Digital Commons Network^™

From Canines To Humans: Clinical Importance Of Staphylococcus Pseudintermedius, Karen C. Carroll, Carey-Ann D. Burnham, Lars F. Westblade

Open Access Publications

No abstract provided.

Screening Of Severe Acute Respiratory Syndrome Coronavirus 2 Rna-Dependent Rna Polymerase Inhibitors Using Computational Approach, Poonam Dhankhar, Vikram Dalal, Viney Kumar

Open Access Publications

The detrimental effect of coronavirus disease 2019 (COVID-19) pandemic has manifested itself as a global crisis. Currently, no specific treatment options are available for COVID-19, so therapeutic interventions to tackle the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection must be urgently established. Therefore, cohesive and multidimensional efforts are required to identify new therapies or investigate the efficacy of small molecules and existing drugs against SARS-CoV-2. Since the RNA-dependent RNA Polymerase (RdRP) of SARS-CoV-2 is a promising therapeutic target, this study addresses the identification of antiviral molecules that can specifically target SARS-CoV-2 RdRP. The computational approach of drug development was …

Adolescent Brain Cognitive Development (Abcd) Study Linked External Data (Led): Protocol And Practices For Geocoding And Assignment Of Environmental Data, Chun Chieh Fan, Andrew Marshall, Harry Smolker, Marybel R Gonzalez, Susan F Tapert, Deanna M Barch, Elizabeth Sowell, Gayathri J Dowling, Carlos Cardenas-Iniguez, Jessica Ross, Wesley K Thompson, Megan M Herting

Open Access Publications

Our brain is constantly shaped by our immediate environments, and while some effects are transient, some have long-term consequences. Therefore, it is critical to identify which environmental risks have evident and long-term impact on brain development. To expand our understanding of the environmental context of each child, the Adolescent Brain Cognitive Development (ABCD) Study® incorporates the use of geospatial location data to capture a range of individual, neighborhood, and state level data based on the child's residential location in order to elucidate the physical environmental contexts in which today's youth are growing up. We review the major considerations and types …

Comparison Of Machine Learning Clustering Algorithms For Detecting Heterogeneity Of Treatment Effect In Acute Respiratory Distress Syndrome: A Secondary Analysis Of Three Randomised Controlled Trials, Pratik Sinha, Alexandra Spicer, Kevin L Delucchi, Daniel F Mcauley, Carolyn S Calfee, Matthew M Churpek

Open Access Publications

BACKGROUND: Heterogeneity in Acute Respiratory Distress Syndrome (ARDS), as a consequence of its non-specific definition, has led to a multitude of negative randomised controlled trials (RCTs). Investigators have sought to identify heterogeneity of treatment effect (HTE) in RCTs using clustering algorithms. We evaluated the proficiency of several commonly-used machine-learning algorithms to identify clusters where HTE may be detected.

METHODS: Five unsupervised: Latent class analysis (LCA), K-means, partition around medoids, hierarchical, and spectral clustering; and four supervised algorithms: model-based recursive partitioning, Causal Forest (CF), and X-learner with Random Forest (XL-RF) and Bayesian Additive Regression Trees were individually applied to three prior …

Identification Of Histone Deacetylase Inhibitors With (Arylidene)Aminoxy Scaffold Active In Uveal Melanoma Cell Lines, Susanna Nencetti, Doretta Cuffaro, Elisa Nuti, Lidia Ciccone, Armando Rossello, Marina Fabbi, Flavio Ballante, Gabriella Ortore, Grazia Carbotti, Francesco Campelli, Irene Banti, Rosaria Gangemi, Garland R Marshall, Elisabetta Orlandini

Open Access Publications

Uveal melanoma (UM) represents an aggressive type of cancer and currently, there is no effective treatment for this metastatic disease. In the last years, histone deacetylase inhibitors (HDACIs) have been studied as a possible therapeutic treatment for UM, alone or in association with other chemotherapeutic agents. Here we synthesised a series of new HDACIs based on the SAHA scaffold bearing an (arylidene)aminoxy moiety. Their HDAC inhibitory activity was evaluated on isolated human HDAC1, 3, 6, and 8 by fluorometric assay and their binding mode in the catalytic site of HDACs was studied by molecular docking. The most promising hit was …

