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Abstract We demonstrate a new tomographic imaging device for 2D cross-sectional and 3D volumetric images of the anterior eye segment. The optical system combines optical sectioning with a stereoscopic camera setup to determine the true spatial location of the ocular structures. Moreover, we propose a calibration procedure to estimate the triangulation function that links the stereo camera pixel indices with the eye-referenced 3D spatial coordinates. The proposed instrument will image the entire anterior chamber and contiguous structures, including the corneal limbus, sclera and eyelids. Furthermore, the system can obtain corneal topography. Finally, we studied the repeatability of the instrument and its agreement with a commercial Scheimpflug imaging tomographer in a group of healthy subjects.

Purpose: To assess whether the combination of en face OCT and OCT angiography (OCTA) can capture observable, but subtle, structural changes that precede clinically evident retinal neovascularization (RNV) in eyes with diabetic retinopathy (DR). Design: Retrospective, longitudinal study. Participants: Patients with DR that had at least 2 visits. Methods: We obtained wide-field OCTA scans of 1 eye from each participant and generated en face OCT, en face OCTA, and cross-sectional OCTA. We identified eyes with RNV sprouts, defined as epiretinal hyperreflective materials on en face OCT with flow signals breaching the internal limiting membrane on the cross-sectional OCTA without recognizable RNV on en face OCTA and RNV fronds, defined as recognizable abnormal vascular structures on the en face OCTA. We examined the corresponding location from follow-up or previous visits for the presence or progression of the RNV. Main Outcome Measures: The characteristics and longitudinal observation of early signs of RNV. Results: From 71 eyes, we identified RNV in 20 eyes with the combination of OCT and OCTA, of which 13 (65%) were photographically graded as proliferative DR, 6 (30%) severe nonproliferative DR, and 1 (5%) moderate nonproliferative diabetic retinopathy. From these eyes, we identified 38 RNV sprouts and 26 RNV fronds at the baseline. Thirty-four RNVs (53%) originated from veins, 24 (38%) were from intraretinal microabnormalities, and 6 (9%) were from a nondilated capillary bed. At the final visit, 53 RNV sprouts and 30 RNV fronds were detected. Ten eyes (50%) showed progression, defined as having a new RNV lesion or the development of an RNV frond from an RNV sprout. Four (11%) RNV sprouts developed into RNV fronds with a mean interval of 7.0 months. Nineteen new RNV sprouts developed during the follow-up, whereas no new RNV frond was observed outside an identified RNV sprout. The eyes with progression were of younger age (P = 0.014) and tended to be treatment naive (P = 0.07) compared with eyes without progression. Conclusions: Longitudinal observation demonstrated that a combination of en face OCT and cross-sectional OCTA can identify an earlier form of RNV before it can be recognized on en face OCTA. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Abstract Non-accidental trauma (NAT) is deadly and difficult to predict. Transformer models pretrained on large datasets have recently produced state of the art performance on diverse prediction tasks, but the optimal pretraining strategies for diagnostic predictions are not known. Here we report the development and external validation of Pretrained and Adapted BERT for Longitudinal Outcomes (PABLO), a transformer-based deep learning model with multitask clinical pretraining, to identify patients who will receive a diagnosis of NAT in the next year. We develop a clinical interface to visualize patient trajectories, model predictions, and individual risk factors. In two comprehensive statewide databases, approximately 1% of patients experience NAT within one year of prediction. PABLO predicts NAT events with area under the receiver operating characteristic curve (AUROC) of 0.844 (95% CI 0.838–0.851) in the California test set, and 0.849 (95% CI 0.846–0.851) on external validation in Florida, outperforming comparator models. Multitask pretraining significantly improves model performance. Attribution analysis shows substance use, psychiatric, and injury diagnoses, in the context of age and racial demographics, as influential predictors of NAT. As a clinical decision support system, PABLO can identify high-risk patients and patient-specific risk factors, which can be used to target secondary screening and preventive interventions at the point-of-care.

Peptides are increasingly important resources for biological and therapeutic development, however, their intrinsic susceptibility to proteolytic degradation represents a big hurdle. As a natural agonist for GLP-1R, glucagon-like peptide 1 (GLP-1) is of significant clinical interest for the treatment of type-2 diabetes mellitus, but its in vivo instability and short half-life have largely prevented its therapeutic application. Here, we describe the rational design of a series of α/sulfono-γ-AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists. Certain GLP-1 hybrid analogues exhibited enhanced stability (t1/2 > 14 days) compared to t1/2 (

Abstract Nuclear architecture underlies the transcriptional programs within the cell to establish cell identity. As previously demonstrated, long-range chromatin interactions of the Oct4 distal enhancer (DE) are correlated with active transcription in naïve state embryonic stem cells. Here, we identify and characterize extreme long-range interactions of the Oct4 DE through a novel CRISPR labeling technique we developed and chromosome conformation capture to identify lethal giant larvae 2 (Llgl2) and growth factor receptor-bound protein 7 (Grb7) as putative functional interacting target genes in different chromosomes. We show that the Oct4 DE directly regulates expression of Llgl2 and Grb7 in addition to Oct4. Expression of Llgl2 and Grb7 closely correlates with the pluripotent state, where knock down of either result in loss of pluripotency, and overexpression enhances somatic cell reprogramming. We demonstrated that biologically important interactions of the Oct4 DE can occur at extreme distances that are necessary for the maintenance of the pluripotent state.

The advancement of wireless networking has significantly enhanced beamforming capabilities in Autonomous Unmanned Aerial Systems (AUAS). This paper presents a simple and efficient classical algorithm to route a collection of AUAS or drone swarms extending our previous work on AUAS. The algorithm is based on the sparse factorization of frequency Vandermonde matrices that correspond to each drone, and its entries are determined through spatiotemporal data of drones in the AUAS. The algorithm relies on multibeam beamforming, making it suitable for large-scale AUAS networking in wireless communications. We show a reduction in the arithmetic and time complexities of the algorithm through theoretical and numerical results. Finally, we also present an ML-based AUAS routing algorithm using the classical AUAS algorithm and feed-forward neural networks. We compare the beamformed signals of the ML-based AUAS routing algorithm with the ground truth signals to minimize the error between them. The numerical error results show that the ML-based AUAS routing algorithm enhances the accuracy of the routing. This error, along with the numerical and theoretical results for over 100 drones, provides the basis for the scalability of the proposed ML-based AUAS algorithms for large-scale deployments.

