Digital Commons Network^™

Emergence Of Compensatory Mutations Reveals The Importance Of Electrostatic Interactions Between Hiv-1 Integrase And Genomic Rna, Christian Shema Mugisha, Tung Dinh, Abhishek Kumar, Kasyap Tenneti, Jenna E Eschbach, Keanu Davis, Robert Gifford, Mamuka Kvaratskhelia, Sebla B Kutluay

2020-Current year OA Pubs

HIV-1 integrase (IN) has a noncatalytic function in virion maturation through its binding to the viral RNA genome (gRNA). Class II IN substitutions inhibit IN-gRNA binding and result in the formation of virions with aberrant morphologies marked by mislocalization of the gRNA between the capsid lattice and the lipid envelope. These viruses are noninfectious due to a block at an early reverse transcription stage in target cells. HIV-1 IN utilizes basic residues within its C-terminal domain (CTD) to bind to the gRNA; however, the molecular nature of how these residues mediate gRNA binding and whether other regions of IN are …

Marijuana Use And Dna Methylation-Based Biological Age In Young Adults, Drew R Nannini, Yinan Zheng, Brian T Joyce, Tao Gao, Lei Liu, David R Jacobs Jr, Pamela Schreiner, Chunyu Liu, Steve Horvath, Ake T Lu, Kristine Yaffe, Stephen Sidney, Philip Greenland, Donald M Lloyd-Jones, Lifang Hou

2020-Current year OA Pubs

BACKGROUND: Marijuana is the third most commonly used drug in the USA and efforts to legalize it for medical and recreational use are growing. Despite the increase in use, marijuana's effect on aging remains understudied and understanding the effects of marijuana on molecular aging may provide novel insights into the role of marijuana in the aging process. We therefore sought to investigate the association between cumulative and recent use of marijuana with epigenetic age acceleration (EAA) as estimated from blood DNA methylation.

RESULTS: A random subset of participants from The Coronary Artery Risk Development in Young Adults (CARDIA) Study with …

Pooled Image-Base Screening Of Mitochondria With Microraft Isolation Distinguishes Pathogenic Mitofusin 2 Mutations, Alex L Yenkin, John C Bramley, Colin L Kremitzki, Jason E Waligorski, Mariel J Liebeskind, Xinyuan E Xu, Vinay D Chandrasekaran, Maria A Vakaki, Graham W Bachman, Robi D Mitra, Jeffrey D Milbrandt, William J Buchser

2020-Current year OA Pubs

Most human genetic variation is classified as variants of uncertain significance. While advances in genome editing have allowed innovation in pooled screening platforms, many screens deal with relatively simple readouts (viability, fluorescence) and cannot identify the complex cellular phenotypes that underlie most human diseases. In this paper, we present a generalizable functional genomics platform that combines high-content imaging, machine learning, and microraft isolation in a method termed "Raft-Seq". We highlight the efficacy of our platform by showing its ability to distinguish pathogenic point mutations of the mitochondrial regulator Mitofusin 2, even when the cellular phenotype is subtle. We also show …

Novel Chelating Agents For Zirconium-89-Positron Emission Tomography (Pet) Imaging: Synthesis, Dft Calculation, Radiolabeling, And In Vitro And In Vivo Complex Stability, Chi Soo Kang, Shuyuan Zhang, Haixing Wang, Yujie Liu, Siyuan Ren, Yanda Chen, Jingbai Li, Nilantha Bandara, Andrey Yu Rogachev, Buck E Rogers, Hyun-Soon Chong

2020-Current year OA Pubs

We report the synthesis and evaluation of novel chelating agents for zirconium-89 (

Human Neutrophil Development And Functionality Are Enabled In A Humanized Mouse Model, Yunjiang Zheng, Esen Sefik, John Astle, Kutay Karatepe, Hasan H Öz, Angel G Solis, Ruaidhrí Jackson, Hongbo R Luo, Emanuela M Bruscia, Stephanie Halene, Liang Shan, Richard A Flavell

