Search

Could the cellular mechanisms that cause sunburns help creating more stable therapeutics? Studying the effect of ultraviolet light on strands of DNA put together in various structures, we have discovered that gentle irradiation could protect the DNA from being degraded. This overcomes a major hurdle for translation into clinics without requiring extensive modifications.

Here, we present a new approach based on manifold learning for knowledge discovery and inverse design with minimal complexity in photonic nanostructures. Our approach builds on studying sub-manifolds of responses of a class of nanostructures with different design complexities in the latent space to obtain valuable insight about the physics of device operation to guide a more intelligent design. In contrast to the current methods for inverse design of photonic nanostructures, which are limited to pre-selected and usually over-complex structures, we show that our method allows evolution from an initial design towards the simplest structure while solving the inverse problem., Comment: 10 pages, 6 figures, 2 tables

PURPOSE: To determine the interreader agreement for incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA) and complete RPE and outer retinal atrophy (cRORA) and their related features in age-related macular degeneration (AMD). DESIGN: Interreader agreement study. PARTICIPANTS: Twelve readers from 6 reading centers. METHODS: After formal training, readers qualitatively assessed 60 OCT B-scans from 60 eyes with AMD for 9 individual features associated with early atrophy and performed 7 different annotations to quantify the spatial extent of OCT features within regions of interest. The qualitative and quantitative features were used to derive the presence of iRORA and cRORA and also in an exploratory analysis to examine if agreement could be improved using different combinations of features to define OCT atrophy. MAIN OUTCOME MEASURES: Interreader agreement based on Gwet's first-order agreement coefficient (AC1) for qualitatively graded OCT features and classification of iRORA and cRORA, and smallest real difference (SRD) for quantitatively graded OCT features. RESULTS: Substantial or better interreader agreement was observed for all qualitatively graded OCT features associated with atrophy (AC1 = 0.63-0.87), except for RPE attenuation (AC1 = 0.46) and disruption (AC1 = 0.26). The lowest SRD for the quantitatively graded horizontal features was observed for the zone of choroidal hypertransmission (± 190.8 μm). Moderate agreement was found for a 3-category classification of no atrophy, iRORA, and cRORA (AC1 = 0.53). Exploratory analyses suggested a significantly higher level of agreement for a 3-category classification using (1) no atrophy; (2) presence of inner nuclear layer and outer plexiform layer subsidence, or a hyporeflective wedge-shaped band, as a less severe atrophic grade; and (3) the latter plus an additional requirement of choroidal hypertransmission of 250 μm or more for a more severe atrophic grade (AC1 = 0.68; P = 0.013). CONCLUSIONS: Assessment of iRORA and cRORA, and most of their associated features, can be performed relatively consistently and robustly. A refined combination of features to define early atrophy could further improve interreader agreement.

Background Accelerated idioventricular rhythm (AIVR) is an uncommon and typically benign dysrhythmia with similarities to more malignant forms of ventricular tachycardia (VT). It is often seen in adults after myocardial infarctions, although it also arises in the newborn period, as well as in children with and without congenital heart disease. Case Report We describe a presentation of AIVR in an otherwise healthy 13-year-old girl, discovered on arrival to the pediatric emergency department in the setting of post-tonsillectomy bleeding. The case reviews the diagnostic criteria of AIVR, associated symptoms, the pathophysiologic origin of AIVR, and potential treatment strategies. Why Should an Emergency Physician Be Aware of This? Given its morphologic similarities to life-threatening forms of VT, AIVR can be misdiagnosed in the emergency department or primary care settings. With an understanding of the dysrhythmia's unique features, emergency physicians can avoid unnecessary interventions and provide the correct diagnosis, workup, and management of AIVR for pediatric patients.

This article describes how community need was addressed through a traffic calming pop-up event in rural Arkansas. The event was conducted on routes connecting a neighborhood, two schools, and a municipal park. A brief survey assessed safety concerns of parents and/or guardians related to children walking or biking to school. Prior to the event, parents/guardians reported it was not safe for their children to walk or bike to school; however, the majority agreed the event made the area safer. Small-scale traffic calming events can provide evidence to stakeholders that built environment changes are an important childhood obesity prevention strategy in rural Extension work.