ABSTRACT Ticks in the family Ixodidae are important vectors of zoonoses, including Lyme disease (LD), which is caused by spirochete bacteria from the Borreliella (Borrelia) burgdorferi sensu lato complex. The blacklegged tick (Ixodes scapularis) continues to expand across Canada, creating hot spots of elevated LD risk at the leading edge of its expanding range. Current efforts to understand the risk of pathogen transmission associated with I. scapularis in Canada focus primarily on targeted screens, while natural variation in the tick microbiome remains poorly understood. Using multiomics consisting of 16S metabarcoding and ribosome-depleted, whole-shotgun RNA transcriptome sequencing, we examined the microbial communities associated with adult I. scapularis (n = 32), sampled from four tissue types (whole tick, salivary glands, midgut, and viscera) and three geographical locations within a LD hot spot near Kingston, Ontario, Canada. The communities consisted of both endosymbiotic and known or potentially pathogenic microbes, including RNA viruses, bacteria, and a Babesia sp. intracellular parasite. We show that β-diversity is significantly higher between the bacterial communities of individual tick salivary glands and midguts than that of whole ticks. Linear discriminant analysis effect size (LEfSe) determined that the three potentially pathogenic bacteria detected by V4 16S rRNA sequencing also differed among dissected tissues only, including a Borrelia strain from the B. burgdorferi sensu lato complex, Borrelia miyamotoi, and Anaplasma phagocytophilum. Importantly, we find coinfection of I. scapularis by multiple microbes, in contrast to diagnostic protocols for LD, which typically focus on infection from a single pathogen of interest (B. burgdorferi sensu stricto). IMPORTANCE As a vector of human health concern, blacklegged ticks (Ixodes scapularis) transmit pathogens that cause tick-borne diseases (TBDs), including Lyme disease (LD). Several hot spots of elevated LD risk have emerged across Canada as I. scapularis expands its range. Focusing on a hot spot in southeastern Ontario, we used high-throughput sequencing to characterize the microbiome of whole ticks and dissected salivary glands and midguts. Compared with whole ticks, salivary glands and midguts were more diverse and associated with distinct bacterial communities that are less dominated by Rickettsia endosymbiont bacteria and are enriched for pathogenic bacteria, including a B. burgdorferi sensu lato-associated Borrelia sp., Borrelia miyamotoi, and Anaplasma phagocytophilum. We also found evidence of coinfection of I. scapularis by multiple pathogens. Overall, our study highlights the challenges and opportunities associated with the surveillance of the microbiome of I. scapularis for pathogen detection using metabarcoding and metatranscriptome approaches.

Abstract Background Approximately 3.8% of adults worldwide have used cannabis in the past year. Understanding how cannabis use is associated with other health conditions is crucial for healthcare providers seeking to understand the needs of their patients, and for health policymakers. This paper analyzes the relationship between documented cannabis use disorders (CUD), cannabis use (CU) and other health diagnoses among primary care patients during a time when medical use of marijuana was permitted by state law in California, United States of America. Methods The study utilized primary care electronic health record (EHR) data from an academic health system, using a case–control design to compare diagnoses among individuals with CUD/CU to those of matched controls, and those of individuals with CUD diagnoses with individuals who had CU otherwise documented. Associations of documented CU and CUD with general medical conditions and health conditions associated with cannabis use (both medical and behavioral) were analyzed using conditional logistic regression. Results Of 1,047,463 patients with ambulatory encounters from 2013–2017, 729 (0.06%) had CUD diagnoses and 3,731 (0.36%) had CU documented in their EHR. Patients with documented CUD and CU patients had significantly (p

Purpose: Timely diagnosis of eye diseases is paramount to obtaining the best treatment outcomes. OCT and OCT angiography (OCTA) have several advantages that lend themselves to early detection of ocular pathology; furthermore, the techniques produce large, feature-rich data volumes. However, the full clinical potential of both OCT and OCTA is stymied when complex data acquired using the techniques must be manually processed. Here, we propose an automated diagnostic framework based on structural OCT and OCTA data volumes that could substantially support the clinical application of these technologies. Design: Cross sectional study. Participants: Five hundred twenty-six OCT and OCTA volumes were scanned from the eyes of 91 healthy participants, 161 patients with diabetic retinopathy (DR), 95 patients with age-related macular degeneration (AMD), and 108 patients with glaucoma. Methods: The diagnosis framework was constructed based on semisequential 3-dimensional (3D) convolutional neural networks. The trained framework classifies combined structural OCT and OCTA scans as normal, DR, AMD, or glaucoma. Fivefold cross-validation was performed, with 60% of the data reserved for training, 20% for validation, and 20% for testing. The training, validation, and test data sets were independent, with no shared patients. For scans diagnosed as DR, AMD, or glaucoma, 3D class activation maps were generated to highlight subregions that were considered important by the framework for automated diagnosis. Main Outcome Measures: The area under the curve (AUC) of the receiver operating characteristic curve and quadratic-weighted kappa were used to quantify the diagnostic performance of the framework. Results: For the diagnosis of DR, the framework achieved an AUC of 0.95 ± 0.01. For the diagnosis of AMD, the framework achieved an AUC of 0.98 ± 0.01. For the diagnosis of glaucoma, the framework achieved an AUC of 0.91 ± 0.02. Conclusions: Deep learning frameworks can provide reliable, sensitive, interpretable, and fully automated diagnosis of eye diseases. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.

