Glaucomatous Focal Perfusion Loss in the Macula Measured by Optical Coherence Tomographic Angiography.

PURPOSE: To measure low perfusion area (LPA) and focal perfusion loss (FPL) in the macula using OCT angiography (OCTA) for glaucoma. DESIGN: Prospective, cross-sectional "case-control" comparison study. METHODS: A total of 60 patients with primary open-angle glaucoma (POAG) and 37 normal participants were analyzed. AngioVue 6 × 6-mm high-definition (400 × 400 transverse pixels) macular OCTA scans were performed on one eye of each participant. Flow signal was calculated using the split-spectrum amplitude-decorrelation angiography algorithm. En face ganglion cell layer plexus (GCLP) and superficial vascular complex (SVC) images were generated. Using custom software, vessel density (VD) maps were obtained by computing the fraction of area occupied by flow pixels after low-pass filtering by local averaging 41 × 41 pixels. LPA was defined by local VD below 0.5 percentile over a contiguous area above 98.5 percentile of the normal reference population. The FPL was the percent VD loss (relative to normal mean) integrated over the LPA. RESULTS: Among patients with POAG, 30 had perimetric and 30 had pre-perimetric glaucoma. The LPAGCLP-VD was 0.16±0.38 mm2 in normal and 5.78±6.30 mm2 in glaucoma subjects (P<0.001). The FPLGCLP-VD was 0.20%±0.47% in normal and 7.52%±8.84% in glaucoma subjects (P<0.001). The perimetric glaucoma diagnostic accuracy, measured by the area under the receiver operating curve, was 0.993 for LPAGCLP-VD and 0.990 for FPLGCLP-VD. The sensitivities were 96.7% and 93.3% at 95% specificity, respectively. The LPAGCLP-VD and FPLGCLP-VD had good repeatability (0.957 and 0.952 by intraclass correlation coefficient). Diagnostic accuracy was better than GCLP VD (AROC 0.950, sensitivity 83.3%) and OCT ganglion cell complex (GCC) thickness (AROC 0.927, sensitivity 80.0%), GCC focal loss volume (AROC 0.957, sensitivity 80.0%). The LPAGCLP-VD and FPLGCLP-VD correlated well with central VF mean deviations (Pearson's r=-0.716 and -0.705 respectively, both P<0.001). CONCLUSION: Assessment of macular focal perfusion loss using OCTA is useful in evaluating glaucomatous damage.

Non-mydriatic ultra-widefield diffraction-limited retinal imaging.

We demonstrate a new non-mydriatic ultra-widefield optical coherence tomography retinal imaging system, designed with custom optics to improve the imaging field of view, lateral resolution, and patient comfort. The key motivation is to address the challenge with conventional systems that require pupillary dilation, adding time, expense, discomfort, and medical risk to the examination of the retina. Our system provides an ultrawide 100° field of view (beam scanning angle at the scanning pivot point) and maintains a lateral resolution of 20 µm on the center. It also allows a generous working distance of 16 mm, 2-3 times longer than existing ultra-widefield OCT imaging systems. This advanced system was able to avoid iris vignetting artifacts without pharmacological dilation and ensure diffraction-limited ultra-widefield imaging under a generalized eye model. This enables a comprehensive evaluation of retina diseases, especially those affecting the peripheral regions.

Landolt Ring-Shaped Epithelial Keratopathy: A Novel Corneal Disease in a Non-Japanese White Patient.

