Retinal ganglion cells play an important role in human vision, and their degeneration results in glaucoma and other neurodegenerative diseases. Imaging these cells in the living human retina can greatly improve the diagnosis and treatment of glaucoma. However, owing to their translucent soma and tight packing arrangement within the ganglion cell layer (GCL), successful imaging has only been achieved with sophisticated research-grade adaptive optics (AO) systems. For the first time we demonstrate that GCL somas can be resolved and cell morphology can be quantified using non-AO optical coherence tomography (OCT) devices with optimal parameter configuration and post-processing.

Impaired retinal blood flow (RBF) autoregulation plays a key role in the development and progression of several ocular diseases, including glaucoma and diabetic retinopathy. Clinically, reproducible RBF quantitation could significantly improve early diagnosis and disease management. Several non-invasive techniques have been developed but are limited for retinal microvasculature flow measurements due to their low signal-to-noise ratio and poor lateral resolution. In this study, we demonstrate reproducible vessel caliber and retinal blood flow velocity measurements in healthy human volunteers using a high-resolution (spatial and temporal) multimodal adaptive optics system with scanning laser ophthalmoscopy and optical coherence tomography.

Wearable ultrasound has the potential to become a disruptive technology enabling new applications not only in traditional clinical settings, but also in settings where ultrasound is not currently used. Understanding the basic engineering principles and limitations of wearable ultrasound is critical for clinicians, scientists, and engineers to advance potential applications and translate the technology from bench to bedside. Wearable ultrasound devices, especially monitoring devices, have the potential to apply acoustic energy to the body for far longer durations than conventional diagnostic ultrasound systems. Thus, bioeffects associated with prolonged acoustic exposure as well as skin health need to be carefully considered for wearable ultrasound devices. This article reviews emerging clinical applications, safety considerations, and future engineering and clinical research directions for wearable ultrasound technology.

Visual perception on virtual reality head-mounted displays (VR HMDs) involves human vision in the imaging pipeline. Image quality evaluation of VR HMDs may need to be expanded from optical bench testing by incorporating human visual perception. In this study, we implement a 5-degree-of-freedom (5DoF) experimental setup that simulates the human eye geometry and rotation mechanism. Optical modulation transfer function (MTF) measurements are performed using various camera rotation configurations namely pupil rotation, eye rotation, and eye rotation with angle kappa of the human visual system. The measured MTFs of the VR HMD are inserted into a human eye contrast sensitivity model to predict the perceptual contrast sensitivity function (CSF) on a VR HMD. At the same time, we develop a WebXR test platform to perform human observer experiments. Monocular CSFs of human subjects with different interpupillary distance (IPD) are extracted and compared with those calculated from optical MTF measurements. The result shows that image quality, measured as MTF and CSF, degrades at the periphery of display field of view, especially for subjects with an IPD different than that of the HMD. We observed that both the shift of visual point on the HMD eyepiece and the angle between the optical axes of the eye and eyepiece degrade image quality due to optical aberration. The computed CSFs from optical measurement correlates with those of the human observer experiment, with the optimal correlation achieved using the eye rotation with angle kappa setup. The finding demonstrates that more precise image quality assessment can be achieved by integrating eye rotation and human eye contrast sensitivity into optical bench testing.

ObjectiveDetermine longitudinal tobacco product discontinuation rates among youth (ages 12–17 years) in the USA between 2013 and 2019.MethodsThe Population Assessment of Tobacco and Health Study, a nationally representative, longitudinal cohort study, was used to determine annual/biennial rates of tobacco product discontinuation behaviours among youth across 2013–2019: (1) discontinuing product use (transition from past 30-day use to no past 30-day use), (2) attempting to quit product use and (3) discontinuing product use among those who attempted to quit. Discontinuing use was evaluated separately for cigarettes, electronic nicotine delivery systems (ENDS), cigars, hookah, smokeless tobacco and any tobacco. Attempting to quit and discontinuing use among those who attempted were each evaluated for cigarettes and ENDS. Generalised estimating equations were used to evaluate linear and non-linear trends in rates across the study period.ResultsBetween 2013 and 2019, biennial rates of discontinuing tobacco product use among youth increased for cigarettes from 29% to 40%, increased for smokeless tobacco from 39% to 60%, and decreased for ENDS from 53% to 27%. By 2018/2019, rates of discontinuing use among attempters were 30% for those who used ENDS and 30% for those who smoked cigarettes.ConclusionsFindings show decreasing rates of discontinuing ENDS use among youth in the USA alongside the changing ENDS marketplace and increasing rates of discontinuing cigarette smoking and smokeless tobacco use. Findings will serve as benchmarks against which future tobacco product discontinuation rates can be compared with evaluating impacts of subsequent tobacco regulatory policies, ENDS product development and public education campaigns.

Blood storage lesion induces cytosolic and membrane changes driven in part by hemoglobin (Hb) oxidation reactions within red blood cells (RBCs). A novel gel formulation containing the antioxidant curcuminoids in a biocompatible solvent system was used to deliver curcumin into RBCs. Incubation of peroxide treated RBCs stored in PBS with curcumin gel led to a reduction in prooxidant ferrylHb and recovery in ATP. Curcumin treatment prevented band 3 tyrosine (Y359 and Y21) phosphorylation. RBCs stored in AS-3 solutions for 28, 35, 42 and 49 days, following a single-dose of 100μM curcuminoids at each time points, caused reduction in protein carbonylation and considerable recovery in ATP levels. Proteomic analysis revealed minimal changes in the proteomic landscape in 35 days. However, a downregulation in fibrinogen was observed in the treated samples which may reduce RBC aggregation. Additionally, we used a guinea pig model where the circulation of infused aged RBCs can be extended (approximately 10%) when treated with curcumin gel at the start of storage. Our data therefore provide mechanistic insights and supportive animal data into benefits of treating stored RBCs with a novel curcuminoid formulation based on the biopreservation of RBC membrane integrity, redox balance, and increased longevity in circulation.