Abstract This study reports the development of prototype swept-source optical coherence tomography (SS-OCT) technology for imaging the anterior eye. Advances in vertical-cavity surface-emitting laser (VCSEL) light sources, signal processing, optics and mechanical designs, enable a unique combination of high speed, long range, and deep penetration that addresses the challenges of anterior eye imaging. We demonstrate SS-OCT with a 325 kHz A-scan rate, 12.2 µm axial resolution (in air), and 15.5 mm depth range (in air) at 1310 nm wavelength. The ultrahigh 325 kHz A-scan rate not only facilitates biometry measurements by minimizing acquisition time and thus reducing motion, but also enables volumetric OCT for comprehensive structural analysis and OCT angiography (OCTA) for visualizing vasculature. The 15.5 mm (~ 11.6 mm in tissue) depth range spans all optical surfaces from the anterior cornea to the posterior lens capsule. The 1310 nm wavelength range enables structural OCT and OCTA deep in the sclera and through the iris. Achieving high speed and long range requires linearizing the VCSEL wavenumber sweep to efficiently utilize analog-to-digital conversion bandwidth. Dual channel recording of the OCT and calibration interferometer fringe signals, as well as sweep to sweep wavenumber compensation, is used to achieve invariant 12.2 µm (~ 9.1 µm in tissue) axial resolution and optimum point spread function throughout the depth range. Dynamic focusing using a tunable liquid lens extends the effective depth of field while preserving the lateral resolution. Improved optical and mechanical design, including parallax “split view” iris cameras and stable, ergonomic patient interface, facilitates accurate instrument positioning, reduces patient motion, and leads to improved imaging data yield and measurement accuracy. We present structural and angiographic OCT images of the anterior eye, demonstrating the unique imaging capabilities using representative scanning protocols which may be relevant to future research and clinical applications.

Purpose: To report the distinct pattern of retinal perfusion loss captured on optical coherence tomographic angiography (OCTA) in a case of compressive optic neuropathy associated with pituitary adenoma. Observations: A 51-year-old male had bitemporal hemianopia caused by a pituitary adenoma that compressed the optic chiasm. OCTA scans in both eyes showed peripapillary nerve fiber layer plexus defects in the nasal hemispheres and papillomacular corridors. On macular scans, the ganglion cell layer plexus showed papillomacular defects. The perfusion defects corresponded with thinning on structural OCT measurement and loss of sensitivity on visual field tests. Conclusions and importance: Chiasm compression produces a characteristic pattern of perfusion loss that can be recognized OCTA. This knowledge may be useful in the diagnosis and classification of optic neuropathies.

Abstract We investigated the time and location of retinal perfusion recovery after surgical intraocular pressure (IOP) lowering in glaucoma by using optical coherent tomography angiography (OCTA). Seventeen patients were analyzed. The 4.5 × 4.5-mm OCTA scans centered on the disc were performed preoperatively and postoperatively at 6 weeks, 3 months, and 6 months. The peripapillary retinal nerve fiber layer (NFL) thickness, NFL plexus capillary density (NFLP-CD) and visual field (VF) were measured overall and in 8 corresponding sectors. The low-perfusion area (LPA) was used to assess the cumulative area where local NFLP-CD was significantly below normal. At 6 months, the average IOP decreased 5.3 mmHg (P = 0.004), LPA decreased by 15% (P = 0.005), and NFLP-CD improved by 12% (P

Abstract Background Physical activity is a cornerstone for treatment of women with polycystic ovary syndrome (PCOS), but there are limited data on their exercise behaviors. A previous study identified PCOS patients of non-White ethnicity to be at higher risk for inadequate physical activity. Further data is needed to identify groups that would benefit from additional counseling in achieving adequate physical activity (APA). Therefore, this study examined correlates of APA within a multiethnic PCOS patient population. Methods Cross-sectional assessment of exercise behaviors within a multiethnic PCOS patient population was performed using the International Physical Activity Questionnaire (IPAQ). Kruskal–Wallis test was used to compare metabolic equivalents from physical activity among racial/ethnic groups. APA was defined as at least 150 min of moderate-intensity, or 75 min of vigorous-intensity, or an equivalent combination of moderate- and vigorous-intensity activity per week. Logistic regression analyses were performed to identify correlates of APA. Results Four hundred and sixty-five women of various racial/ethnic backgrounds were included in analysis: 62% (n = 287) self-identified as White, 15% (n = 71) as Hispanic, 11% (n = 52) as East/Southeast Asian, 7% (n = 32) as South Asian, and 5% (n = 23) as Black/African American. Significant differences were observed in metabolic equivalents (METs) from vigorous-intensity and total (moderate plus vigorous-intensity) exercise across racial/ethnic groups (p

Abstract The emergence and rapid global spread of SARS-CoV-2 demonstrates the importance of infectious disease surveillance, particularly during the early stages. Viral genomes can provide key insights into transmission chains and pathogenicity. Nasopharyngeal swabs were obtained from thirty-two of the first SARS-CoV-2 positive cases (March 18–30) in Kingston Ontario, Canada. Viral genomes were sequenced using Ion Torrent (n = 24) and MinION (n = 27) sequencing platforms. SARS-CoV-2 genomes carried forty-six polymorphic sites including two missense and three synonymous variants in the spike protein gene. The D614G point mutation was the predominate viral strain in our cohort (92.6%). A heterozygous variant (C9994A) was detected by both sequencing platforms but filtered by the ARTIC network bioinformatic pipeline suggesting that heterozygous variants may be underreported in the SARS-CoV-2 literature. Phylogenetic analysis with 87,738 genomes in the GISAID database identified global origins and transmission events including multiple, international introductions as well as community spread. Reported travel history validated viral introduction and transmission inferred by phylogenetic analysis. Molecular epidemiology and evolutionary phylogenetics may complement contact tracing and help reconstruct transmission chains of emerging diseases. Earlier detection and screening in this way could improve the effectiveness of regional public health interventions to limit future pandemics.

Optical coherence tomography (OCT) has changed the standard of care for diagnosis and management of macular diseases in adults. Current commercially available OCT systems, including handheld OCT for pediatric use, have a relatively narrow field of view (FOV), which has limited the potential application of OCT to retinal diseases with primarily peripheral pathology, including many of the most common pediatric retinal conditions. More broadly, diagnosis of all types of retinal detachment (exudative, tractional, and rhegmatogenous) may be improved with OCT-based assessment of retinal breaks, identification of proliferative vitreoretinopathy (PVR) membranes, and the pattern of subretinal fluid. Intraocular tumors both benign and malignant often occur outside of the central macula and may be associated with exudation, subretinal and intraretinal fluid, and vitreoretinal traction. The development of wider field OCT systems thus has the potential to improve the diagnosis and management of myriad diseases in both adult and pediatric retina. In this paper, we present a case series of pediatric patients with complex vitreoretinal pathology undergoing examinations under anesthesia (EUA) using a portable widefield (WF) swept-source (SS)-OCT device.

