VF) testing, VEP testing, as well as peripapillary retinal nerve fiber layer optical coherence tomography imaging studies with post-acquisition CORDA applied. Statistical analysis was performed using means and ranges, ANOVA, post-hoc comparisons using Turkey's adjustment, Fisher's Exact test, area under the curve, and Spearman correlation coefficients. RESULTS: Parameters from VEP and CORDA correlated significantly with VF mean deviation (MD) (P<0.05). In distinguishing glaucomatous eyes from controls, VEP demonstrated area under the curve (AUC) values of 0.64-0.75 for amplitude and 0.67-0.81 for latency. The CORDA HR1 parameter was highly discriminative for glaucomatous eyes vs controls (AUC=0.94). CONCLUSION: Significant correlations are found between MD and parameters of short-duration transient VEP and CORDA, diagnostic modalities which warrant further consideration in identifying glaucoma characteristics.

COAGULASE-NEGATIVE STAPHYLOCOCCUS-INDUCED FROSTED BRANCH ANGIITIS AFTER INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR INJECTION.

PURPOSE: To describe a case of frosted branch angiitis after intravitreal ranibizumab injection. METHODS: Retrospective chart review. RESULTS: A patient with a history of neovascular age-related macular degeneration underwent intravitreal ranibizumab injection and subsequently developed coagulase-negative Staphylococcus endophthalmitis with findings of frosted branch angiitis. CONCLUSION: Endophthalmitis presenting as frosted branch angiitis is a rare complication after intravitreal anti-vascular endothelial growth factor injection. Early recognition is critical to optimize outcomes. To our knowledge, this is the second reported case of frosted branch angiitis as a presentation of endophthalmitis with coagulase-negative Staphylococcus.

Content-based histopathology image retrieval using CometCloud.

BACKGROUND: The development of digital imaging technology is creating extraordinary levels of accuracy that provide support for improved reliability in different aspects of the image analysis, such as content-based image retrieval, image segmentation, and classification. This has dramatically increased the volume and rate at which data are generated. Together these facts make querying and sharing non-trivial and render centralized solutions unfeasible. Moreover, in many cases this data is often distributed and must be shared across multiple institutions requiring decentralized solutions. In this context, a new generation of data/information driven applications must be developed to take advantage of the national advanced cyber-infrastructure (ACI) which enable investigators to seamlessly and securely interact with information/data which is distributed across geographically disparate resources. This paper presents the development and evaluation of a novel content-based image retrieval (CBIR) framework. The methods were tested extensively using both peripheral blood smears and renal glomeruli specimens. The datasets and performance were evaluated by two pathologists to determine the concordance. RESULTS: The CBIR algorithms that were developed can reliably retrieve the candidate image patches exhibiting intensity and morphological characteristics that are most similar to a given query image. The methods described in this paper are able to reliably discriminate among subtle staining differences and spatial pattern distributions. By integrating a newly developed dual-similarity relevance feedback module into the CBIR framework, the CBIR results were improved substantially. By aggregating the computational power of high performance computing (HPC) and cloud resources, we demonstrated that the method can be successfully executed in minutes on the Cloud compared to weeks using standard computers. CONCLUSIONS: In this paper, we present a set of newly developed CBIR algorithms and validate them using two different pathology applications, which are regularly evaluated in the practice of pathology. Comparative experimental results demonstrate excellent performance throughout the course of a set of systematic studies. Additionally, we present and evaluate a framework to enable the execution of these algorithms across distributed resources. We show how parallel searching of content-wise similar images in the dataset significantly reduces the overall computational time to ensure the practical utility of the proposed CBIR algorithms.

Patterns of failure in colorectal patients with liver metastases after yttrium-90 radioembolization.

OBJECTIVES: To assess patterns of failure and factors affecting recurrence patterns in colorectal cancer patients treated with Y-labeled resin microspheres for metastatic liver disease. METHODS: We retrospectively reviewed 30 colorectal patients treated with Yttrium-90 radioembolization and assessed follow-up computed tomography scans and positron emission tomography scans to determine disease outcomes. All patients were included in survival analysis. Twenty-six patients with hepatic metastases were assessed for patterns of failure after radioembolization treatment and grouped into 3 patterns: (1) hepatic; (2) extrahepatic; and (3) intrahepatic and extrahepatic. RESULTS: The median overall survival and progression-free survival for all colorectal patients treated with radioembolization was 9.4 and 3.2 months, respectively. Overall survival and progression-free survival were not significantly different between patterns of failure (P=0.43 and 0.26, respectively). Logistic regression analysis demonstrated a trend toward the predictive value of tumor volume in determining patterns of failure. Smaller tumor volumes had a higher predictive probability for extrahepatic failure than larger tumor volumes (P=0.057). Tumor volumes <300 mL were predictive for extrahepatic failure patterns compared with hepatic recurrence (P=0.046). CONCLUSIONS: Radioembolization with Y-labeled resin microspheres continues to be an effective salvage treatment for colorectal liver metastases. Analysis of patterns of radiologic failure demonstrated that patients treated by radioembolization develop a greater proportion of extrahepatic failure. Tumor volumes >300 mL were predictive for hepatic recurrence, suggesting that increased dosing or retreatment of these lesions may lead to improved hepatic control of disease and better patient outcomes.