PURPOSE: Landolt ring-shaped epithelial keratopathy is a corneal disease that has only been reported in 11 Japanese patients in 2014.1 We describe the first case of Landolt ring-shaped epithelial keratopathy in the United States in a patient of European background. METHODS: This is a single case report with longitudinal care. RESULTS: A 35-year-old White patient presented with a history of ocular burning, photophobia, and decreased vision. Corneal examination showed bilateral and asymmetric microcystic lesions in a unique Landolt ring (or the letter "C") shape, distributed randomly in the epithelium. Confocal microscopy revealed cellular ballooning and hyperreflective opacities in the basal layer of the corneal epithelium. The patient has had multiple recurrences of her symptoms year-round, each lasting 4 to 8 days. Topical treatment with cyclosporine, steroids, and lubrication resolved her symptoms but without complete resolution of signs on examination. CONCLUSIONS: Our patient's clinical signs and symptoms are similar to those described previously in 11 Japanese patients. However, unlike those patients, our patient demonstrates symptomatic response to topical treatment, no seasonal association to her condition, and to date, incomplete resolution of her disease after more than 2 years. This case highlights that Landolt ring-shaped epithelial keratopathy, a novel corneal disease of unclear origin, has relevance outside of the Japanese population.

Automatic Population of the Case Report Forms for an International Multifactorial Adaptive Platform Trial Amid the COVID-19 Pandemic.

OBJECTIVES: To automatically populate the case report forms (CRFs) for an international, pragmatic, multifactorial, response-adaptive, Bayesian COVID-19 platform trial. METHODS: The locations of focus included 27 hospitals and 2 large electronic health record (EHR) instances (1 Cerner Millennium and 1 Epic) that are part of the same health system in the United States. This paper describes our efforts to use EHR data to automatically populate four of the trial's forms: baseline, daily, discharge, and response-adaptive randomization. RESULTS: Between April 2020 and May 2022, 417 patients from the UPMC health system were enrolled in the trial. A MySQL-based extract, transform, and load pipeline automatically populated 499 of 526 CRF variables. The populated forms were statistically and manually reviewed and then reported to the trial's international data coordinating center. CONCLUSIONS: We accomplished automatic population of CRFs in a large platform trial and made recommendations for improving this process for future trials.

Panretinal handheld OCT angiography for pediatric retinal imaging.

Comprehensive visualization of retina morphology is essential in the diagnosis and management of retinal diseases in pediatric populations. Conventional imaging techniques often face challenges in effectively capturing the peripheral retina, primarily due to the limitations in current optical designs, which lack the necessary field of view to characterize the far periphery. To address this gap, our study introduces a novel ultra-widefield optical coherence tomography angiography (OCTA) system. This system, specifically tailored for pediatric applications, incorporates an ultrahigh-speed 800 kHz swept-source laser. The system's innovative design achieves a 140° field of view while maintaining excellent optical performance. Over the last 15 months, we have conducted 379 eye examinations on 96 babies using this system. It demonstrates marked efficacy in the diagnosis of retinopathy of prematurity, providing detailed and comprehensive peripheral retinal angiography. The capabilities of the ultra-widefield handheld OCTA system in enhancing the clarity and thoroughness of retina vascularization assessments have significantly improved the precision of diagnoses and the customization of treatment strategies. Our findings underscore the system's potential to advance pediatric ophthalmology and broaden the scope of retinal imaging.

Heparin Dose Intensity and Organ Support-Free Days in Patients Hospitalized for COVID-19.

Background: Clinical trials suggest that therapeutic-dose heparin may prevent critical illness and vascular complications due to COVID-19, but knowledge gaps exist regarding the efficacy of therapeutic heparin including its comparative effect relative to intermediate-dose anticoagulation. Objectives: The authors performed 2 complementary secondary analyses of a completed randomized clinical trial: 1) a prespecified per-protocol analysis; and 2) an exploratory dose-based analysis to compare the effect of therapeutic-dose heparin with low- and intermediate-dose heparin. Methods: Patients who received initial anticoagulation dosed consistently with randomization were included. The primary outcome was organ support-free days (OSFDs), a combination of in-hospital death and days free of organ support through day 21. Results: Among 2,860 participants, 1,761 (92.8%) noncritically ill and 857 (89.1%) critically ill patients were treated per-protocol. Among noncritically ill per-protocol patients, the posterior probability that therapeutic-dose heparin improved OSFDs as compared with usual care was 99.3% (median adjusted OR: 1.36; 95% credible interval [CrI]: 1.07-1.74). Therapeutic heparin had a high posterior probability of efficacy relative to both low- (94.6%; adjusted OR: 1.26; 95% CrI: 0.95-1.64) and intermediate- (99.8%; adjusted OR: 1.80; 95% CrI: 1.22-2.62) dose thromboprophylaxis. Among critically ill per-protocol patients, the posterior probability that therapeutic heparin improved outcomes was low. Conclusions: Among noncritically ill patients hospitalized for COVID-19 who were randomized to and initially received therapeutic-dose anticoagulation, heparin, compared with usual care, was associated with improved OSFDs, a combination of in-hospital death and days free of organ support. Therapeutic heparin appeared superior to both low- and intermediate-dose thromboprophylaxis.