2020-Current year OA Pubs

Mice with a functional human immune system serve as an invaluable tool to study the development and function of the human immune system in vivo. A major technological limitation of all current humanized mouse models is the lack of mature and functional human neutrophils in circulation and tissues. To overcome this, we generated a humanized mouse model named MISTRGGR, in which the mouse granulocyte colony-stimulating factor (G-CSF) was replaced with human G-CSF and the mouse G-CSF receptor gene was deleted in existing MISTRG mice. By targeting the G-CSF cytokine-receptor axis, we dramatically improved the reconstitution of mature circulating and tissue-infiltrating …

Ring-Fused 2-Pyridones Effective Against Multidrug-Resistant Gram-Positive Pathogens And Synergistic With Standard-Of-Care Antibiotics, Taylor M Nye, Hasan Tükenmez, Pardeep Singh, Ana L Flores-Mireles, Chloe L P Obernuefemann, Jerome S Pinkner, Souvik Sarkar, Mari Bonde, Anders E G Lindgren, Karen W Dodson, Jörgen Johansson, Fredrik Almqvist, Michael G Caparon, Scott J Hultgren

2020-Current year OA Pubs

The alarming rise of multidrug-resistant Gram-positive bacteria has precipitated a healthcare crisis, necessitating the development of new antimicrobial therapies. Here we describe a new class of antibiotics based on a ring-fused 2-pyridone backbone, which are active against vancomycin-resistant enterococci (VRE), a serious threat as classified by the Centers for Disease Control and Prevention, and other multidrug-resistant Gram-positive bacteria. Ring-fused 2-pyridone antibiotics have bacteriostatic activity against actively dividing exponential phase enterococcal cells and bactericidal activity against nondividing stationary phase enterococcal cells. The molecular mechanism of drug-induced killing of stationary phase cells mimics aspects of fratricide observed in enterococcal biofilms, where both …

Discovery Of A Novel Genomic Alteration That Renders Leukemic Cells Resistant To Cd19-Targeted Immunotherapies, Armin Ghobadi, Jack H Landmann, Alun Carter, Matthew L Cooper, Mehmet Emrah Selli, Jufang Chang, Christopher A Miller, Francesca Ferraro, David Y Chen, Amanda M Smith, Taylor A Lavalle, Eric J Duncavage, Nathan Singh, Et Al.

2020-Current year OA Pubs

No abstract provided.

Somatic Mutations In Fat Cadherin Family Members Constitute An Underrecognized Subtype Of Colorectal Adenocarcinoma With Unique Clinicopathologic Features, Liang-Li Wang, Wei Zheng, Xiu-Li Liu, Feng Yin

2020-Current year OA Pubs

BACKGROUND: The FAT cadherin family members (FAT1, FAT2, FAT3 and FAT4) are conserved tumor suppressors that are recurrently mutated in several types of human cancers, including colorectal carcinoma (CRC).

AIM: To characterize the clinicopathologic features of CRC patients with somatic mutations in FAT cadherin family members.

METHODS: We analyzed 526 CRC cases from The Cancer Genome Atlas PanCancer Atlas dataset. CRC samples were subclassified into 2 groups based on the presence or absence of somatic mutations in

RESULTS: This CRC study cohort had frequent mutations in the

CONCLUSION:

The Impact Of Tsc-1 And -2 Mutations On Response To Therapy In Malignant Pecoma: A Multicenter Retrospective Analysis, Lawrence Liu, Nikhil Grandhi, Yang Lyu, Xiao Zhang, Jingqin Luo, Mia Weiss, Brian Van Tine, Angela C Hirbe, Et Al.

2020-Current year OA Pubs

BACKGROUND: Perivascular epithelioid cell neoplasms (PEComas) are a diverse family of mesenchymal tumors with myomelanocytic differentiation that disproportionately affect women and can be associated with tuberous sclerosis (TS). Although mTOR inhibition is widely used as first-line treatment, it is unclear what genomic alterations exist in these tumors and how they influence the response to therapy.