Purpose: To propose a deep-learning−based method to differentiate arteries from veins in montaged widefield OCT angiography (OCTA). Design: Cross-sectional study. Participants: A total of 232 participants, including 109 participants with diabetic retinopathy (DR), 64 participants with branch retinal vein occlusion (BRVO), 27 participants with diabetes but without DR, and 32 healthy participants. Methods: We propose a convolutional neural network (CAVnet) to classify retinal blood vessels on montaged widefield OCTA en face images as arteries and veins. A total of 240 retinal angiograms from 88 eyes were used to train CAVnet, and 302 retinal angiograms from 144 eyes were used for testing. This method takes the OCTA images as input and outputs the segmentation results with arteries and veins down to the level of precapillary arterioles and postcapillary venules. The network also identifies their intersections. We evaluated the agreement (in pixels) between segmentation results and the manually graded ground truth using sensitivity, specificity, F1-score, and Intersection over Union (IoU). Measurements of arterial and venous caliber or tortuosity are made on our algorithm’s output of healthy and diseased eyes. Main Outcome Measures: Classification of arteries and veins, arterial and venous caliber, and arterial and venous tortuosity. Results: For classification and identification of arteries, the algorithm achieved average sensitivity of 95.3%, specificity of 99.6%, F1 score of 94.2%, and IoU of 89.3%. For veins, the algorithm achieved average sensitivity of 94.4%, specificity of 99.7%, F1 score of 94.1%, and IoU of 89.2%. We also achieved an average sensitivity of 76.3% in identifying intersection points. The results show CAVnet has high accuracy on differentiating arteries and veins in DR and BRVO cases. These classification results are robust across 2 instruments and multiple scan volume sizes. Outputs of CAVnet were used to measure arterial and venous caliber or tortuosity, and pixel-wise caliber and tortuosity maps were generated. Differences between healthy and diseased eyes were demonstrated, indicating potential clinical utility. Conclusions: The CAVnet can classify arteries and veins and their branches with high accuracy and is potentially useful in the analysis of vessel type-specific features on diseases such as branch retinal artery occlusion and BRVO.

Purpose: To determine whether handheld widefield OCT can be used to document retinopathy of prematurity (ROP) stage while using scleral depression to improve peripheral views. Design: Prospective, observational study. Participants: Consecutive neonates admitted to the neonatal intensive care unit in a single academic medical center who also met criteria for ROP screening and whose parents or guardians consented for them to undergo research imaging. Methods: Scleral depression was combined with widefield OCT using an investigational 400-kHz, 55° field of view, handheld OCT during routine ROP screening from October 28, 2020, through March 3, 2021. Main Outcome Measures: Acquisition of en face and B-scan imaging of the peripheral retina to assess early vitreoretinal pathologic features objectively, including the demarcation between vascularized and anterior avascular retina, the presence of early ridge formation, and small neovascular tufts. Results: Various stages of ROP were detected using a rapid-acquisition OCT system. In 1 neonate, serial OCT imaging over a 5-week period demonstrated accumulation of neovascular tufts with progression to stage 3 ROP with extraretinal fibrovascular proliferation along the ridge. Videography of this technique is included in this report for instructional purposes. Conclusions: Serial examinations using widefield OCT and scleral depression are feasible and may improve detection and documentation of ROP disease progression. Earlier detection of ROP-related proliferation may prevent vitreoretinal traction, retinal detachment, and blindness.

This study identifies women college engineering students' perception of online Science, technology, engineering, and mathematics (STEM) learning and factors that influence their learning motivation during the COVID-19 period. By conducting interviews with ten women engineering students and applying attention, relevance, confidence, and satisfaction (ARCS) model, this study aims to answer two questions: (1) How did women college engineering students perceive their experience with online STEM learning during the pandemic? (2) What category/categories based on ARCS motivational design model primarily account for women college engineering students' learning motivation with online STEM learning during the pandemic? The results show that the online learning format influenced women college engineering students' perception regarding their academic plans, learning styles, learning environments, peer learning, and learning satisfaction. The most influential categories from ARCS model were 'confidence' and 'attention'. Findings suggest that the online STEM learning format influenced women college engineering students' learning motivation. The online format led to (1) low expectations for attention category when analyzed using ARCS model, (2) anticipation of more self-control, and (3) a desire for more peer interactions in their online STEM learning. As students would have new expectations for the role of online learning due to their experience during the pandemic, assessing women students' emerging motivational needs for STEM online learning is critical in developing a more inclusive instructional system design process in the future.

BackgroundDifferentiated service delivery (DSD) models are recommended for stable people living with HIV on antiretroviral therapy (ART) but there are few rigorous evaluations of patient outcomes.MethodsAdherence clubs (ACs) are a form of DSD run by community health workers at community venues with 2-4 monthly ART refills and annual nurse assessments). Clinic-based care involves 2-monthly ART refills and 4-monthly nurse/doctor assessments. We compared virologic outcomes in stable adults randomised to ACs at four months post-ART initiation to those randomised to primary health care (PHC) ART clinics through 12 months on ART in Cape Town, South Africa (NCT03199027). We hypothesised that adults randomised to ACs would be more likely to be virally suppressed at 12 months post-ART initiation, versus adults randomised to continued PHC care. We enrolled consecutive adults on ART for 3-5 months who met local DSD ['adherence clubs' (AC)] eligibility (clinically stable, VLResultsBetween January 2017 and April 2018, 220 adults were randomised (mean age 35 years; 67% female; median ART duration 18 weeks); 85% and 94% of participants randomised to ACs and PHCs attended their first service visit on schedule respectively. By 12 months on ART, 91% and 93% randomised to ACs and PHCs had a VLConclusionStable adults referred to DSDs at 4 months post-ART initiation had comparable virologic outcomes at 12 months on ART versus PHC clinics, with no evidence of superiority. Further research on long-term outcomes is required.