A Hybrid Deep Learning Classification of Perimetric Glaucoma Using Peripapillary Nerve Fiber Layer Reflectance and Other OCT Parameters from Three Anatomy Regions.

Précis: A hybrid deep-learning model combines NFL reflectance and other OCT parameters to improve glaucoma diagnosis. Objective: To investigate if a deep learning model could be used combine nerve fiber layer (NFL) reflectance and other OCT parameters for glaucoma diagnosis. Patients and Methods: This is a prospective observational study where of 106 normal subjects and 164 perimetric glaucoma (PG) patients. Peripapillary NFL reflectance map, NFL thickness map, optic head analysis of disc, and macular ganglion cell complex thickness were obtained using spectral domain OCT. A hybrid deep learning model combined a fully connected network (FCN) and a convolution neural network (CNN) to develop to combine those OCT maps and parameters to distinguish normal and PG eyes. Two deep learning models were compared based on whether the NFL reflectance map was used as part of the input or not. Results: The hybrid deep learning model with reflectance achieved 0.909 sensitivity at 99% specificity and 0.926 at 95%. The overall accuracy was 0.948 with 0.893 sensitivity and 1.000 specificity, and the AROC was 0.979, which is significantly better than the logistic regression models (p < 0.001). The second best model is the hybrid deep learning model w/o reflectance, which also had significantly higher AROC than logistic regression models (p < 0.001). Logistic regression with reflectance model had slightly higher AROC or sensitivity than the other logistic regression model without reflectance (p = 0.024). Conclusions: Hybrid deep learning model significantly improved the diagnostic accuracy, without or without NFL reflectance. Hybrid deep learning model, combining reflectance/NFL thickness/GCC thickness/ONH parameter, may be a practical model for glaucoma screen purposes.

Key residues in the VDAC2-BAK complex can be targeted to modulate apoptosis.

BAK and BAX execute intrinsic apoptosis by permeabilising the mitochondrial outer membrane. Their activity is regulated through interactions with pro-survival BCL-2 family proteins and with non-BCL-2 proteins including the mitochondrial channel protein VDAC2. VDAC2 is important for bringing both BAK and BAX to mitochondria where they execute their apoptotic function. Despite this important function in apoptosis, while interactions with pro-survival family members are well characterised and have culminated in the development of drugs that target these interfaces to induce cancer cell apoptosis, the interaction between BAK and VDAC2 remains largely undefined. Deep scanning mutagenesis coupled with cysteine linkage identified key residues in the interaction between BAK and VDAC2. Obstructive labelling of specific residues in the BH3 domain or hydrophobic groove of BAK disrupted this interaction. Conversely, mutating specific residues in a cytosol-exposed region of VDAC2 stabilised the interaction with BAK and inhibited BAK apoptotic activity. Thus, this VDAC2-BAK interaction site can potentially be targeted to either inhibit BAK-mediated apoptosis in scenarios where excessive apoptosis contributes to disease or to promote BAK-mediated apoptosis for cancer therapy.

Isolated Retinal Neovascularization in Retinopathy of Prematurity: Clinical Associations and Prognostic Implications.