Histone arginine methylation is a prevalent posttranslational modification (PTM) in eukaryotic cells and contributes to the histone codes for epigenetic regulation of gene transcription. In this study, we determined how local changes on adjacent residues in the histone H4 substrate regulate arginine asymmetric dimethylation and symmetric dimethylation catalysed by the major protein arginine methyltransferase (PRMT) enzymes PRMT1 and PRMT5, respectively. We found that phosphorylation at histone H4 Ser-1 site (H4S1) was inhibitory to activities of PRMT1 and PRMT5 in both monomethylating and dimethylating H4R3. Also, a positively charged H4K5 was important for PRMT1 catalysis because acetylation of H4K5 or the loss of the H4K5 ��-amine had a similar effect in reducing the catalytic efficiency of asymmetric dimethylation of H4R3. An opposite effect was observed in that acetylation of H4K5 or the loss of the H4K5 ��-amine enhanced PRMT5-mediated symmetric dimethylation of H4R3. Furthermore, we observed that N-terminal acetylation of H4 modestly decreased asymmetric dimethylation of H4R3 by PRMT1 and symmetric dimethylation of H4R3 by PRMT5. This work highlights the significance of local chemical changes in the substrate to regulating PRMT activity and unravels the pattern complexities and subtleties of histone codes.

We present a new approach based on pruning neural networks for solving inverse design in nanophotonics and show how this approach can be used to solve inverse problem with minimal complexity without imposing significant error.

Mean sensitivity (MS) derived from a standard test grid using microperimetry is a sensitive outcome measure in clinical trials investigating new treatments for degenerative retinal diseases. This study hypothesizes that the functional decline is faster at the edge of the dense scotoma (eMS) than by using the overall MS.Multicenter, international, prospective cohort study: ProgStar Study.Stargardt disease type 1 patients (carrying at least 1 mutation in the ABCA4 gene) were followed over 12 months using microperimetry with a Humphrey 10-2 test grid. Customized software was developed to automatically define and selectively follow the test points directly adjacent to the dense scotoma points and to calculate their mean sensitivity (eMS).Among 361 eyes (185 patients), the mean age was 32.9 ± 15.1 years old. At baseline, MS was 10.4 ± 5.2 dB (n = 361), and the eMS was 9.3 ± 3.3 dB (n = 335). The yearly progression rate of MS (1.5 ± 2.1 dB/year) was significantly lower (β = -1.33; P.001) than that for eMS (2.9 ± 2.9 dB/year). There were no differences between progression rates using automated grading and those using manual grading (β = .09; P = .461).In Stargardt disease type 1, macular sensitivity declines significantly faster at the edge of the dense scotoma than in the overall test grid. An automated, time-efficient approach for extracting and grading eMS is possible and appears valid. Thus, eMS offers a valuable tool and sensitive outcome parameter with which to follow Stargardt patients in clinical trials, allowing clinical trial designs with shorter duration and/or smaller cohorts.

Throughout history, oral administration has been regarded as the most convenient mode of drug delivery, as it requires minimal expertise and invasiveness. Although oral delivery works well for small-molecule drugs, oral delivery of macromolecules (particularly proteins and peptides) has been limited by acidic conditions in the stomach and low permeability across the intestinal epithelium. Accordingly, the large numbers of biologic drugs that have become available in the past 10 years typically require administration by injection or infusion. As such, a renewed emphasis has been placed on the development of novel materials that overcome the physiological challenges of oral delivery for macromolecular agents. This Review provides an overview of physiological barriers to the oral delivery of biologics and highlights the advances made in materials across various length scales, from small molecules to macroscopic devices. This Review also describes the current status of materials for oral delivery of protein and peptide drugs. New materials, beyond those that have already obtained regulatory approval, are needed to improve the bioavailability of orally administered proteins. In this Review, barriers to the oral delivery of protein-based therapies are discussed, along with the current translational landscape and state of the art of materials for oral protein delivery.

Suppose $$p \ge 1$$ is a computable real. We extend previous work of Clanin, Stull, and McNicholl by determining the degrees of categoricity of the separable $$L^p$$ spaces whose underlying measure spaces are atomic but not purely atomic. In addition, we ascertain the complexity of associated projection maps.