Recent advances in portable optical coherence tomography (OCT) and OCT angiography (OCTA) have resulted in wider fields of view (FOV) and shorter capture times, further expanding the potential clinical role of OCT technology in the diagnosis and management of retinopathy of prematurity (ROP). Using a prototype, handheld OCT device, retinal imaging was obtained in non-sedated infants in the neonatal intensive care unit (NICU) as well as sedated infants in the operating room of Oregon Health & Science University (OHSU) Hospital. In this observational study, we provide an overview of potential advantages of OCT-based disease assessment in ROP. We observed that next-generation OCT imaging (a) may be sufficient for objective diagnosis and zone/stage/plus disease categorization, (b) allows for minimally-invasive longitudinal monitoring of disease progression and post-treatment course, (c) provides three-dimensional mapping of the vitreoretinal interface, and (d) with OCTA, enables dye-free visualization of normal and pathologic vascular development.

Climate finance institutions have been tasked with effectively and efficiently allocating funds to spur the transition to low-carbon, climate-resilient economies. The Green Climate Fund (GCF) is expected to assist the most vulnerable adapt to and mitigate climate change because of its mandate to contribute to a paradigm shift. To understand if the GCF’s portfolio is on track to achieve this aim, we review the project documents of GCF investments through March 2020 (N = 125 projects). We examine attributes of these investments by applying a framework for potential transformational change, comprised of eight components. We use bivariate statistics and multivariate cluster analysis to examine the GCF’s project portfolio of mitigation, cross-cutting and adaptation projects. Bivariate tests find that adaptation projects show the greater intention to integrate policy change into national planning processes and that both adaptation and cross-cutting projects require a greater need for and expectation of behaviour change. Results from cluster analysis shows how adaptation projects dominate clusters with high and medium potential for transformational change (with 47% and 78% of projects, respectively). However, even the high potential cluster only displays the highest average scores for four of the eight components in our framework of transformational change. These findings present learning opportunities for the GCF’s future project selection. The GCF should leverage its current resources carefully to attain transformational impacts especially within adaptation where the Fund has a greater market share compared to mitigation projects.

ABSTRACT PLG0206 is an engineered antimicrobial peptide that has completed phase 1 clinical studies. A prospective study was completed on explanted implants from chronic periprosthetic joint infections (n = 17). At a concentration of 1 mg/mL for 15 min, there was a mean 4-log10 reduction (range, 1 to 7) in the bacterial CFU identified from the implants. IMPORTANCE Chronically infected prosthetics of the knee were exposed to PLG0206, an engineered antimicrobial peptide, at a concentration of 1 mg/mL for 15 min. A mean 4-log10 reduction (range, 1 to 7) in the number of bacteria occurred, which may translate to improved clinical outcomes for persons with prosthetic joint infection of the knee.

Purpose: To examine the efficacy of a deep learning-based algorithm to quantify the nonperfusion area (NPA) on montaged widefield OCT angiography (OCTA) for assessment of diabetic retinopathy (DR) severity. Design: Cross-sectional study. Participants: One hundred thirty-seven participants with a full range of DR severity and 26 healthy participants. Methods: A deep learning-based algorithm was developed for detecting and quantifying NPA in the superficial vascular complex on widefield OCTA comprising 3 horizontally montaged 6 × 6-mm OCTA scans from the nasal, macular, and temporal regions. We trained the algorithm on 978 volumetric OCTA scans from all participants using 5-fold cross-validation. The algorithm can distinguish NPA from shadow artifacts. The F1 score evaluated segmentation accuracy. The area under the receiver operating characteristic curve and sensitivity with specificity fixed at 95% quantified network performance to distinguish patients with diabetes from healthy control participants, referable DR from nonreferable DR (nonproliferative DR [NPDR] less than moderate severity), and severe DR (severe NPDR, proliferative DR, or DR with edema) from nonsevere DR (mild to moderate NPDR). Main Outcome Measures: Widefield OCTA NPA, visual acuity (VA), and DR severities. Results: Automatically segmented NPA showed high agreement with the manually delineated ground truth, with a mean ± standard deviation F1 score of 0.78 ± 0.05 in nasal, 0.82 ± 0.07 in macular, and 0.78 ± 0.05 in temporal scans. The extrafoveal avascular area (EAA) in the macular scan showed the best sensitivity at 54% for differentiating those with diabetes from healthy control participants, whereas montaged widefield OCTA scan showed significantly higher sensitivity than macular scans (P < 0.0001, McNemar’s test) for detecting eyes with DR at 66%, referable DR at 63%, and severe DR at 62%. Montaged widefield OCTA showed the highest correlation (Spearman ρ = 0.74; P < 0.0001) between EAA and DR severity. The macular scan showed the strongest negative correlation (Pearson ρ = –0.42; P < 0.0001) between EAA and best-corrected VA. Conclusions: A deep learning-based algorithm for montaged widefield OCTA can detect NPA accurately and can improve the detection of clinically important DR.

Purpose: This study aimed to define how the coronavirus disease of 2019 (COVID-19) pandemic affected the role, timing, and delivery of radiation therapy (RT) in a high-prevalence region at the height of the initial U.S. outbreak. Methods and Materials: We performed a retrospective review of all patients seen at 3 radiation oncology departments within the Rutgers Robert Wood Johnson Barnabas Health system in New Jersey during the initial COVID-19 surge. The primary endpoints were to define and quantify COVID-related, radiation-specific care changes, and identify predictive factors of experiencing COVID-related care changes. Results: A total of 545 patients with cancer were seen during the study period, 99 of whom (18.1%) experienced ≥1 COVID-related care change. RT delays were the most common, accounting for 51.5% of all care changes. Physician-directed delays accounted for 41.2% of RT delays, and patient fears, COVID testing, and access barriers were responsible for 27.5%, 17.6%, and 13.7%, respectively. Patient age (P = .040), intent of treatment (P = .047), and cancer type (P < .001) were significantly associated with experiencing a COVID-related care change, as we found that older, curative intent and patients with rectal cancer were more likely to experience care changes. On multivariate analysis, patient age remained significant when controlling for treatment intent and cancer type. Conclusions: Our study provides a perspective on how care was adapted to protect patients with cancer during a pandemic while maximizing disease control. The positive correlation between age and likelihood of care changes may reflect extra precaution taken with older patients given their vulnerability to severe COVID illness. The lower observed likelihood of COVID-related care changes among patients undergoing palliative RT may reflect either the more urgent needs addressed by palliative RT or simply be logistical, because palliative radiation is often delivered in short courses with less exposure risk. Assessing adaptations others have implemented and monitoring how they affect patient outcomes will be crucial.