PurposeThe study objective is to document value created by real-world evidence from the Abdominal Core Health Quality Collaborative (ACHQC) for regulatory decisions. The ACHQC is a national effort that generates data on hernia repair techniques and devices.MethodsTwo retrospective cohort evaluations compared cost and time of ACHQC analyses to traditional postmarket studies. The first analysis was based on 25 reports submitted to the European Medicines Agency of 20 mesh products for post-market surveillance. A second analysis supported label expansion submitted to the Food and Drug Administration, Center for Devices and Radiological Health for a robotic-assisted surgery device to include ventral hernia repair. Estimated costs of counterfactual studies, defined as studies that might have been done if the registry had not been available, were derived from a model described in the literature. Return on investment, percentage of cost savings, and time savings were calculated.Results45,010 patients contributed to the two analyses. The cost and time differences between individual 25 ACHQC analyses (41,112 patients) and traditional studies ranged from $1.3 to $2.2 million and from 3 to 4.8 years, both favoring use of the ACHQC. In the second label expansion analysis (3,898 patients), the estimated return on investment ranged from 11 to 461% with time savings of 5.1 years favoring use of the ACHQC.ConclusionsCompared to traditional postmarket studies, use of ACHQC data can result in cost and time savings when used for appropriate regulatory decisions in light of key assumptions.

Abstract Background: The transplantation of human organs, and some human tissues, is often the only life-saving therapy available for serious and life-threatening congenital, inherited, or acquired diseases. However, it is associated with a risk of transmission of communicable diseases from donor to recipient. It is imperative to understand the characteristics of the donor population to inform policies that protect recipient safety. The Tissue and Organ Donor Epidemiology Study (TODES) was a pilot project designed to identify and collect standardized information on deceased persons referred for organ, tissue, and/or eye donation, and to estimate (to the extent possible) infectious disease prevalence and incidence of HIV, HBV, and/or HCV in this population. TODES is summarized here to shed light on addressable limitations on accessing data needed for transplant recipient safety. Limitations, future research needs, and potential pathways to solve the remaining data needs are explored. Methods: Retrospective data for all deceased donors during a 5-year period from 2009 to 2013 were obtained from participating organ procurement organizations (OPOs), tissue establishments, and eye banks. These decedent data on actual donors and potential donors were used to ascertain whether the available real-world data (RWD) could be used to inform donor screening and testing policy. Results: The TODES database contains 291,848 records received from nine OPOs and 42,451 records received from four eye banks. Data were analyzed from deceased donors with at least one organ, tissue, or ocular tissue recovered with the intent to transplant. Results for potential donors were not analyzed. Available RWD at the time of the TODES study were not fit-for-purpose to help characterize the organ- and tissue eye donor populations and/or to inform donor screening policy. Conclusions: Recent advances in electronic data collection systems make it more realistic to now collect fit-for-purpose RWD that address the research needed to improve transplant safety.

Aberrant signaling of BRAFV600E is a major cancer driver. Current FDA-approved RAF inhibitors selectively inhibit the monomeric BRAFV600E and suffer from tumor resistance. Recently, dimer-selective and equipotent RAF inhibitors have been developed; however, the mechanism of dimer selectivity is poorly understood. Here, we report extensive molecular dynamics (MD) simulations of the monomeric and dimeric BRAFV600E in the apo form or in complex with one or two dimer-selective (PHI1) or equipotent (LY3009120) inhibitor(s). The simulations uncovered the unprecedented details of the remarkable allostery in BRAFV600E dimerization and inhibitor binding. Specifically, dimerization retrains and shifts the αC helix inward and increases the flexibility of the DFG motif; dimer compatibility is due to the promotion of the αC-in conformation, which is stabilized by a hydrogen bond formation between the inhibitor and the αC Glu501. A more stable hydrogen bond further restrains and shifts the αC helix inward, which incurs a larger entropic penalty that disfavors monomer binding. This mechanism led us to propose an empirical way based on the co-crystal structure to assess the dimer selectivity of a BRAFV600E inhibitor. Simulations also revealed that the positive cooperativity of PHI1 is due to its ability to preorganize the αC and DFG conformation in the opposite protomer, priming it for binding the second inhibitor. The atomically detailed view of the interplay between BRAF dimerization and inhibitor allostery as well as cooperativity has implications for understanding kinase signaling and contributes to the design of protomer selective RAF inhibitors.

Project Optimus is a US Food and Drug Administration Oncology Center of Excellence initiative aimed at reforming the dose selection and optimization paradigm in oncology drug development. This project seeks to bring together pharmaceutical companies, international regulatory agencies, academic institutions, patient advocates, and other stakeholders. Although there is much promise in this initiative, there are several challenges that need to be addressed, including multidimensionality of the dose optimization problem in oncology, the heterogeneity of cancer and patients, importance of evaluating long-term tolerability beyond dose-limiting toxicities, and the lack of reliable biomarkers for long-term efficacy. Through the lens of Totality of Evidence and with the mindset of model-informed drug development, we offer insights into dose optimization by building a quantitative knowledge base integrating diverse sources of data and leveraging quantitative modeling tools to build evidence for drug dosage considering exposure, disease biology, efficacy, toxicity, and patient factors. We believe that rational dose optimization can be achieved in oncology drug development, improving patient outcomes by maximizing therapeutic benefit while minimizing toxicity.