Pilot study of angiogenic response to yttrium-90 radioembolization with resin microspheres.

PURPOSE: To investigate the impact of radioembolization with yttrium-90 resin microspheres on the regulation of angiogenesis through observation of serial changes in a spectrum of angiogenic markers and other cytokines after therapy. MATERIALS AND METHODS: This prospective pilot study enrolled 22 patients with liver-dominant disease deriving from biopsy-proven hepatocellular carcinoma (HCC) (n = 7) or metastatic colorectal carcinoma (mCRC) (n = 15). Circulating angiogenic markers were measured from serum samples drawn at baseline and at time points after therapy ranging from 6 hours to 120 days. Using multiplex enzyme-linked immunosorbent assay, several classic angiogenesis factors (vascular endothelial growth factor [VEGF], angiopoietin-2 [Ang-2], basic fibroblast growth factor [bFGF], platelet-derived growth factor subunit BB [PDGF-BB], thrombospondin-1 [Tsp-1]) and nonclassic factors (follistatin, leptin, interleukin [IL]-8) were evaluated. RESULTS: Increases in cytokine levels ≥ 50% over baseline were observed in more than half of all patients studied for many cytokines, including classic angiogenic factors such as VEGF, Ang-2, and Tsp-1 as well as nonclassic factors IL-8 and follistatin (range, 36%-82% for all cytokines). Baseline cytokine levels in patients with overall survival (OS) < 6 months differed significantly from patients with longer survival for Ang-2 (P = .033) and IL-8 (P = .041). Patients with OS ≤ 6 months exhibited transient increases in VEGF and PDGF-BB after therapy compared with patients with OS > 6 months. CONCLUSIONS: Radioembolization is associated with early transient increases in many angiogenic cytokines. In this small sample size, some of these changes were associated with worse OS. This research has important implications for future studies of radioembolization with antiangiogenic therapy performed during and after the procedure.

Evaluation of hepatic tumor response to yttrium-90 radioembolization therapy using texture signatures generated from contrast-enhanced CT images.

RATIONALE AND OBJECTIVES: The aim of this study was to explore the use of texture features generated from liver computed tomographic (CT) datasets as potential image-based indicators of patient response to radioembolization (RE) with yttrium-90 ((90)Y) resin microspheres, an emerging locoregional therapy for advanced-stage liver cancer. MATERIALS AND METHODS: Overall posttherapy survival and percent change in serologic tumor marker at 3 months posttherapy represent the primary clinical outcomes in this study. Thirty advanced-stage liver cancer cases (primary and metastatic) treated with RE over a 3-year period were included. Texture signatures for tumor regions, which were delineated to reveal boundaries with normal regions, were computed from pretreatment contrast-enhanced liver CT studies and evaluated for their ability to classify patient serologic response and survival. RESULTS: A series of systematic leave-one-out cross-validation studies using soft-margin support vector machine (SVM) classifiers showed hepatic tumor texton and local binary pattern (LBP) signatures both achieve high accuracy (96%) in discriminating subjects in terms of their serologic response. The image-based indicators were also accurate in classifying subjects by survival status (80% and 93% accuracy for texton and LBP signatures, respectively). CONCLUSIONS: Hepatic texture signatures generated from tumor regions on pretreatment triphasic CT studies were highly accurate in differentiating among subjects in terms of serologic response and survival. These image-based computational markers show promise as potential predictive tools in candidate evaluation for locoregional therapy such as RE.

Association of flat feet with knee pain and cartilage damage in older adults.