Antimicrobial peptides (AMPs) have recently gained attention for their potential to treat diseases related to bacterial and viral infections, as many traditional antimicrobial drugs have reduced efficacy in treating these infections due to the increased prevalence of drug-resistant pathogens. PLG0206, an engineered cationic antibiotic peptide that is 24 residues long, has been designed to address some limitations of other natural AMPs, such as toxicity and limited activity due to pH and ion concentrations. Nonclinical studies have shown that PLG0206 is highly selective for targeting bacterial cells and is not toxic to human blood cells. Antibiofilm experiments demonstrated that PLG0206 is effective at reducing both biotic and abiotic biofilm burdens following direct biofilm contact. PLG0206 has rapid and broad-spectrum activity against both Gram-positive and Gram-negative bacteria that are implicated as etiologic agents in periprosthetic joint infections, including multidrug-resistant ESKAPE pathogens and colistin-resistant isolates. A recent first-in-human study demonstrated that PLG0206 is well tolerated and safe as an intravenous infusion in healthy volunteers. Studies are planned to determine the efficacy of PLG0206 in patients for the treatment of periprosthetic joint infections. This review summarizes the chemistry, pharmacology, and microbiology of PLG0206 and explores its current preclinical, clinical, and regulatory status.

Purpose: The purpose of this study is to analyze early retinal angiomatous proliferation (RAP) utilizing a novel imaging modality, Projection-Resolved Optical Coherence Tomography Angiography (PR-OCTA). Observations: Five months prior to the diagnosis of a RAP lesion, cross-sectional PR-OCTA demonstrated flow in the outer retina contiguous with the deep retinal capillary plexus (DCP) and adjacent to a small pigment epithelial detachment. After development of a clinically visible RAP lesion, cross-sectional PR-OCTA demonstrated the RAP lesion connecting DCP and sub-retinal pigment epithelial neovascularization. Conclusions & importance: This is the first report of PR-OCTA demonstrating abnormal flow in the outer retina prior to the development of a clinically detectable RAP lesion. PR-OCTA may be useful for surveillance and to help further characterize and stage RAP lesions.

Background We hypothesized that multiple cardiovascular comorbidities, incorporated in the CHA2DS2‐VASc score, may be useful in the assessment of ventricular tachyarrhythmias (VTAs) and mortality risk in heart failure (HF) patients. Methods and Results We evaluated the association between the CHA2DS2‐VASc score (dichotomized as high at the upper quartile [≥5] and further assessed as a continuous measure) and the risk of VTA and death among 1804 patients enrolled in MADIT‐CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy). A high CHA2DS2‐VASc score (n=464; 26%) was inversely associated with the risk of any VTA (hazard ratio [HR]: 0.64; P=0.001), fast VTA >200 beats/min (HR; 0.51; P

Purpose: To report a case of age-related hypertrophy of the nonpigmented ciliary epithelium (ARH-NPCE) clinically resembling a ciliary body melanoma and report the optical coherence tomography angiography (OCTA) findings associated with this lesion. Observations: A 51-year-old male was referred for evaluation of a deeply pigmented ciliary body mass with extension through the iris root. Iridocyclectomy was performed due to concern for ciliary body melanoma. Histopathologic analysis was instead consistent with ARH-NPCE, also known as Fuchs' adenoma. Prior to surgery, OCTA images revealed abnormal vasculature in the area of the lesion. Vessels in the peripheral iris approaching the lesion appeared more tortuous and were non-radial as compared with normal iris vessels. The ciliary body mass itself could not be penetrated using an OCTA system operating at 1050 nm. Conclusions and importance: ARH-NPCE may clinically resemble a pigmented ciliary body melanoma. This is the second case describing this clinical scenario, which may be more common than previously thought. Non-invasive imaging with OCTA revealed an abnormal peripheral iris vasculature pattern in the area of the iridociliary mass characterized by disorganized, tortuous, and non-radial vessels. Despite advances in longer wavelength OCTA systems, poor penetration of the ciliary body lesion precluded imaging of the intratumoral vessels in this location.

Optical coherence tomography angiography (OCTA) is a functional extension of OCT that provides information on retinal and choroidal circulations without the need for dye injections. With the recent development of high-speed OCT systems and efficient algorithms, OCTA has become clinically feasible. In this review article, we discuss the technical principles of OCTA, including image processing and artifacts, and its clinical applications in ophthalmology. We summarize recent studies which qualitatively or quantitatively assess disease presentation, progression, and/or response to treatment.

Purpose: To report two cases of pediatric choroidal neovascularization (CNV) and the associated neovascular and retinal findings identified on Optical Coherence Tomography Angiography (OCTA) imaging. Methods: A 14-year-old boy with handheld laser-induced maculopathy-related CNV and a 13-year-old boy with idiopathic CNV were evaluated with visual acuity testing, slit-lamp exam, fundus photography, fluorescein angiography, indocyanine green angiography, spectral domain optical coherence tomography, and OCTA. Results: Macular CNV were identified in both pediatric patients using OCTA imaging. The first case demonstrated a classic pediatric type II CNV with a “tree-like” pattern and a single vessel in-growth site, while the second case demonstrated a type I CNV with a “glomerular” pattern. Conclusion: Distinct choroidal neovascular patterns were visualized in these two cases of pediatric CNV when compared to adult subtypes. OCTA is a noninvasive imaging modality capable of evaluating and characterizing pediatric CNV and their associated vascular patterns.

Owing to their pleiotropic metabolic benefits, glucagon-like peptide-1 receptor (GLP-1R) agonists have been successfully utilized for treating metabolic diseases, such as type 2 diabetes and obesity. As part of our efforts in developing long-acting peptide therapeutics, we have previously reported a peptide engineering strategy that combines peptide side chain stapling with covalent integration of a serum protein-binding motif in a single step. Herein, we have used this strategy to develop a second generation extendin-4 analog rigidified with a symmetrical staple, which exhibits an excellent in vivo efficacy in an animal model of diabetes and obesity. To simplify the scale-up manufacturing of the lead GLP-1R agonist, a semisynthesis protocol was successfully developed, which involves recombinant expression of the linear peptide followed by attachment of a polyethylene glycol (PEG)-fatty acid staple in a subsequent chemical reaction step.