METHODS: This was a multicenter study conducted at five sites within the US. The data were collected from 1 January 2004 to 31 January 2021. We conducted a retrospective analysis to identify PEComa patients with next-generation sequencing (NGS) data and compared outcomes based on mutations. …

Personalized Ctdna Micro-Panels Can Monitor And Predict Clinical Outcomes For Patients With Triple-Negative Breast Cancer, Erica K Barnell, Bryan Fisk, Zachary L Skidmore, Kelsy C Cotto, Anamika Basu, Aparna Anand, Megan M Richters, Jingqin Luo, Catrina Fronick, Meenakshi Anurag, Robert Fulton, Matthew J Ellis, Obi L Griffith, Malachi Griffith, Foluso O Ademuyiwa

2020-Current year OA Pubs

Circulating tumor DNA (ctDNA) in peripheral blood has been used to predict prognosis and therapeutic response for triple-negative breast cancer (TNBC) patients. However, previous approaches typically use large comprehensive panels of genes commonly mutated across all breast cancers. Given the reduction in sequencing costs and decreased turnaround times associated with panel generation, the objective of this study was to assess the use of custom micro-panels for tracking disease and predicting clinical outcomes for patients with TNBC. Paired tumor-normal samples from patients with TNBC were obtained at diagnosis (T0) and whole exome sequencing (WES) was performed to identify somatic variants associated …

The Mechanics Of Implementation Strategies And Measures: Advancing The Study Of Implementation Mechanisms, Cara C Lewis, Predrag Klasnja, Aaron R Lyon, Byron J Powell, Rebecca Lengnick-Hall, Gretchen Buchanan, Rosemary D Meza, Michelle C Chan, Marcella H Boynton, Bryan J Weiner

2020-Current year OA Pubs

BACKGROUND: There is a fundamental gap in understanding the causal mechanisms by which strategies for implementing evidence-based practices address local barriers to effective, appropriate service delivery. Until this gap is addressed, scientific knowledge and practical guidance about which implementation strategies to use in which contexts will remain elusive. This research project aims to identify plausible strategy-mechanism linkages, develop causal models for mechanism evaluation, produce measures needed to evaluate such linkages, and make these models, methods, and measures available in a user-friendly website. The specific aims are as follows: (1) build a database of strategy-mechanism linkages and associated causal pathway diagrams, …

A Randomized Feasibility Pilot-Study Of Intravenous And Subcutaneous Administration Of Ketamine To Prevent Postpartum Depression After Planned Cesarean Delivery Under Neuraxial Anesthesia, David Thomas Monks, Arvind Palanisamy, Danish Jaffer, Preet Mohinder Singh, Ebony Carter, Shannon Lenze

2020-Current year OA Pubs

BACKGROUND: Evidence suggests ketamine may prevent postpartum depression (PPD) after cesarean delivery (CD) although intolerability and inconvenience of administration are problematic. We assessed the feasibility of studying ketamine (0.5 mg/kg, via subcutaneous injection or 40-min intravenous infusion) to prevent PPD after CD.

METHODS: Twenty-three women scheduled for cesarean delivery under neuraxial anesthesia were randomized to one of three groups: subcutaneous ketamine (SC Group, n = 8), intravenous ketamine (IV Group, n = 8) or placebo (n = 7). We measured depression (Edinburgh Postpartum Depression Scale [EPDS]) scores pre-operatively and at 1, 2, 21 and 42 days postoperatively. Anxiety, adverse effects, …

Integrated Host-Microbe Plasma Metagenomics For Sepsis Diagnosis In A Prospective Cohort Of Critically Ill Adults, Katrina L Kalantar, Pratik Sinha, Et Al.