OBJECTIVE: Isolated retinal neovascularization (IRNV) is a common finding in patients with stage 2 and 3 retinopathy of prematurity (ROP). This study aimed to further classify the clinical course and significance of these lesions (previously described as "popcorn" based on clinical appearance) in patients with ROP as visualized with ultrawidefield OCT (UWF-OCT). DESIGN: Single center, retrospective case series. PARTICIPANTS: Images were collected from 136 babies in the Oregon Health and Science University neonatal intensive care unit. METHODS: A prototype UWF-OCT device captured en face scans (>140°), which were reviewed for the presence of IRNV along with standard zone, stage, and plus classification. In a cross-sectional analysis we compared demographics and the clinical course of eyes with and without IRNV. Longitudinally, we compared ROP severity using a clinician-assigned vascular severity score (VSS) and compared the risk of progression among eyes with and without IRNV using multivariable logistic regression. MAIN OUTCOME MEASURES: Differences in clinical demographics and disease progression between patients with and without IRNV. RESULTS: Of the 136 patients, 60 developed stage 2 or worse ROP during their disease course, 22 of whom had IRNV visualized on UWF-OCT (37%). On average, patients with IRNV had lower birth weights (BWs) (660.1 vs. 916.8 g, P = 0.001), gestational age (GA) (24.9 vs. 26.1 weeks, P = 0.01), and were more likely to present with ROP in zone I (63.4% vs. 15.8%, P < 0.001). They were also more likely to progress to stage 3 (68.2% vs. 13.2%, P < 0.001) and receive treatment (54.5% vs. 15.8%, P = 0.002). Eyes with IRNV had a higher peak VSS (5.61 vs. 3.73, P < 0.001) and averaged a higher VSS throughout their disease course. On multivariable logistic regression, IRNV was independently associated with progression to stage 3 (P = 0.02) and requiring treatment (P = 0.03), controlling for GA, BW, and initial zone 1 disease. CONCLUSIONS: In this single center study, we found that IRNV occurs in higher risk babies and was an independent risk factor for ROP progression and treatment. These findings may have implications for OCT-based ROP classifications in the future. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Metformin for sepsis-associated AKI: a protocol for the Randomized Clinical Trial of the Safety and FeasibiLity of Metformin as a Treatment for sepsis-associated AKI (LiMiT AKI).

INTRODUCTION: Acute kidney injury (AKI) is a common complication of sepsis associated with increased risk of death. Preclinical data and observational human studies suggest that activation of AMP-activated protein kinase, an ubiquitous master regulator of energy that can limit mitochondrial injury, with metformin may protect against sepsis-associated AKI (SA-AKI) and mortality. The Randomized Clinical Trial of the Safety and FeasibiLity of Metformin as a Treatment for sepsis-associated AKI (LiMiT AKI) aims to evaluate the safety and feasibility of enteral metformin in patients with sepsis at risk of developing SA-AKI. METHODS AND ANALYSIS: Blind, randomised, placebo-controlled clinical trial in a single-centre, quaternary teaching hospital in the USA. We will enrol adult patients (18 years of age or older) within 48 hours of meeting Sepsis-3 criteria, admitted to intensive care unit, with oral or enteral access. Patients will be randomised 1:1:1 to low-dose metformin (500 mg two times per day), high-dose metformin (1000 mg two times per day) or placebo for 5 days. Primary safety outcome will be the proportion of metformin-associated serious adverse events. Feasibility assessment will be based on acceptability by patients and clinicians, and by enrolment rate. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board. All patients or surrogates will provide written consent prior to enrolment and any study intervention. Metformin is a widely available, inexpensive medication with a long track record for safety, which if effective would be accessible and easy to deploy. We describe the study methods using the Standard Protocol Items for Randomized Trials framework and discuss key design features and methodological decisions. LiMiT AKI will investigate the feasibility and safety of metformin in critically ill patients with sepsis at risk of SA-AKI, in preparation for a future large-scale efficacy study. Main results will be published as soon as available after final analysis. TRIAL REGISTRATION NUMBER: NCT05900284.

Visualizing features with wide-field volumetric OCT angiography.