Insulin And Glucose Metabolism With Olanzapine And A Combination Of Olanzapine And Samidorphan: Exploratory Phase 1 Results In Healthy Volunteers, Frederico G S Toledo, William F Martin, Linda Morrow, Carine Beysen, Daiva Bajorunas, Ying Jiang, Bernard L Silverman, David Mcdonnell, Mark N Namchuk, John W Newcomer, Christine Graham

Open Access Publications

A combination of olanzapine and samidorphan (OLZ/SAM) received US Food and Drug Administration approval in May 2021 for the treatment of adults with schizophrenia or bipolar I disorder. OLZ/SAM provides the efficacy of olanzapine, while mitigating olanzapine-associated weight gain. This exploratory study characterized the metabolic profile of OLZ/SAM in healthy volunteers to gain mechanistic insights. Volunteers received once-daily oral 10 mg/10 mg OLZ/SAM, 10 mg olanzapine, or placebo for 21 days. Assessments included insulin sensitivity during an oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, other measures of glucose/lipid metabolism, and adverse event (AE) monitoring. Treatment effects were estimated with analysis …

A Reevaluation Of The Tolerability And Effects Of Single-Dose Ivermectin Treatment On Onchocerca Volvulus Microfilariae In The Skin And Eyes In Eastern Ghana, Nicholas O Opoku, Michael E Gyasi, Felix Doe, Daphne Lew, Augustine R Hong, Sithembele Chithenga, Peter U Fischer, Christopher L King, Gary J Weil

Open Access Publications

Mass administration of ivermectin (IVM) has significantly reduced onchocerciasis prevalence, intensity, and morbidity in most endemic areas. Most IVM clinical trials were performed long ago in persons with high-intensity infections that are uncommon in West Africa today. This cohort treatment study recruited participants from a hypoendemic area in eastern Ghana to reevaluate the efficacy and tolerability of IVM with a special focus on the kinetics of microfilaria (Mf) clearance. Mf in the skin and anterior chambers (AC) were assessed by skin snip and slit lamp examinations at baseline and at 3 and 6 months after treatment with IVM 150 μg/kg. …

Opening Of A Cryptic Pocket In Β-Lactamase Increases Penicillinase Activity, Catherine R Knoverek, Upasana L Mallimadugula, Sukrit Singh, Enrico Rennella, Thomas E Frederick, Tairan Yuwen, Shreya Raavicharla, Lewis E Kay, Gregory R Bowman

Open Access Publications

Understanding the functional role of protein-excited states has important implications in protein design and drug discovery. However, because these states are difficult to find and study, it is still unclear if excited states simply result from thermal fluctuations and generally detract from function or if these states can actually enhance protein function. To investigate this question, we consider excited states in β-lactamases and particularly a subset of states containing a cryptic pocket which forms under the Ω-loop. Given the known importance of the Ω-loop and the presence of this pocket in at least two homologs, we hypothesized that these excited …

Identification Of Disease-Linked Hyperactivating Mutations In Ube3a Through Large-Scale Functional Variant Analysis, Kellan P Weston, Xiaoyi Gao, Jinghan Zhao, Kwang-Soo Kim, Susan E Maloney, Jill Gotoff, Sumit Parikh, Yen-Chen Leu, Kuen-Phon Wu, Marwan Shinawi, Joshua P Steimel, Joseph S Harrison, Jason J Yi

Open Access Publications

The mechanisms that underlie the extensive phenotypic diversity in genetic disorders are poorly understood. Here, we develop a large-scale assay to characterize the functional valence (gain or loss-of-function) of missense variants identified in UBE3A, the gene whose loss-of-function causes the neurodevelopmental disorder Angelman syndrome. We identify numerous gain-of-function variants including a hyperactivating Q588E mutation that strikingly increases UBE3A activity above wild-type UBE3A levels. Mice carrying the Q588E mutation exhibit aberrant early-life motor and communication deficits, and individuals possessing hyperactivating UBE3A variants exhibit affected phenotypes that are distinguishable from Angelman syndrome. Additional structure-function analysis reveals that Q588 forms a regulatory site …

Impact Of Annual Versus Semiannual Mass Drug Administration With Ivermectin And Albendazole On Helminth Infections In Southeastern Liberia, Obiora A Eneanya, Lincoln Gankpala, Charles W Goss, Fatorma K Bolay, Gary J Weil, Peter U Fischer