OBJECTIVE: To assess the cross-sectional relation of planus foot morphology to ipsilateral knee pain and compartment-specific knee cartilage damage in older adults. METHODS: In the Framingham Studies, we adapted the Staheli Arch Index (SAI) to quantify standing foot morphology from pedobarographic recordings. We inquired about knee pain and read 1.5 T magnetic resonance image (MRI) scans using the Whole-Organ MRI Score. Logistic regression compared the odds of knee pain among the most planus feet to the odds among all other feet, and estimated odds within categories of increasing SAI. Similar methods estimated the odds of cartilage damage in each knee compartment. Generalized estimating equations adjusted for age, sex, body mass index, and nonindependent observations. RESULTS: Among 1,903 participants (56% women, mean ± SD age 65 ± 9 years), 22% of knees were painful most days. Cartilage damage was identified in 45% of medial tibiofemoral (TF), 27% of lateral TF, 58% of medial patellofemoral (PF), and 42% of lateral PF compartments. Compared with other feet, the most planus feet had 1.3 times (95% confidence interval [95% CI] 1.1-1.6) the odds of knee pain (P = 0.009), and 1.4 times (95% CI 1.1-1.8) the odds of medial TF cartilage damage (P = 0.002). Odds of pain (P for linear trend = 0.05) and medial TF cartilage damage (P for linear trend = 0.001) increased linearly across categories of increasing SAI. There was no association between foot morphology and cartilage damage in other knee compartments. CONCLUSION: Planus foot morphology is associated with frequent knee pain and medial TF cartilage damage in older adults.

Lipid raft components cholesterol and sphingomyelin increase H+/OH- permeability of phosphatidylcholine membranes.

H+/OH- permeation through lipid bilayers occurs at anomalously high rates and the determinants of proton flux through membranes are poorly understood. Since all life depends on proton gradients, it is important to develop a greater understanding of proton leak phenomena. We have used stopped-flow fluorimetry to probe the influence of two lipid raft components, chol (cholesterol) and SM (sphingomyelin), on H+/OH- and water permeability. Increasing the concentrations of both lipids in POPC (palmitoyl-2-oleoyl phosphatidylcholine) liposomes decreased water permeability in a concentration-dependent manner, an effect that correlated with increased lipid order. Surprisingly, proton flux was increased by increasing the concentration of chol and SM. The chol effect was complex with molar concentrations of 17.9, 33 and 45.7% giving 2.8-fold (P<0.01), 2.2-fold (P<0.001) and 5.1-fold (P<0.001) increases in H+/OH- permeability from a baseline of 2.4x10(-2) cm/s. SM at 10 mole% effected a 2.8-fold increase (P<0.01), whereas 20 and 30 mole% enhanced permeability by 3.6-fold (P<0.05) and 4.1-fold respectively (P<0.05). Supplementing membranes containing chol with SM did not enhance H+/OH- permeability. Of interest was the finding that chol addition to soya-bean lipids decreased H+/OH- permeability, consistent with an earlier report [Ira and Krishnamoorthy (2001) J. Phys. Chem. B 105, 1484-1488]. We speculate that the presence of proton carriers in crude lipid extracts might contribute to this result. We conclude that (i) chol and SM specifically and independently increase rates of proton permeation in POPC bilayers, (ii) domains enriched in these lipids or domain interfaces may represent regions with high H+/OH- conductivity, (iii) H+/OH- fluxes are not governed by lipid order and (iv) chol can inhibit or promote H+/OH- permeability depending on the total lipid environment. Theories of proton permeation are discussed in the light of these results.

Permeabilities of teleost and elasmobranch gill apical membranes: evidence that lipid bilayers alone do not account for barrier function.

Teleosts and elasmobranchs faced with considerable osmotic challenges living in sea water, use compensatory mechanisms to survive the loss of water (teleosts) and urea (elasmobranchs) across epithelial surfaces. We hypothesized that the gill, with a high surface area for gas exchange must have an apical membrane of exceptionally low permeability to prevent equilibration between seawater and plasma. We isolated apical membrane vesicles from the gills of Pleuronectes americanus (winter flounder) and Squalus acanthias (dogfish shark) and demonstrated approximately sixfold enrichment of the apical marker, ADPase compared to homogenate. We also isolated basolateral membranes from shark gill (enriched 2.3-fold for Na-K-ATPase) and using stopped-flow fluorometry measured membrane permeabilities to water, urea, and NH(3). Apical membrane water permeabilities were similar between species and quite low (7.4 +/- 0.7 x 10(-4) and 6.6 +/- 0.8 x 10(-4) cm/s for shark and flounder, respectively), whereas shark basolateral membranes showed twofold higher water permeability (14 +/- 2 x 10(-4) cm/s). Permeabilities to urea and NH(3) were also low in apical membranes. Because of the much lower apical to basolateral surface area we conclude that the apical membrane represents an effective barrier. However, the values we obtained were not low enough to account for low water loss (teleosts) and urea loss (elasmobranchs) measured in vivo by others. We conclude that there are other mechanisms which permit gill epithelia to serve as effective barriers. This conclusion has implications for the function of other barrier epithelia, such as the gastric mucosa, mammalian bladder, and renal thick ascending limb.