Purpose. To quantify corneal epithelial thickness changes after myopic LASIK by OCT. Methods. Epithelial thickness before and after myopic LASIK were measured by a Fourier-domain OCT system. Average central (within 1 mm diameter) and paracentral epithelial thickness (5~6 mm diameter) before and after LASIK were compared. Correlation between central epithelial thickness change and laser spherical equivalent setting was evaluated. An epithelial smoothing constant was estimated based on a mathematical model published previously. Results. Nineteen eyes from 11 subjects were included in the study. Eyes had myopic LASIK ranging from −1.69 D to −6.75 D spherical equivalent. The average central epithelial thickness was 52.6 ± 4.1 μm before LASIK and 56.2 ± 4.3 μm 3 months after LASIK (p=0.002). The average paracentral epithelial thickness was 51.6 ± 6.6 μm before LASIK and 54.8 ± 4.3 μm 3 months after LASIK (p=0.007). The change in average central epithelial thickness was correlated with laser spherical equivalent (R2 = 0.40, p=0.028). The epithelial smoothing constant was estimated to be 0.46 mm. Conclusions. Corneal epithelial thickens centrally and paracentrally after myopic LASIK. The extent of epithelial remodeling correlated with the amount of LASIK correction and could be predicted by a mathematical model.

Purpose. To evaluate Fourier-domain optical coherence tomography (FD-OCT) as an adjunct to traditional slit lamp examination of donor corneas with suspected Anterior Stromal Opacities. Methods. Seven corneas suspected of having anterior stromal opacities by slit lamp examination were evaluated with FD-OCT. Each cornea was evaluated to confirm the presence of opacity and, if present, the depth of opacity was measured. Results. The opacity depth ranged from 82 μm to 624 μm. The initial slit lamp impressions of five of the seven corneas were confirmed by OCT. In two corneas, the OCT findings were different from the initial slit lamp impressions. Slit lamp examination of the first cornea gave the impression of anterior stromal scarring, but OCT showed that the opacity was limited to the epithelium. Slit lamp examination of the second cornea suggested opacity limited to the epithelium, but OCT identified significant sub-Bowman's scarring. In all cases, the Eye Bank Technicians reported that the location and depth of corneal opacity were more sharply defined by OCT than by slit lamp. Conclusion. The high resolution of OCT makes it easier to determine the location of corneal opacities compared to slit lamp examinations. This enhanced visualization can improve decisions regarding transplant suitability of donor corneas.

Bone is the most common site of breast cancer metastasis and once established, it is frequently incurable. Critical to our ability to prevent and treat bone metastasis is the identification of the key factors mediating its establishment and understanding their biological function. To address this issue we previously carried out an in vivo selection process to isolate murine mammary tumor sublines possessing an enhanced ability to colonize the bone. A comparison of gene expression between parental cells and sublines by genome-wide cDNA microarray analysis revealed several potential mediators of bone metastasis, including the pyrophosphate-generating ectoenzyme Enpp1. By qRT-PCR and Western analysis we found that expression of Enpp1 was elevated in human breast cancer cell lines known to produce bone metastasis in animal models compared to non-metastatic and normal mammary epithelial cell lines. Further, in clinical specimens, levels of Enpp1 were significantly elevated in human primary breast tumors relative to normal mammary epithelium, with highest levels observed in breast-bone metastasis as determined by qRT-PCR and immunohistochemical analysis. To examine the potential role of Enpp1 in the development of bone metastasis, Enpp1 expression was stably increased in the breast cancer cell line MDA-MB-231 and the ability to colonize the bone following intracardiac and direct intratibial injection of athymic nude mice was determined. By both routes of administration, increased expression of Enpp1 enhanced the ability of MDA-MB-231 cells to form tumors in the bone relative to cells expressing vector alone, as determined by digital radiography and histological analysis. Taken together, these data suggest a potential role for Enpp1 in the development of breast cancer bone metastasis.

We used optical coherence tomography (OCT) angiography with a high-speed swept-source OCT system to investigate retinal blood flow changes induced by visual stimulation with a reversing checkerboard pattern. The split-spectrum amplitude-decorrelation angiography (SSADA) algorithm was used to quantify blood flow as measured with parafoveal flow index (PFI), which is proportional to the density of blood vessels and the velocity of blood flow in the parafoveal region of the macula. PFI measurements were taken in 15 second intervals during a 4 minute period consisting of 1 minute of baseline, 2 minutes with an 8 Hz reversing checkerboard pattern stimulation, and 1 minute without stimulation. PFI measurements increased 6.1±4.7% (p = .001) during the first minute of stimulation, with the most significant increase in PFI occurring 30 seconds into stimulation (p

Patients with Type 1 Diabetes (T1D) are particularly vulnerable to development of Diabetic nephropathy (DN) leading to End Stage Renal Disease. Hence a better understanding of the factors affecting kidney disease progression in T1D is urgently needed. In recent years microRNAs have emerged as important post-transcriptional regulators of gene expression in many different health conditions. We hypothesized that urinary microRNA profile of patients will differ in the different stages of diabetic renal disease.We studied urine microRNA profiles with qPCR in 40 T1D with >20 year follow up 10 who never developed renal disease (N) matched against 10 patients who went on to develop overt nephropathy (DN), 10 patients with intermittent microalbuminuria (IMA) matched against 10 patients with persistent (PMA) microalbuminuria. A Bayesian procedure was used to normalize and convert raw signals to expression ratios. We applied formal statistical techniques to translate fold changes to profiles of microRNA targets which were then used to make inferences about biological pathways in the Gene Ontology and REACTOME structured vocabularies. A total of 27 microRNAs were found to be present at significantly different levels in different stages of untreated nephropathy. These microRNAs mapped to overlapping pathways pertaining to growth factor signaling and renal fibrosis known to be targeted in diabetic kidney disease.Urinary microRNA profiles differ across the different stages of diabetic nephropathy. Previous work using experimental, clinical chemistry or biopsy samples has demonstrated differential expression of many of these microRNAs in a variety of chronic renal conditions and diabetes. Combining expression ratios of microRNAs with formal inferences about their predicted mRNA targets and associated biological pathways may yield useful markers for early diagnosis and risk stratification of DN in T1D by inferring the alteration of renal molecular processes.