2020-Current year OA Pubs

We carried out integrated host and pathogen metagenomic RNA and DNA next generation sequencing (mNGS) of whole blood (n = 221) and plasma (n = 138) from critically ill patients following hospital admission. We assigned patients into sepsis groups on the basis of clinical and microbiological criteria. From whole-blood gene expression data, we distinguished patients with sepsis from patients with non-infectious systemic inflammatory conditions using a trained bagged support vector machine (bSVM) classifier (area under the receiver operating characteristic curve (AUC) = 0.81 in the training set; AUC = 0.82 in a held-out validation set). Plasma RNA also yielded a …

A Comparison Of Bioimpedance Analysis Vs. Dual X-Ray Absorptiometry For Body Composition Assessment In Postpartum Women And Non-Postpartum Controls, Valene Garr Barry, Samantha L Martin, Paula Chandler-Laney, Ebony B Carter, Camille S Worthington

2020-Current year OA Pubs

Postpartum fat mass (FM) and fat-free mass (FFM) may be informative predictors of future disease risk among women; hence, there is growing use of bioelectrical impedance analysis (BIA) to quantify FFM and FM among postpartum women due to the quick, non-invasive, and inexpensive nature of BIA. Despite this, very few studies have examined BIA's performance, and it remains unclear as to whether specific BIA equations are needed for postpartum women. To explore these questions, we measured total body FFM and FM with a multi-frequency, segmental BIA, and dual-X-ray absorptiometry (DXA) in (1) women at one and four months postpartum (

Complete Genome Sequence Of The Uropathogenic Methicillin-Resistant Staphylococcus Aureus Strain Mrsa-1369, Hasan Tükenmez, Taylor M Nye, Mari Bonde, Michael G Caparon, Fredrik Almqvist, Scott J Hultgren, Jörgen Johansson

2020-Current year OA Pubs

MRSA-1369 is a uropathogenic methicillin-resistant Staphylococcus aureus (MRSA) strain. Here, we present the complete genome sequence of MRSA-1369, which consists of one chromosome (2.87 Mb) and two plasmids (16.68 kb and 3.13 kb). This will serve as a reference genome for future Staphylococcus aureus pathogenesis and multiomic studies.

Neoplastic Cell Enrichment Of Tumor Tissues Using Coring And Laser Microdissection For Proteomic And Genomic Analyses Of Pancreatic Ductal Adenocarcinoma, Qing Kay Li, Daniel Cui Zhou, Yize Li, Rita Jui-Hsien Lu, Li Ding, Et Al.

2020-Current year OA Pubs

BACKGROUND: The identification of differentially expressed tumor-associated proteins and genomic alterations driving neoplasia is critical in the development of clinical assays to detect cancers and forms the foundation for understanding cancer biology. One of the challenges in the analysis of pancreatic ductal adenocarcinoma (PDAC) is the low neoplastic cellularity and heterogeneous composition of bulk tumors. To enrich neoplastic cells from bulk tumor tissue, coring, and laser microdissection (LMD) sampling techniques have been employed. In this study, we assessed the protein and KRAS mutation changes associated with samples obtained by these enrichment techniques and evaluated the fraction of neoplastic cells in …

Semi-Automated Assembly Of High-Quality Diploid Human Reference Genomes, Erich D Jarvis, Sarah Cody, Robert S Fulton, Lucinda L Fulton, Daofeng Li, Tina Lindsay, Nathan O Stitziel, Ting Wang, Et Al.

2020-Current year OA Pubs

The current human reference genome, GRCh38, represents over 20 years of effort to generate a high-quality assembly, which has benefitted society^1,2. However, it still has many gaps and errors, and does not represent a biological genome as it is a blend of multiple individuals^3,4. Recently, a high-quality telomere-to-telomere reference, CHM13, was generated with the latest long-read technologies, but it was derived from a hydatidiform mole cell line with a nearly homozygous genome⁵. To address these limitations, the Human Pangenome Reference Consortium formed with the goal of creating high-quality, cost-effective, diploid genome assemblies for a …

Can The "Female Protective Effect" Liability Threshold Model Explain Sex Differences In Autism Spectrum Disorder?, Joseph D Dougherty, Natasha Marrus, Susan E Maloney, Benjamin Yip, Sven Sandin, Tychele N Turner, Din Selmanovic, Kristen L Kroll, David H Gutmann, John N Constantino, Lauren A Weiss

