Long-Term Health Outcomes of Individuals With Pseudodeficiency Alleles in IDUA May Inform Newborn Screening Practices for Mucopolysaccharidosis Type I.

Mucopolysaccharidosis type I (MPS I), a lysosomal disorder caused by variants in IDUA, was added to the Recommended Uniform Screening Panel for newborn screening in 2016. Positive screening results for MPS I are commonly due to variants known as "pseudodeficiency alleles," which decrease in vitro alpha-L-iduronidase enzyme activity but are thought to provide sufficient in vivo activity. Despite the historic assumption that these variants are biologically benign, the possibility that they could give rise to complex, multigenic, or attenuated phenotypes has not been systemically evaluated in adults.

Building Block-Based Binding Predictions for DNA-Encoded Libraries.

DNA-encoded libraries (DELs) provide the means to make and screen millions of diverse compounds against a target of interest in a single experiment. However, despite producing large volumes of binding data at a relatively low cost, the DEL selection process is susceptible to noise, necessitating computational follow-up to increase signal-to-noise ratios. In this work, we present a set of informatics tools to employ data from prior DEL screen(s) to gain information about which building blocks are most likely to be productive when designing new DELs for the same target.

DNA-Encoded Library Hit Confirmation: Bridging the Gap Between On-DNA and Off-DNA Chemistry.

DNA-encoded library (DEL) technology is a powerful platform for hit identification in academia and the pharmaceutical industry. When conducting off-DNA resynthesis hit confirmation after affinity selection, PCR/sequencing, and data analysis, one typically assumes a "one-to-one" relationship between the DNA tag and the chemical structure of the attached small-molecule it encodes. Because library synthesis often yields a mixture, this approximation increases the risk of overlooking positive discoveries and valuable information.

Independent real-world application of a clinical-grade automated prostate cancer detection system.

Artificial intelligence (AI)-based systems applied to histopathology whole-slide images have the potential to improve patient care through mitigation of challenges posed by diagnostic variability, histopathology caseload, and shortage of pathologists. We sought to define the performance of an AI-based automated prostate cancer detection system, Paige Prostate, when applied to independent real-world data. The algorithm was employed to classify slides into two categories: benign (no further review needed) or suspicious (additional histologic and/or immunohistochemical analysis required).

Impact of COVID-19 on Cancer Care: How the Pandemic Is Delaying Cancer Diagnosis and Treatment for American Seniors.

Purpose: While the immediate care and access disruptions associated with the COVID-19 pandemic have received growing attention in certain areas, the full range of gaps in cancer screenings and treatment is not yet well understood or well documented throughout the country comprehensively.

Methods: This study used a large medical claims clearinghouse database representing 5%-7% of the Medicare fee-for-service population to characterize changes in the utilization of cancer care services and gain insight into the impact of COVID-19 on the US cancer population, including identification of new patients, gaps in access to care, and disruption of treatment journeys.

Results: In March-July 2020, in comparison with the baseline period of March-July 2019, there is a substantial decrease in cancer screenings, visits, therapy, and surgeries, with variation by cancer type and site of service.

Orthostatic Vital Signs Algorithm: Decreasing Falls in Patients Undergoing Blood and Marrow Transplantation or Treatment With Cellular Immunotherapy.

Background: Falls experienced by patients undergoing blood and marrow transplantation or treatment with cellular immunotherapy (BMT-CI) may result in injury or death. An algorithm was developed using the patient fall circumstances identified in a chart analysis from 2016.

Objectives: This study aimed to determine if the Moffitt BMT-CI Orthostatic Vital Signs Algorithm could decrease inpatient falls.

Novel artificial intelligence system increases the detection of prostate cancer in whole slide images of core needle biopsies.

Prostate cancer (PrCa) is the second most common cancer among men in the United States. The gold standard for detecting PrCa is the examination of prostate needle core biopsies. Diagnosis can be challenging, especially for small, well-differentiated cancers.

The Provision of Education and Employment Support At the Outreach and Support in South London (OASIS) Service for People at Clinical High Risk for Psychosis.