Background Although adolescents and young adults may be particularly prone to mental health symptoms after heart transplant, screening practices are variable. Objective To assess the feasibility of using patient-reported outcome (PRO) measures to assess mental health, functional status, and resiliency in posttransplant adolescents and young adult patients. Methods Patients transplanted between ages 15 and 25 years at 3 centers completed 6 PRO instruments via web-based platforms: PROMIS instruments for anxiety, depression, satisfaction with social roles, and physical functioning; the Posttraumatic Stress Diagnostic Scale for Diagnostic and Statistical Manual of Mental Disorders, version 5; and the Connor-Davidson Resilience Scale-10. Feasibility (completion, time to completion, and measure missingness) and PRO results were described and compared between patients with congenital heart disease and cardiomyopathy. Results Nineteen patients (median age at transplant 17.7 y [interquartile range 16.3, 19.2 y], 84% male) were enrolled at an average of 3 ± 1.8 years after transplant. Enrollment was 90% among eligible patients. Measure missingness was zero. The average completion time was 12 ± 15 minutes for all instruments. Timely PRO completion was facilitated by in-clinic application. The PRO results indicated that 9 patients (47%) had at least mild posttraumatic stress disorder symptoms (≥11 points on Posttraumatic Stress Diagnostic Scale for Diagnostic and Statistical Manual of Mental Disorders, version 5). Among them, 4 patients had scores >28 suggestive of probable posttraumatic stress disorder. Two (11%) and 6 (32%) patients had anxious and depressive symptoms, respectively. The cardiomyopathy cohort had a higher median Posttraumatic Stress Diagnostic Scale for Diagnostic and Statistical Manual of Mental Disorders, version 5 score than that of the congenital heart disease subgroup (11.0 vs 6.0; P = 0.015). Twelve (63%) had resiliency scores that were lower than the population average. No significant differences were found in PRO results between patients with cardiomyopathy and congenital heart disease apart from the posttraumatic stress disorder assessment. Conclusions This novel PRO-based approach to psychiatric screening of adolescents and young adult patients after transplant appears feasible for assessing mental health, functional status, and resiliency, with excellent enrollment and completion rates. These instruments characterized the burden of mental health symptoms within this adolescents and young adult heart transplant cohort, with a high prevalence of posttraumatic stress disorder symptoms. Resiliency scores were lower than in a comparison population. Electronically-administered PRO administration could facilitate more consistent mental health screening in this at-risk group.

A new deep-learning approach based on dimensionality reduction techniques for the design and knowledge discovery in nanophotonic structures will be presented. It is shown that reducing the dimensionality of the response and design spaces in a class of nanophotonic structures can provide new insight into the physics of light-matter interaction in such nanostructures while facilitating their inverse design. These unique features are achieved while considerably reducing the computation complexity through dimensionality reduction. It is also shown that this approach can enable an evolutionary design method in which the initial design can be evolved intelligently into an alternative with favorable specification like less complexity, more robustness, less power consumption, etc. In addition to providing the details about the fundamental aspects of the latent learning approach, its application to design of reconfigurable metasurfaces will be demonstrated.

Methyllysine reader proteins bind to methylated lysine residues and alter gene transcription by changing the compaction state of chromatin or by the recruitment of other multiprotein complexes. The polycomb paralog family of methyllysine readers bind to trimethylated lysine on the tail of histone 3 via a highly conserved aromatic cage located in their chromodomains. Each of the polycomb paralogs are implicated in several disease states. CBX6 and CBX8 are members of the polycomb paralog family with two structurally similar chromodomains. By exploring the structure-activity relationships of a previously reported CBX6 inhibitor we have discovered more potent and cell permeable analogs. Our current report includes potent, dual-selective inhibitors of CBX6 and CBX8. We have shown that the –2 position in our scaffold is an important residue for selectivity amongst the polycomb paralogs. Preliminary cell-based studies show that the new inhibitors impact cell proliferation in a rhabdoid tumor cell line. This report includes data on inhibitor design, inhibitor synthesis, compound characterization by LCMS, compound activity by fluorescence polarization, analysis of structure-activity relationships, rhabdoid tumor cell line activity.