2020-Current year OA Pubs

Male sex is a strong risk factor for autism spectrum disorder (ASD). The leading theory for a "female protective effect" (FPE) envisions males and females have "differing thresholds" under a "liability threshold model" (DT-LTM). Specifically, this model posits that females require either a greater number or larger magnitude of risk factors (i.e., greater liability) to manifest ASD, which is supported by the finding that a greater proportion of females with ASD have highly penetrant genetic mutations. Herein, we derive testable hypotheses from the DT-LTM for ASD, investigating heritability, familial recurrence, correlation between ASD penetrance and sex ratio, population traits, clinical …

Activity-Dependent Translation Dynamically Alters The Proteome Of The Perisynaptic Astrocyte Process, Darshan Sapkota, Kristina Sakers, Kayla R Nygaard, Yating Liu, Sarah K Koester, Stuart B Fass, Allison M Lake, Rohan Khazanchi, Susan E Maloney, Joseph D Dougherty, Et Al.

2020-Current year OA Pubs

Within eukaryotic cells, translation is regulated independent of transcription, enabling nuanced, localized, and rapid responses to stimuli. Neurons respond transcriptionally and translationally to synaptic activity. Although transcriptional responses are documented in astrocytes, here we test whether astrocytes have programmed translational responses. We show that seizure activity rapidly changes the transcripts on astrocyte ribosomes, some predicted to be downstream of BDNF signaling. In acute slices, we quantify the extent to which cues of neuronal activity activate translation in astrocytes and show that this translational response requires the presence of neurons, indicating that the response is non-cell autonomous. We also show that …

Prenatal Exposure To Maternal Social Disadvantage And Psychosocial Stress And Neonatal White Matter Connectivity At Birth, Rachel E Lean, Christopher D Smyser, Rebecca G Brady, Regina L Triplett, Sydney Kaplan, Jeanette K Kenley, Joshua S Shimony, Tara A Smyser, J Phillip Miller, Deanna M Barch, Joan L Luby, Barbara B Warner, Cynthia E Rogers

2020-Current year OA Pubs

Early life adversity (social disadvantage and psychosocial stressors) is associated with altered microstructure in fronto-limbic pathways important for socioemotional development. Understanding when these associations begin to emerge may inform the timing and design of preventative interventions. In this longitudinal study, 399 mothers were oversampled for low income and completed social background measures during pregnancy. Measures were analyzed with structural equation analysis resulting in two latent factors: social disadvantage (education, insurance status, income-to-needs ratio [INR], neighborhood deprivation, and nutrition) and psychosocial stress (depression, stress, life events, and racial discrimination). At birth, 289 healthy term-born neonates underwent a diffusion MRI (dMRI) scan. …

Cellular Landscaping Of Covid-19 And Gynaecological Cancers: An Infrequent Correlation, Rahul Bhattacharjee, Debanjan Das, Radheka Bhadhuri, Srija Chakraborty, Tanima Dey, Rupam Buragohain, Asim Nath, Kartik Muduli, Pranjan Barman, Rohit Gundamaraju

2020-Current year OA Pubs

COVID-19 resulted in a mortality rate of 3-6% caused by SARS-CoV-2 and its variant leading to unprecedented consequences of acute respiratory distress septic shock and multiorgan failure. In such a situation, evaluation, diagnosis, treatment, and care for cancer patients are difficult tasks faced by medical staff. Moreover, patients with gynaecological cancer appear to be more prone to severe infection and mortality from COVID-19 due to immunosuppression by chemotherapy and coexisting medical disorders. To deal with such a circumtances oncologists have been obliged to reconsider the entire diagnostic, treatment, and management approach. This review will provide and discuss the molecular link …

A Quantitative Metric Of Pioneer Activity Reveals That Hnf4a Has Stronger In Vivo Pioneer Activity Than Foxa1, Jeffrey L Hansen, Barak A Cohen

2020-Current year OA Pubs

BACKGROUND: We and others have suggested that pioneer activity - a transcription factor's (TF's) ability to bind and open inaccessible loci - is not a qualitative trait limited to a select class of pioneer TFs. We hypothesize that most TFs display pioneering activity that depends on the TF concentration and the motif content at their target loci.

