Digital Commons Network^™

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 …

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. …

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 …

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 …

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 …

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 …

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.

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 …

A Class Ii Mhc-Targeted Vaccine Elicits Immunity Against Sars-Cov-2 And Its Variants, Novalia Pishesha, Paul W Rothlauf, Mariel J Liebeskind, Maria A Vakaki, Louis-Marie Bloyet, Marjorie Cornejo Pontelli, Ma Xenia G Ilagan, William J Buchser, Sean P J Whelan, Et Al

Open Access Publications

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 100 million infections and millions of deaths. Effective vaccines remain the best hope of curtailing SARS-CoV-2 transmission, morbidity, and mortality. The vaccines in current use require cold storage and sophisticated manufacturing capacity, which complicates their distribution, especially in less developed countries. We report the development of a candidate SARS-CoV-2 vaccine that is purely protein based and directly targets antigen-presenting cells. It consists of the SARS-CoV-2 Spike receptor-binding domain (Spike

Long-Term Prognosis And Educational Determinants Of Brain Network Decline In Older Adult Individuals, Micaela Y Chan, Liang Han, Claudia A Carreno, Ziwei Zhang, Rebekah M Rodriguez, Megan Larose, Jason Hassenstab, Gagan S Wig

Open Access Publications

Older adults with lower education are at greater risk for dementia. It is unclear which brain changes lead to these outcomes. Longitudinal imaging-based measures of brain structure and function were examined in adult individuals (baseline age, 45-86 years; two to five visits per participant over 1-9 years). College degree completion differentiates individual-based and neighborhood-based measures of socioeconomic status and disadvantage. Older adults (~65 years and over) without a college degree exhibit a pattern of declining large-scale functional brain network organization (resting-state system segregation) that is less evident in their college-educated peers. Declining brain system segregation predicts impending changes in dementia …

Tai Chi For Cancer Survivors: A Systematic Review Toward Consensus-Based Guidelines, Lin Yang, Kerri Winters-Stone, Benny Rana, Chao Cao, Linda E Carlson, Kerry S Courneya, Christine M Friedenreich, Kathryn H Schmitz

Open Access Publications

To manage acute, long-term, and late effects of cancer, current guidelines recommend moderate-to-vigorous intensity aerobic and resistance exercise. Unfortunately, not all cancer survivors are able or willing to perform higher intensity exercise during difficult cancer treatments or because of other existing health conditions. Tai Chi is an equipment-free, multicomponent mind-body exercise performed at light-to-moderate intensity that may provide a more feasible alternative to traditional exercise programs for some cancer survivors. This systematic review evaluated the therapeutic efficacy of Tai Chi across the cancer care continuum. We searched MEDLINE/PubMed, Embase, SCOPUS, and CINAHL databases for interventional studies from inception to 18 …

Diagnostics To Support Elimination Of Lymphatic Filariasis-Development Of Two Target Product Profiles, Kimberly Y. Won, Gary J. Weil, Et Al

Open Access Publications

As lymphatic filariasis (LF) programs move closer to established targets for validation elimination of LF as a public health problem, diagnostic tools capable of supporting the needs of the programs are critical for success. Known limitations of existing diagnostic tools make it challenging to have confidence that program endpoints have been achieved. In 2019, the World Health Organization (WHO) established a Diagnostic Technical Advisory Group (DTAG) for Neglected Tropical Diseases tasked with prioritizing diagnostic needs including defining use-cases and target product profiles (TPPs) for needed tools. Subsequently, disease-specific DTAG subgroups, including one focused on LF, were established to develop TPPs …

Cardiac Myosin Contraction And Mechanotransduction In Health And Disease, Samantha K Barrick, Michael J Greenberg