Digoxin has been associated with lower interstage mortality (ISM) following stage 1 palliation (S1P). Despite a substantial increase in digoxin use nationally, ISM has not declined. We aimed to determine the impact of digoxin on ISM in the current era. This study analyzed data from the National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) registry. All patients who survived to hospital discharge following S1P were included. Comparisons were made between pre-specified eras (1: 2010-2015, 2: 2016-2019) based on digoxin use. ISM risk was estimated using the previously published NEONATE score (excluding digoxin). Multivariable Cox proportional hazard models assessed the impact of digoxin on ISM and freedom from unplanned readmission in era 2. A total of 1400 (46.8%) patients were included from era 1 and 1589 (53.2%) from era 2. Digoxin use (22.4% vs 61.7%, p0.001) and the proportion of high-risk patients (9.1% vs 20.3%, p0.001) increased across eras. There was no difference in predicted ISM risk between those who did vs did not receive digoxin in era 2 (p = 0.82). In era 2, digoxin use was independently associated with lower ISM (AHR 0.60, 95%CI 0.36 to 0.98, p = 0.043) and greater freedom from unplanned readmission (AHR 0.44, 95%CI 0.32 - 0.59, p0.001). In conclusion, digoxin is independently associated with lower ISM and greater freedom from interstage readmission. The lack of improvement in overall ISM in the current era may be secondary to a greater proportion of high-risk patients and/or disproportionately higher digoxin use in lower risk patients, who may not derive the same benefit.

Solar photovoltaic power generation capacity is growing rapidly, increasing the need for dynamic load balancing when solar production dips. This balancing might be delivered using energy storage and/or advanced power generation cycles, that are compact, dynamic, and highly efficient, such as supercritical carbon dioxide (sCO2) cycles. Here, the load balancing capability of a sCO2 combined cycle plant was compared to open cycle and steam combined cycle gas turbines. A characteristic-based transient model was developed to evaluate the impact of machinery ramp rates, minimum part loads, and cycle efficiencies. High resolution demand and solar irradiance data from the University of Virginia campus, before and after installation of a major solar project, was used to represent low and high levels of solar deployment in the grid. The results suggest that under high deployment of solar power, sCO2 cycles and steam combined cycle systems with ramp rates greater than 5.75%/minute can balance load and provide comparable levelized costs of electricity ($0.057/kWh). Solar curtailment was driven by the minimum part load capabilities. A sCO2 cycle with a minimum part load of 30% was predicted to have a curtailment of 15% in the high solar scenario without a battery, and 4% with a 30 MWh battery.

A new artificial-intelligence (AI) approach based on dimensionality reduction techniques for the design and knowledge discovery in metamaterial structures will be presented. It is shown that reducing the dimensionality of the response and design spaces by using a pseudoencoder can reduce the computation time by 2–3 orders of magnitude. In addition, using pruning techniques can simplify the trained algorithm to further reduce the computation time while providing simpler paths for relating input-output relationships for understanding the role of design parameters (i.e., knowledge discovery). It is also shown that this approach can enable an evolutionary design method in which the initial design can be evolved intelligently into an alternative with favorable specifications. The application of these AI approaches for both optical and acoustic metamaterials will be presented.

The functional properties of colloidal materials can be tailored by tuning the shape of their constituent particles. Unfortunately, a reliable, general methodology for purifying colloidal materials solely based on shape is still lacking. Here we exploit the single-particle analysis and sorting capabilities of the fluorescence-activated cell sorting (FACS) instrument, a commonly used tool in biomedical research, and demonstrate the ability to separate mixtures of synthetic microparticles based solely on their shape with high purity. We achieve this by simultaneously obtaining four independent optical scattering signals from the FACS instrument to create shape-specific 'scattering signatures' that can be used for particle classification and sorting. We demonstrate that these four-dimensional signatures can overcome the confounding effects of particle orientation on shape-based characterization. Using this strategy, robust discrimination of particles differing only slightly in shape and an efficient selection of desired shapes from mixtures comprising particles of diverse sizes and materials is demonstrated.