Cell-substrate adherence is a fundamental property of microorganisms that enables them to exist in biofilms. Our study focuses on adherence of the fungal pathogen Candida albicans to one substrate, silicone, that is relevant to device-associated infection. We conducted a mutant screen with a quantitative flow-cell assay to identify thirty transcription factors that are required for adherence. We then combined nanoString gene expression profiling with functional analysis to elucidate relationships among these transcription factors, with two major goals: to extend our understanding of transcription factors previously known to govern adherence or biofilm formation, and to gain insight into the many transcription factors we identified that were relatively uncharacterized, particularly in the context of adherence or cell surface biogenesis. With regard to the first goal, we have discovered a role for biofilm regulator Bcr1 in adherence, and found that biofilm regulator Ace2 is a major functional target of chromatin remodeling factor Snf5. In addition, Bcr1 and Ace2 share several target genes, pointing to a new connection between them. With regard to the second goal, our findings reveal existence of a large regulatory network that connects eleven adherence regulators, the zinc-response regulator Zap1, and approximately one quarter of the predicted cell surface protein genes in this organism. This limited yet sensitive glimpse of mutant gene expression changes had thus defined one of the broadest cell surface regulatory networks in C. albicans.

Human plasma has long been a rich source for biomarker discovery. It has recently become clear that plasma RNA molecules, such as microRNA, in addition to proteins are common and can serve as biomarkers. Surveying human plasma for microRNA biomarkers using next generation sequencing technology, we observed that a significant fraction of the circulating RNA appear to originate from exogenous species. With careful analysis of sequence error statistics and other controls, we demonstrated that there is a wide range of RNA from many different organisms, including bacteria and fungi as well as from other species. These RNAs may be associated with protein, lipid or other molecules protecting them from RNase activity in plasma. Some of these RNAs are detected in intracellular complexes and may be able to influence cellular activities under in vitro conditions. These findings raise the possibility that plasma RNAs of exogenous origin may serve as signaling molecules mediating for example the human-microbiome interaction and may affect and/or indicate the state of human health.

Purpose. To assess optical coherence tomography (OCT) for guiding design and fit of a prosthetic device for corneal disease. Methods. A prototype time domain OCT scanner was used to image the anterior segment of patients fitted with large diameter (18.5–20 mm) prosthetic devices for corneal disease. OCT images were processed and analyzed to characterize corneal diameter, corneal sagittal height, scleral sagittal height, scleral toricity, and alignment of device. Within-subject variance of OCT-measured parameters was evaluated. OCT-measured parameters were compared with device parameters for each eye fitted. OCT image correspondence with ocular alignment and clinical fit was assessed. Results. Six eyes in 5 patients were studied. OCT measurement of corneal diameter (coefficient of variation, %), cornea sagittal height (%), and scleral sagittal height (%) is highly repeatable within each subject. OCT image-derived measurements reveal strong correlation between corneal sagittal height and device corneal height () and modest correlation between scleral and on-eye device toricity (). Qualitative assessment of a fitted device on OCT montages reveals correspondence with slit lamp images and clinical assessment of fit. Conclusions. OCT imaging of the anterior segment is suitable for custom design and fit of large diameter (18.5–20 mm) prosthetic devices used in the treatment of corneal disease.

New advances in anterior segment optical coherence tomography (OCT) technology development allow visualizing the anterior chamber angle of the eye with high speed and high resolution. Fourier-domain (FD) OCT instruments working at 840 nm can reliably identify fine angle structures such as the Schwalbe's line. This paper demonstrates quantitative angle assessment with 840 nm FD-OCT and provides diagnostic cutoff values for occludable angle detection. This is useful for angle closure glaucoma diagnosis and management. Moreover, 840 nm FD-OCT is a useful tool for postsurgical evaluation in glaucoma patients.

Purpose. This cross-sectional, observational study used Fourier-domain optical coherence tomography (OCT) to examine the position, patency, and the interior entrance site of anterior chamber (AC) aqueous tube shunts. Methods. The OCT, slitlamp biomicroscopy, and gonioscopy findings of 23 eyes of 18 patients with AC shunts were collected and compared. Results. OCT images demonstrated the shunt position and patency in all 23 eyes, and the details of the AC entrance in 16 eyes. The position of the tube varied, with the majority (14/23) on the surface of the iris. The exact position of the AC entrance relative to Schwalbe’s line (SL) could be determined in 9 eyes (posterior to SL in 7 eyes, anterior in 2 eyes). At the AC entrance, growth of fibrous scar tissue was present between the tube and the corneal endothelium in all 16 eyes in which the entrance could be clearly visualized. It’s a new finding that could not be visualized by slitlamp examination or lower resolution OCT. Conclusion. Compared to slitlamp examination, Fourier-domain OCT of AC tube shunts provided more detailed anatomic information regarding the insertion level relative to SL, scar tissue between the tube and the corneal endothelium, and patency of the tube opening.

Pathological bone resorption is a source of significant morbidity in diseases affecting the skeleton such as rheumatoid arthritis, periodontitis, and cancer metastasis to bone. Evidence indicates that elevated levels of inflammatory mediators such as IL-1, IL-6, and TNF-α play a role in this process by promoting the formation of bone-resorbing osteoclasts. Additionally, current studies have identified inflammatory chemokines of the macrophage inflammatory protein (MIP) family as potential mediators of pathological bone resorption, where both MIP-1α and -3α have been shown to enhance osteoclast (OCL) development. In this study we provide evidence that MIP-1δ, whose expression is associated with renal cell carcinoma bone metastasis and rheumatoid arthritis, enhances OCL formation in vitro via a direct effect on OCL precursors. Consistent with this ability, exposure of OCL precursors to MIP-1δ resulted in the activation of PLCγ2 and NF-κB, two signaling pathways known to regulate OCL differentiation. Moreover, MIP-1δ induced expression and nuclear translocation of NFATc1, a master regulator of osteoclastogenesis, which was dependent on activation of both the PLCγ2 and NFκB signaling pathways. Lastly, consistent with in vitro studies, in vivo administration of MIP-1δ significantly increased OCL number and resorption area as determined using a murine calvarial bone resorption model. Taken together, these data highlight the potential of MIP-1δ as a mediator of pathological bone resorption and provide insight into the molecular mechanism through which MIP-1δ enhances osteoclastogenesis.