Clinical services for the early detection of individuals at clinical high risk of psychosis, such as Outreach and Support in South-London (OASIS), have been successful in providing psychological intervention and psychosocial support to young people experiencing emerging signs of serious mental disorders. Despite this, several studies have repeatedly shown that vocational and functional recovery in the clinical high risk for psychosis population is still low. This study aimed at evaluating the presence and nature of educational and employment focused interventions within the OASIS service, in order to inform research and clinical interventions aimed at supporting young people with early signs of psychosis on their path to vocational recovery.

Precise measurement of coronary stenosis diameter with CCTA using CT number calibration.

Purpose: Coronary x-ray computed tomography angiography (CCTA) continues to develop as a noninvasive method for the assessment of coronary vessel geometry and the identification of physiologically significant lesions. The uncertainty of quantitative lesion diameter measurement due to limited spatial resolution and vessel motion reduces the accuracy of CCTA diagnoses. In this paper, we introduce a new technique called computed tomography (CT)-number-Calibrated Diameter to improve the accuracy of the vessel and stenosis diameter measurements with CCTA.

DNA-Encoded Macrocyclic Peptide Library.

DNA-encoded library technology (ELT) is a cutting-edge enabling technology platform for drug discovery. Here we describe how to design and synthesize a macrocyclic DNA-encoded library; how to perform selection, sequencing, and data analysis to identify potential active peptides; and how to synthesize off-DNA peptides to confirm activity. This approach provides an effective tool for pharmaceutical research based on peptides.

Development of a Selection Method for Discovering Irreversible (Covalent) Binders from a DNA-Encoded Library.

DNA-encoded libraries (DELs) have been broadly applied to identify chemical probes for target validation and lead discovery. To date, the main application of the DEL platform has been the identification of reversible ligands using multiple rounds of affinity selection. Irreversible (covalent) inhibition offers a unique mechanism of action for drug discovery research.

Generation of Patient-Specific Cardiac Vascular Networks: A Hybrid Image-Based and Synthetic Geometric Model.

Objective: In this paper, we propose an algorithm for the generation of a patient-specific cardiac vascular network starting from segmented epicardial vessels down to the arterioles.

Method: We extend a tree generation method based on satisfaction of functional principles, named constrained constructive optimization, to account for multiple, competing vascular trees. The algorithm simulates angiogenesis under vascular volume minimization with flow-related and geometrical constraints adapting the simultaneous tree growths to patient priors.

Lumen boundaries extracted from coronary computed tomography angiography on computed fractional flow reserve (FFRCT): validation with optical coherence tomography.

Aims: The aim of this study was to evaluate the accuracy of minimum lumen area (MLA) by coronary computed tomography angiography (cCTA) and its impact on fractional flow reserve (FFRCT).

Methods And Results: Fifty-seven patients (118 lesions, 72 vessels) who underwent cCTA and optical coherence tomography (OCT) were enrolled. OCT and cCTA were co-registered and MLAs were measured with both modalities.

Automated estimation of image quality for coronary computed tomographic angiography using machine learning.

Objectives: Our goal was to evaluate the efficacy of a fully automated method for assessing the image quality (IQ) of coronary computed tomography angiography (CCTA).

Methods: The machine learning method was trained using 75 CCTA studies by mapping features (noise, contrast, misregistration scores, and un-interpretability index) to an IQ score based on manual ground truth data. The automated method was validated on a set of 50 CCTA studies and subsequently tested on a new set of 172 CCTA studies against visual IQ scores on a 5-point Likert scale.

Identification of High-Risk Plaques Destined to Cause Acute Coronary Syndrome Using Coronary Computed Tomographic Angiography and Computational Fluid Dynamics.

Objectives: The authors investigated the utility of noninvasive hemodynamic assessment in the identification of high-risk plaques that caused subsequent acute coronary syndrome (ACS).

Background: ACS is a critical event that impacts the prognosis of patients with coronary artery disease. However, the role of hemodynamic factors in the development of ACS is not well-known.

Association Between Blood Pressure and Retinal Vessel Diameters Among Police Officers in the US Northeast.

Objective: The aim of this study was to examine relationships of blood pressure with central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) among 242 police officers.