Optical coherence tomography (OCT) and its extension OCT angiography (OCTA) have become essential clinical imaging modalities due to their ability to provide depth-resolved angiographic and tissue structural information non-invasively and at high resolution. Within a field of view, the anatomic detail available is sufficient to identify several structural and vascular pathologies that are clinically relevant for multiple prevalent blinding diseases, including age-related macular degeneration (AMD), diabetic retinopathy (DR), and vein occlusions. The main limitation in contemporary OCT devices is that this field of view is limited due to a fundamental trade-off between system resolution/sensitivity, sampling density, and imaging window dimensions. Here, we describe a swept-source OCT device that can capture up to a 12 × 23-mm field of view in a single shot and show that it can identify conventional pathologic features such as non-perfusion areas outside of conventional fields of view. We also show that our approach maintains sensitivity sufficient to visualize novel features, including choriocapillaris morphology beneath the macula and macrophage-like cells at the inner limiting membrane, both of which may have implications for disease.

Co-operation of MCL-1 and BCL-XL anti-apoptotic proteins in stromal protection of MM cells from carfilzomib mediated cytotoxicity.

Introduction: BCL-2 family proteins are important for tumour cell survival and drug resistance in multiple myeloma (MM). Although proteasome inhibitors are effective anti-myeloma drugs, some patients are resistant and almost all eventually relapse. We examined the function of BCL-2 family proteins in stromal-mediated resistance to carfilzomib-induced cytotoxicity in MM cells. Methods: Co-cultures employing HS5 stromal cells were used to model the interaction with stroma. MM cells were exposed to CFZ in a 1-hour pulse method. The expression of BCL-2 family proteins was assessed by flow cytometry and WB. Pro-survival proteins: MCL-1, BCL-2 and BCL-XL were inhibited using S63845, ABT-199 and A-1331852 respectively. Changes in BIM binding partners were examined by immunoprecipitation and WB. Results: CFZ induced dose-dependent cell death of MM cells, primarily mediated by apoptosis. Culture of MM cells on HS-5 stromal cells resulted in reduced cytotoxicity to CFZ in a cell contact-dependent manner, upregulated expression of MCL-1 and increased dependency on BCL-XL. Inhibiting BCL-XL or MCL-1 with BH-3 mimetics abrogated stromal-mediated protection only at high doses, which may not be achievable in vivo. However, combining BH-3 mimetics at sub-therapeutic doses, which alone were without effect, significantly enhanced CFZ-mediated cytotoxicity even in the presence of stroma. Furthermore, MCL-1 inhibition led to enhanced binding between BCL-XL and BIM, while blocking BCL-XL increased MCL-1/BIM complex formation, indicating the cooperative role of these proteins. Conclusion: Stromal interactions alter the dependence on BCL-2 family members, providing a rationale for dual inhibition to abrogate the protective effect of stroma and restore sensitivity to CFZ.

Pharmacological expansion of type 2 alveolar epithelial cells promotes regenerative lower airway repair.

Type 2 alveolar epithelial cells (AEC2s) are stem cells in the adult lung that contribute to lower airway repair. Agents that promote the selective expansion of these cells might stimulate regeneration of the compromised alveolar epithelium, an etiology-defining event in several pulmonary diseases. From a high-content imaging screen of the drug repurposing library ReFRAME, we identified that dipeptidyl peptidase 4 (DPP4) inhibitors, widely used type 2 diabetes medications, selectively expand AEC2s and are broadly efficacious in several mouse models of lung damage. Mechanism of action studies revealed that the protease DPP4, in addition to processing incretin hormones, degrades IGF-1 and IL-6, essential regulators of AEC2 expansion whose levels are increased in the luminal compartment of the lung in response to drug treatment. To selectively target DPP4 in the lung with sufficient drug exposure, we developed NZ-97, a locally delivered, lung persistent DPP4 inhibitor that broadly promotes efficacy in mouse lung damage models with minimal peripheral exposure and good tolerability. This work reveals DPP4 as a central regulator of AEC2 expansion and affords a promising therapeutic approach to broadly stimulate regenerative repair in pulmonary disease.

Identification of a hyperinflammatory sepsis phenotype using protein biomarker and clinical data in the ProCESS randomized trial.