Open Access Publications

Cardiac myosin is the molecular motor that powers heart contraction by converting chemical energy from ATP hydrolysis into mechanical force. The power output of the heart is tightly regulated to meet the physiological needs of the body. Recent multiscale studies spanning from molecules to tissues have revealed complex regulatory mechanisms that fine-tune cardiac contraction, in which myosin not only generates power output but also plays an active role in its regulation. Thus, myosin is both shaped by and actively involved in shaping its mechanical environment. Moreover, these studies have shown that cardiac myosin-generated tension affects physiological processes beyond muscle contraction. …

Development Of A Resource Guide To Help Patients Receive Appropriate Care, Erin D Solomon, Heidi Walsh, Meredith Parsons, Tristan Mcintosh, Jessica Mozersky, James M Dubois

Open Access Publications

After 10 years researching physician wrongdoing (i.e., sexual violations, improper prescribing, and unnecessary procedures), we developed a resource guide to help patients receive appropriate care and respond to inappropriate care. We gathered evaluative patient feedback, engaged physicians, and disseminated the guide. It is available at beforeyourvisit.org.

Factors Associated With The Mechanism Of Acl Tears In The National Football League: A Video-Based Analysis, Robert Brophy, Edward Wojtys, Christina Mack, Kalyani Hawaldar, Mackenzie Herzog, Brett D Owens

Open Access Publications

Background: The factors associated with anterior cruciate ligament (ACL) injury mechanism in professional American football players are not well-understood.

Hypothesis: It was hypothesized that football-related and player-specific factors, such as position and body mass index (BMI), are associated with ACL injury mechanism in these athletes.

Study Design: Descriptive epidemiology study.

Methods: Videos of ACL tears occurring in National Football League (NFL) games over 6 consecutive seasons from 2014 to 2019 were reviewed by 2 orthopaedic surgeons who specialize in sports medicine. For each injury, the role of contact (

Results: Of the 140 ACL tears, a minority occurred via direct …

Cardiac Stereotactic Ablative Radiotherapy For Control Of Refractory Ventricular Tachycardia: Initial Uk Multicentre Experience, Justin Lee, Clifford Robinson, Phillip Cuculich, Geoffrey Hugo, Et Al

Open Access Publications

BACKGROUND: Options for patients with ventricular tachycardia (VT) refractory to antiarrhythmic drugs and/or catheter ablation remain limited. Stereotactic radiotherapy has been described as a novel treatment option.

METHODS: Seven patients with recurrent refractory VT, deemed high risk for either first time or redo invasive catheter ablation, were treated across three UK centres with non-invasive cardiac stereotactic ablative radiotherapy (SABR). Prior catheter ablation data and non-invasive mapping were combined with cross-sectional imaging to generate radiotherapy plans with aim to deliver a single 25 Gy treatment. Shared planning and treatment guidelines and prospective peer review were used.

RESULTS: Acute suppression of VT …

Biofilm Formation And Virulence Of Shigella Flexneri Are Modulated By Ph Of Gastrointestinal Tract, I-Ling Chiang, Yi Wang, Satoru Fujii, Brian D Muegge, Qiuhe Lu, Phillip I Tarr, Thaddeus S Stappenbeck

Open Access Publications

No abstract provided.

Mast Cell Activation Symptoms Are Prevalent In Long-Covid, Leonard B Weinstock, Jill B Brook, Arthur S Walters, Ashleigh Goris, Lawrence B Afrin, Gerhard J Molderings

Open Access Publications

OBJECTIVES: Hyper-inflammation caused by COVID-19 may be mediated by mast cell activation (MCA) which has also been hypothesized to cause Long-COVID (LC) symptoms. We determined prevalence/severity of MCA symptoms in LC.

METHODS: Adults in LC-focused Facebook support groups were recruited for online assessment of symptoms before and after COVID-19. Questions included presence and severity of known MCA and LC symptoms and validated assessments of fatigue and quality of life. General population controls and mast cell activation syndrome (MCAS) patients were recruited for comparison if they were ≥18 years of age and never had overt COVID-19 symptoms.

RESULTS: There were 136 …