Methods: Computerized retinal images of each eye were taken. Mean values of CRAE and CRVE were compared across hypertension status categories using analysis of variance and analysis of covariance.

Design and Application of a DNA-Encoded Macrocyclic Peptide Library.

A DNA-encoded macrocyclic peptide library was designed and synthesized with 2.4 × 10 members composed of 4-20 natural and non-natural amino acids. Affinity-based selection was performed against two therapeutic targets, VHL and RSV N protein.

The Exonuclease Activity of Herpes Simplex Virus 1 UL12 Is Required for Production of Viral DNA That Can Be Packaged To Produce Infectious Virus.

The herpes simplex virus (HSV) type I alkaline nuclease, UL12, has 5'-to-3' exonuclease activity and shares homology with nucleases from other members of the family. We previously reported that a UL12-null virus exhibits a severe defect in viral growth. To determine whether the growth defect was a result of loss of nuclease activity or another function of UL12, we introduced an exonuclease-inactivating mutation into the viral genome.

Shiftwork and the Retinal Vasculature Diameters Among Police Officers.

Objective: To investigate associations of central retinal arteriolar equivalent (CRAE), a measure of retinal arteriolar width, and central retinal venular equivalents (CRVE), a measure of retinal venular width, with shiftwork in 199 police officers (72.9% men).

Methods: Shiftwork (day, afternoon, night) was assessed using electronic payroll records.

High quality clinical grade human embryonic stem cell lines derived from fresh discarded embryos.

Background: Human embryonic stem cells (hESCs) hold tremendous promise for cell replacement therapies for a range of degenerative diseases. In order to provide cost-effective treatments affordable by public health systems, HLA-matched allogeneic tissue banks of the highest quality clinical-grade hESCs will be required. However only a small number of existing hESC lines are suitable for clinical use; they are limited by moral and ethical concerns and none of them apply Good Manufacturing Practice (GMP) standards to the earliest and critical stages of gamete and embryo procurement.

Discovery and Characterization of a Class of Pyrazole Inhibitors of Bacterial Undecaprenyl Pyrophosphate Synthase.

Undecaprenyl pyrophosphate synthase (UppS) is an essential enzyme in bacterial cell wall synthesis. Here we report the discovery of Staphylococcus aureus UppS inhibitors from an Encoded Library Technology screen and demonstrate binding to the hydrophobic substrate site through cocrystallography studies. The use of bacterial strains with regulated uppS expression and inhibitor resistant mutant studies confirmed that the whole cell activity was the result of UppS inhibition, validating UppS as a druggable antibacterial target.

Contrast Driven Elastica for Image Segmentation.

Minimization of boundary curvature is a classic regularization technique for image segmentation in the presence of noisy image data. Techniques for minimizing curvature have historically been derived from gradient descent methods which could be trapped by a local minimum and, therefore, required a good initialization. Recently, combinatorial optimization techniques have overcome this barrier by providing solutions that can achieve a global optimum.

DNA-Encoded Library Screening Identifies Benzo[b][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors.

The recent discovery of the role of receptor interacting protein 1 (RIP1) kinase in tumor necrosis factor (TNF)-mediated inflammation has led to its emergence as a highly promising target for the treatment of multiple inflammatory diseases. We screened RIP1 against GSK's DNA-encoded small-molecule libraries and identified a novel highly potent benzoxazepinone inhibitor series. We demonstrate that this template possesses complete monokinase selectivity for RIP1 plus unique species selectivity for primate versus nonprimate RIP1.

ICP8 Filament Formation Is Essential for Replication Compartment Formation during Herpes Simplex Virus Infection.

Unlabelled: Herpes simplex virus (HSV) dramatically reorganizes the infected-cell nucleus, leading to the formation of prereplicative sites and replication compartments. This process is driven by the essential viral single-stranded DNA (ssDNA) binding protein ICP8, which can form double-helical filaments in the absence of DNA. In this paper, we show that two conserved motifs, FNF (F1142, N1143, and F1144) and FW (F843 and W844), are essential for ICP8 self-interactions, and we propose that the FNF motif docks into the FW region during filament formation.