Sepsis is a heterogeneous syndrome and phenotypes have been proposed using clinical data. Less is known about the contribution of protein biomarkers to clinical sepsis phenotypes and their importance for treatment effects in randomized trials of resuscitation. The objective is to use both clinical and biomarker data in the Protocol-Based Care for Early Septic Shock (ProCESS) randomized trial to determine sepsis phenotypes and to test for heterogeneity of treatment effect by phenotype comparing usual care to protocolized early, goal-directed therapy(EGDT). In this secondary analysis of a subset of patients with biomarker sampling in the ProCESS trial (n = 543), we identified sepsis phenotypes prior to randomization using latent class analysis of 20 clinical and biomarker variables. Logistic regression was used to test for interaction between phenotype and treatment arm for 60-day inpatient mortality. Among 543 patients with severe sepsis or septic shock in the ProCESS trial, a 2-class model best fit the data (p = 0.01). Phenotype 1 (n = 66, 12%) had increased IL-6, ICAM, and total bilirubin and decreased platelets compared to phenotype 2 (n = 477, 88%, p < 0.01 for all). Phenotype 1 had greater 60-day inpatient mortality compared to Phenotype 2 (41% vs 16%; p < 0.01). Treatment with EGDT was associated with worse 60-day inpatient mortality compared to usual care (58% vs. 23%) in Phenotype 1 only (p-value for interaction = 0.05). The 60-day inpatient mortality was similar comparing EGDT to usual care in Phenotype 2 (16% vs. 17%). We identified 2 sepsis phenotypes using latent class analysis of clinical and protein biomarker data at randomization in the ProCESS trial. Phenotype 1 had increased inflammation, organ dysfunction and worse clinical outcomes compared to phenotype 2. Response to EGDT versus usual care differed by phenotype.

Radon Exposure and Incident Stroke Risk in the Women's Health Initiative.

BACKGROUND AND OBJECTIVES: Little is known about the role of radon in the epidemiology of stroke among women. We therefore examined the association between home radon exposure and risk of stroke among middle-aged and older women in the United States. METHODS: We conducted a prospective cohort study of postmenopausal women aged 50-79 years at baseline (1993-1998) in the Women's Health Initiative. We measured exposures as 2-day, indoor, lowest living-level average radon concentrations in picocuries per liter (pCi/L) as estimated in 1993 by the US Geological Survey and reviewed by the Association of American State Geologists under the Indoor Radon Abatement Act. We used Cox proportional hazards models to estimate risk of incident, neurologist-adjudicated stroke during follow-up through 2020 as a hazard ratio and 95% CI, adjusting for study design and participant demographic, social, behavioral, and clinical characteristics. RESULTS: Among 158,910 women without stroke at baseline (mean age 63.2 years; 83% white), 6,979 incident strokes were identified over follow-up (mean 13.4 years). Incidence rates were 333, 343, and 349 strokes per 100,000 woman-years at radon concentrations of <2, 2-4, and >4 pCi/L, respectively. Compared with women living at concentrations <2 pCi/L, those at 2-4 and >4 pCi/L had higher covariate-adjusted risks of incident stroke: hazard ratio (95% CI) 1.06 (0.99-1.13) and 1.14 (1.05-1.22). Using nonlinear spline functions to model radon, stroke risk was significantly elevated at concentrations ranging from 2 to 4 pCi/L (p = 0.0004), that is, below the United States Environmental Protection Agency Radon Action Level for mitigation (4 pCi/L). Associations were slightly stronger for ischemic (especially cardioembolic, small vessel occlusive, and large artery atherosclerotic) than hemorrhagic stroke, but otherwise robust in sensitivity analyses. DISCUSSION: Radon exposure is associated with moderately increased stroke risk among middle-aged and older women in the United States, suggesting that promulgation of a lower Radon Action Level may help reduce the domestic impact of cerebrovascular disease on public health.

Deep learning-based target tracking with X-ray images for radiotherapy: a narrative review.