Open Access Publications

We compared the impact of three rounds of annual and five rounds of semiannual mass drug administration (MDA) with albendazole plus ivermectin on helminthic infections in Liberia. Repeated annual cross-sectional community surveys were conducted between 2013 and 2019 in individuals of 5 years and older. Primary outcome was the change of infection prevalence estimates from baseline to month 36 (12 months after the last treatment). After three rounds of annual MDA, Wuchereria bancrofti circulating filarial antigen (CFA) and microfilaria (Mf) prevalence estimates decreased from 19.7% to 4.3% and from 8.6% to 0%, respectively; after semiannual MDA, CFA and Mf prevalences …

Covid-19 Vaccine Hesitancy And Attitude Toward Booster Doses Among Us Healthcare Workers, Suman Pal, Rahul Shekhar, Saket Kottewar, Shubhra Upadhyay, Mriganka Singh, Dola Pathak, Devika Kapuria, Eileen Barrett, Abu Baker Sheikh

Open Access Publications

Vaccine reluctance among healthcare workers (HCW) can have widespread negative ramifications, including modeling behavior for the general population and challenges with maintaining a healthy workforce so we can respond to a resurgence of the pandemic. We previously reported that only one-third of HCW were willing to take the vaccine as soon as it became available prior to its Emergency Use Authorization (EUA). Here, we re-examine the attitude toward COVID-19 vaccines among HCW several months after the vaccines have been made widely available. In this study, only 7.9% (n = 107) of respondents were hesitant to take the first or second …

Slo2.1/Nalcn A Sodium Signaling Complex That Regulates Uterine Activity, Juan J Ferreira, Chinwendu Amazu, Lis C Puga-Molina, Xiaofeng Ma, Sarah K England, Celia M Santi

Open Access Publications

Depolarization of the myometrial smooth muscle cell (MSMC) resting membrane potential is necessary for the uterus to transition from a quiescent state to a contractile state. The molecular mechanisms involved in this transition are not completely understood. Here, we report that a coupled system between the Na

A Polygenic Risk Score Predicts Incident Prostate Cancer Risk In Older Men But Does Not Select For Clinically Significant Disease, Andrew Bakshi, Yin Cao, Et Al

Open Access Publications

Despite the high prevalence of prostate cancer in older men, the predictive value of a polygenic risk score (PRS) remains uncertain in men aged ≥70 years. We used a 6.6 million-variant PRS to predict the risk of incident prostate cancer in a prospective study of 5701 men of European descent aged ≥70 years (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial. The study endpoint was prostate cancer, including metastatic or non-metastatic disease, confirmed by an expert panel. After excluding participants with a history of prostate cancer at enrolment, we used a …

Visual Prototypes In The Ventral Stream Are Attuned To Complexity And Gaze Behavior, Olivia Rose, James Johnson, Binxu Wang, Carlos R Ponce

Open Access Publications

Early theories of efficient coding suggested the visual system could compress the world by learning to represent features where information was concentrated, such as contours. This view was validated by the discovery that neurons in posterior visual cortex respond to edges and curvature. Still, it remains unclear what other information-rich features are encoded by neurons in more anterior cortical regions (e.g., inferotemporal cortex). Here, we use a generative deep neural network to synthesize images guided by neuronal responses from across the visuocortical hierarchy, using floating microelectrode arrays in areas V1, V4 and inferotemporal cortex of two macaque monkeys. We hypothesize …

Dasatinib And Dexamethasone Followed By Hematopoietic Cell Transplantation For Adults With Ph-Positive All, Matthew J. Wieduwilt, Geoffrey L. Uy, Et Al

Open Access Publications

No abstract provided.