Background and Objective: As one of the main treatment modalities, radiotherapy (RT) (also known as radiation therapy) plays an increasingly important role in the treatment of cancer. RT could benefit greatly from the accurate localization of the gross tumor volume and circumambient organs at risk (OARs). Modern linear accelerators (LINACs) are typically equipped with either gantry-mounted or room-mounted X-ray imaging systems, which provide possibilities for marker-less tracking with two-dimensional (2D) kV X-ray images. However, due to organ overlapping and poor soft tissue contrast, it is challenging to track the target directly and precisely with 2D kV X-ray images. With the flourishing development of deep learning in the field of image processing, it is possible to achieve real-time marker-less tracking of targets with 2D kV X-ray images in RT using advanced deep-learning frameworks. This article sought to review the current development of deep learning-based target tracking with 2D kV X-ray images and discuss the existing limitations and potential solutions. Finally, it also discusses some common challenges and potential future developments. Methods: Manual searches of the Web of Science, and PubMed, and Google Scholar were carried out to retrieve English-language articles. The keywords used in the searches included "radiotherapy, radiation therapy, motion tracking, target tracking, motion estimation, motion monitoring, X-ray images, digitally reconstructed radiographs, deep learning, convolutional neural network, and deep neural network". Only articles that met the predetermined eligibility criteria were included in the review. Ultimately, 23 articles published between March 2019 and December 2023 were included in the review. Key Content and Findings: In this article, we narratively reviewed deep learning-based target tracking with 2D kV X-ray images in RT. The existing limitations, common challenges, possible solutions, and future directions of deep learning-based target tracking were also discussed. The use of deep learning-based methods has been shown to be feasible in marker-less target tracking and real-time motion management. However, it is still quite challenging to directly locate tumor and OARs in real-time with 2D kV X-ray images, and more technical and clinical efforts are needed. Conclusions: Deep learning-based target tracking with 2D kV X-ray images is a promising method in motion management during RT. It has the potential to track the target in real time, recognize motion, reduce the extended margin, and better spare the normal tissue. However, it still has many issues that demand prompt attention, and further development before it can be put into clinical practice.

Real-time line-field optical coherence tomography for cellular resolution imaging of biological tissue.

A real-time line-field optical coherence tomography (LF-OCT) system is demonstrated with image acquisition rates of up to 5000 B-frames or 2.5 million A-lines per second for 500 A-lines per B-frame. The system uses a high-speed low-cost camera to achieve continuous data transfer rates required for real-time imaging, allowing the evaluation of future applications in clinical or intraoperative environments. The light source is an 840 nm super-luminescent diode. Leveraging parallel computing with GPU and high speed CoaXPress data transfer interface, we were able to acquire, process, and display OCT data with low latency. The studied system uses anamorphic beam shaping in the detector arm, optimizing the field of view and sensitivity for imaging biological tissue at cellular resolution. The lateral and axial resolution measured in air were 1.7 µm and 6.3 µm, respectively. Experimental results demonstrate real-time inspection of the trabecular meshwork and Schlemm's canal on ex vivo corneoscleral wedges and real-time imaging of endothelial cells of human subjects in vivo.

Risk Prediction in Male Adolescents With Congenital Long QT Syndrome: Implications for Sex-Specific Risk Stratification in Potassium Channel-Mediated Long QT Syndrome.