Optimization Of Non-Coding Regions For A Non-Modified Mrna Covid-19 Vaccine, Makda S Gebre, Susanne Rauch, Adrianus C M Boon, Et Al

Open Access Publications

The CVnCoV (CureVac) mRNA vaccine for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was recently evaluated in a phase 2b/3 efficacy trial in humans

Dual Lactate Clearance In The Viability Assessment Of Livers Donated After Circulatory Death With Ex Situ Normothermic Machine Perfusion, Min Xu, Fangyu Zhou, Ola Ahmed, Lucy V Randle, Jun-Kyu Shin, Yuehui Zhu, Gundumi A Upadhya, Kathleen Byrnes, Brian Wong, Jae-Sung Kim, Yiing Lin, William C Chapman

Open Access Publications

Perfusate lactate clearance (LC) is considered one of the useful indicators of liver viability assessment during normothermic machine perfusion (NMP); however, the applicable scope and potential mechanisms of LC remain poorly defined in the setting of liver donation after circulatory death.

Methods: The ex situ NMP of end-ischemic human livers was performed using the OrganOx Metra device. We further studied the extracellular signal-regulated kinases (phospho-extracellular signal-regulated kinase1/2 [pERK1/2]) pathway and several clinical parameters of these livers with successful LC (sLC, n = 5) compared with non-sLC (nLC, n = 5) in the perfusate (<2.2 mmol/L at 2 h, n = 5, rapid retrieval without normothermic regional perfusion).

Results: We found the pERK1/2 level …

Identifying Barriers To Evidence-Based Care For Sickle Cell Disease: Results From The Sickle Cell Disease Implementation Consortium Cross-Sectional Survey Of Healthcare Providers In The Usa, Matthew Smeltzer, Kristen Howell, Marsha Treadwell, Liliana Preiss, Allison King, Jeffrey Glassberg, Paula Tanabe, Sherif Badawy, Lisa Dimartino, Robert Gibson, Julie Kanter, Lisa Klesges, Jane Hankins, Sickle Cell Disease Implementation Consortium

Open Access Publications

OBJECTIVES: Sickle cell disease (SCD) leads to chronic and acute complications that require specialised care to manage symptoms and optimise clinical results. The National Heart Lung and Blood Institute (NHLBI) evidence-based guidelines assist providers in caring for individuals with SCD, but adoption of these guidelines by providers has not been optimal. The objective of this study was to identify barriers to treating individuals with SCD.

METHODS: The SCD Implementation Consortium aimed to investigate the perception and level of comfort of providers regarding evidence-based care by surveying providers in the regions of six clinical centres across the USA, focusing on non-emergency …

Predictors Of Coronary Artery Calcium And Long-Term Risks Of Death, Myocardial Infarction, And Stroke In Young Adults, Aamir Javaid, Joshua D Mitchell, Todd C Villines

Open Access Publications

Background Coronary artery calcium (CAC) is well-validated for cardiovascular disease risk stratification in middle to older-aged adults; however, the 2019 American College of Cardiology/American Heart Association guidelines state that more data are needed regarding the performance of CAC in low-risk younger adults. Methods and Results We measured CAC in 13 397 patients aged 30 to 49 years without known cardiovascular disease or malignancy between 1997 and 2009. Outcomes of myocardial infarction (MI), stroke, major adverse cardiovascular events (MACE; MI, stroke, or cardiovascular death), and all-cause mortality were assessed using Cox proportional hazard models, controlling for baseline risk factors (including atrial …

Gene Regulatory Networks Controlling Temporal Patterning, Neurogenesis, And Cell-Fate Specification In Mammalian Retina, Pin Lyu, Ariel E Telger, Brian S Clark, Et Al

Open Access Publications

Gene regulatory networks (GRNs), consisting of transcription factors and their target sites, control neurogenesis and cell-fate specification in the developing central nervous system. In this study, we use integrated single-cell RNA and single-cell ATAC sequencing (scATAC-seq) analysis in developing mouse and human retina to identify multiple interconnected, evolutionarily conserved GRNs composed of cell-type-specific transcription factors that both activate genes within their own network and inhibit genes in other networks. These GRNs control temporal patterning in primary progenitors, regulate transition from primary to neurogenic progenitors, and drive specification of each major retinal cell type. We confirm that NFI transcription factors selectively …

Burdens Of Post-Acute Sequelae Of Covid-19 By Severity Of Acute Infection, Demographics And Health Status, Yan Xie, Benjamin Bowe, Ziyad Al-Aly

Open Access Publications

The Post-Acute Sequelae of SARS-CoV-2 infection (PASC) have been characterized; however, the burden of PASC remains unknown. Here we used the healthcare databases of the US Department of Veterans Affairs to build a cohort of 181,384 people with COVID-19 and 4,397,509 non-infected controls and estimated that burden of PASC-defined as the presence of at least one sequela in excess of non-infected controls-was 73.43 (72.10, 74.72) per 1000 persons at 6 months. Burdens of individual sequelae varied by demographic groups (age, race, and sex) but were consistently higher in people with poorer baseline health and in those with more severe acute …

Angiotensin Receptor-Neprilysin Inhibition In Acute Myocardial Infarction, Marc A Pfeffer, Douglas L Mann, Et Al

Open Access Publications

BACKGROUND: In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking.

METHODS: We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident …

Estradiol Protects Against Noise-Induced Hearing Loss And Modulates Auditory Physiology In Female Mice, Benjamine Shuster, Ryan Casserly, Erika Lipford, Rafal Olszewski, Beatrice Milon, Shaun Viechweg, Kanisa Davidson, Jennifer Enoch, Mark Mcmurray, Mark A. Rutherford, Kevin K. Ohlemiller, Michael Hoa, Didier A. Depireux, Jessica A. Mong, Ronna Hertzano

Open Access Publications

No abstract provided.

Matched Cohort Study Of Germline Brca Mutation Carriers With Triple Negative Breast Cancer In Brightness, Otto Metzger-Filho, Katharine Collier, Sarah Asad, Mark Watson, Et Al

Open Access Publications

No abstract provided.

Ero1-Pdi Redox Signaling In Health And Disease, Vishwanath Jha, Tripti Kumari, Vijayprakash Manickam, Zahra Assar, Kirk L. Olsen, Jeong-Ki Min, Jaehyung Cho

Open Access Publications

No abstract provided.

Directed Flow Of Beta Band Communication During Reorienting Of Attention Within The Dorsal Attention Network, Sara Spadone, Miroslaw Wyczesany, Stefania Della Penna, Maurizio Corbetta, Paolo Capotosto

Open Access Publications

No abstract provided.

Cognitive Deficits And Impaired Hippocampal Long-Term Potentiation In K Atp-Induced Dend Syndrome, Shaul Yahil, David F Wozniak, Zihan Yan, Steven Mennerick, Maria S Remedi

Open Access Publications

ATP-sensitive potassium (K

Using Postmarket Surveillance To Assess Safety-Related Events In A Digital Rehabilitation App (Kaia App): Observational Study, Deeptee Jain, Kevin Norman, Zachary Werner, Bar Makovoz, Turner Baker, Stephan Huber

Open Access Publications

BACKGROUND: Low back pain (LBP) affects nearly 4 out of 5 individuals during their lifetime and is the leading cause of disability globally. Digital therapeutics are emerging as effective treatment options for individuals experiencing LBP. Despite the growth of evidence demonstrating the benefits of these therapeutics in reducing LBP and improving functional outcomes, little data has been systematically collected on their safety profiles.

OBJECTIVE: This study aims to evaluate the safety profile of a multidisciplinary digital therapeutic for LBP, the Kaia App, by performing a comprehensive assessment of reported adverse events (AEs) by users as captured by a standardized process …

Synaptic Zn 2+ Potentiates The Effects Of Cocaine On Striatal Dopamine Neurotransmission And Behavior, Juan L. Gomez, Marco Pignatelli, Et Al

Open Access Publications

No abstract provided.

Premature Differentiation Of Nephron Progenitor Cell And Dysregulation Of Gene Pathways Critical To Kidney Development In A Model Of Preterm Birth, Aleksandra Cwiek, Masako Suzuki, Kimberly Deronde, Mark Conaway, Kevin M Bennett, Samir El Dahr, Kimberly J Reidy, Jennifer R Charlton

Open Access Publications

Preterm birth is a leading cause of neonatal morbidity. Survivors have a greater risk for kidney dysfunction and hypertension. Little is known about the molecular changes that occur in the kidney of individuals born preterm. Here, we demonstrate that mice delivered two days prior to full term gestation undergo premature cessation of nephrogenesis, resulting in a lower glomerular density. Kidneys from preterm and term groups exhibited differences in gene expression profiles at 20- and 27-days post-conception, including significant differences in the expression of fat-soluble vitamin-related genes. Kidneys of the preterm mice exhibited decreased proportions of endothelial cells and a lower …