BACKGROUND: Sex-specific risk management may improve outcomes in congenital long QT syndrome (LQTS). We recently developed a prediction score for cardiac events (CEs) and life-threatening events (LTEs) in postadolescent women with LQTS. In the present study, we aimed to develop personalized risk estimates for the burden of CEs and LTEs in male adolescents with potassium channel-mediated LQTS. METHODS AND RESULTS: The prognostic model was derived from the LQTS Registry headquartered in Rochester, NY, comprising 611 LQT1 or LQT2 male adolescents from age 10 through 20 years, using the following variables: genotype/mutation location, QTc-specific thresholds, history of syncope, and ß-blocker therapy. Anderson-Gill modeling was performed for the end point of CE burden (total number of syncope, aborted cardiac arrest, and appropriate defibrillator shocks). The applicability of the CE prediction model was tested for the end point of the first LTE (excluding syncope and adding sudden cardiac death) using Cox modeling. A total of 270 CEs occurred during follow-up. The genotype-phenotype risk prediction model identified low-, intermediate-, and high-risk groups, comprising 74%, 14%, and 12% of the study population, respectively. Compared with the low-risk group, high-risk male subjects experienced a pronounced 5.2-fold increased risk of recurrent CEs (P<0.001), whereas intermediate-risk patients had a 2.1-fold (P=0.004) increased risk . At age 20 years, the low-, intermediate-, and high-risk adolescent male patients had on average 0.3, 0.6, and 1.4 CEs per person, respectively. Corresponding 10-year adjusted probabilities for a first LTE were 2%, 6%, and 8%. CONCLUSIONS: Personalized genotype-phenotype risk estimates can be used to guide sex-specific management in male adolescents with potassium channel-mediated LQTS.

Enhanced Photocatalytic and Photovoltaic Performance Arising from Unconventionally Low Donor-Y6 Ratios.

Development of both organic photovoltaics (OPVs) and organic photocatalysts has focused on utilizing the bulk heterojunction (BHJ). The BHJ promotes charge separation and enhances the carrier lifetime, but may give rise to increased charge traps, hindering performance. Here, high photocatalytic and photovoltaic performance is displayed by electron donor-acceptor (D-A) nanoparticles (NPs) and films, using the nonfullerene acceptor Y6 and polymer donor PIDT-T8BT. In contrast to conventional D-A systems, the charge generation in PIDT-T8BT:Y6 NPs is mainly driven by Y6, allowing a high performance even at a low D:A mass ratio of 1:50. The high performance at the low mass ratio is attributed to the amorphous behavior of PIDT-T8BT. Low ratios are generally thought to yield lower efficiency than the more conventional ≈1:1 ratio. However, the OPVs exhibit peak performance at a D:A ratio of 1:5. Similarly the NPs used for photocatalytic hydrogen evolution show peak performance at the 1:6.7 D:A ratio. Interestingly, for the PIDT-T8BT:Y6 system, as the polymer proportion increases, a reduced photocatalytic and photovoltaic performance is observed. The unconventional D:A ratios provide lower recombination losses and increased charge-carrier lifetime with undisrupted ambipolar charge transport in bulk Y6, enabling better performance than conventional ratios. This work reports novel light-harvesting materials in which performance is reduced due to unfavorable morphology as D:A ratios move toward conventional ratios of 1:1.2-1:1.

Role of Singlet and Triplet Excited States in the Oxygen-Mediated Photophysics and Photodegradation of Polyacenes.

Polyacenes, such as tetracene and pentacene, are common model systems for the study of photophysical phenomena such as singlet fission (SF) and triplet fusion, processes which may lead to increased photovoltaic efficiencies. While they exhibit desirable photophysical properties, these materials are not photostable and convert to unwanted endoperoxides in the presence of oxygen and light, limiting their use in real-world applications. Not only does oxygen degrade polyacenes but also it can affect their photophysics, leading to both the sensitization and quenching of different excited states. In this study, we characterize the effect of oxygen on 5,12-bis(triisopropylsilylethynyl) tetracene (TIPS-Tn) and 6,13-bis(triisopropylsilylethynyl) pentacene (TIPS-Pn) using transient absorption spectroscopy, and show that oxygen can significantly influence the population of excited states, in particular enhancing the polyacene triplet population. We additionally combine the time-resolved excited-state dynamics with photodegradation studies to determine the predominant mechanism of photooxidation, which has previously been unclear. We find that both molecules photodegrade predominantly via singlet oxygen; however, for TIPS-Tn, this occurs through the triplet state, whereas for TIPS-Pn, degradation occurs through the excited singlet. The photodegradation of TIPS-Tn is thus enhanced by faster rates of SF, whereas SF in TIPS-Pn increases the molecule's photostability. This work has implications both for the design of new materials for next-generation photovoltaics that can avoid photooxidation and for the study of their photophysics in real-world environments.