RESULTS: Here, we present a quantitative in vivo measure of pioneer activity that captures the relative difference in a TF's ability to bind accessible versus inaccessible DNA. The metric is based on experiments that use CUT&Tag to measure the binding of doxycycline-inducible TFs. …

Cross-Species Efficacy Of Enzyme Replacement Therapy For Cln1 Disease In Mice And Sheep, Hemanth R. Nelvagal, Sophie H. Wang, Elizabeth M. Eultgen, Keigo Takashash, Steven Q. Le, Rachel Nesbitt, Joshua T. Dearborn, Patricia I. Dickson, Mark S. Sands, Jonathan D. Cooper, Et Al.

2020-Current year OA Pubs

CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by administering monthly infusions of recombinant human PPT1 (rhPPT1) to PPT1-deficient …

Il-1Β-Dependent Extravasation Of Preexisting Lung-Restricted Autoantibodies During Lung Transplantation Activates Complement And Mediates Primary Graft Dysfunction, Wenbin Yang, Daniel Kreisel, Et Al.

2020-Current year OA Pubs

Preexisting lung-restricted autoantibodies (LRAs) are associated with a higher incidence of primary graft dysfunction (PGD), although it remains unclear whether LRAs can drive its pathogenesis. In syngeneic murine left lung transplant recipients, preexisting LRAs worsened graft dysfunction, which was evident by impaired gas exchange, increased pulmonary edema, and activation of damage-associated pathways in lung epithelial cells. LRA-mediated injury was distinct from ischemia-reperfusion injury since deletion of donor nonclassical monocytes and host neutrophils could not prevent graft dysfunction in LRA-pretreated recipients. Whole LRA IgG molecules were necessary for lung injury, which was mediated by the classical and alternative complement pathways and …

Hsf1 Is A Driver Of Leukemia Stem Cell Self-Renewal In Acute Myeloid Leukemia, Qianze Dong, Nick Borcherding, Et Al.

2020-Current year OA Pubs

Acute myeloid leukemia (AML) is maintained by self-renewing leukemic stem cells (LSCs). A fundamental problem in treating AML is that conventional therapy fails to eliminate LSCs, which can reinitiate leukemia. Heat shock transcription factor 1 (HSF1), a central regulator of the stress response, has emerged as an important target in cancer therapy. Using genetic Hsf1 deletion and a direct HSF1 small molecule inhibitor, we show that HSF1 is specifically required for the maintenance of AML, while sparing steady-state and stressed hematopoiesis. Mechanistically, deletion of Hsf1 dysregulates multifaceted genes involved in LSC stemness and suppresses mitochondrial oxidative phosphorylation through downregulation of …

Bold Cofluctuation 'Events' Are Predicted From Static Functional Connectivity, Zach Ladwig, Benjamin A. Seitzman, Ally Dworetsky, Yuhua Yu, Babatunde Adeyemo, Derek M. Smith, Steven E. Petersen, Caterina Gratton

2020-Current year OA Pubs

Recent work identified single time points ("events") of high regional cofluctuation in functional Magnetic Resonance Imaging (fMRI) which contain more large-scale brain network information than other, low cofluctuation time points. This suggested that events might be a discrete, temporally sparse signal which drives functional connectivity (FC) over the timeseries. However, a different, not yet explored possibility is that network information differences between time points are driven by sampling variability on a constant, static, noisy signal. Using a combination of real and simulated data, we examined the relationship between cofluctuation and network structure and asked if this relationship was unique, or …

Trial Of Ultrasound Guided Carpal Tunnel Release Versus Traditional Open Release (Tutor), Kyle R. Eberlin, Christopher J. Dy, Mark D. Fischer, James L. Gluck, F. Thomas D. Kaplan, Thomas J. Mcdonald, Larry E. Miller, Alexander Palmer, Marc E. Walker, James F. Watt

2020-Current year OA Pubs

BACKGROUND: Carpal tunnel release (CTR) is a surgical treatment option for patients with carpal tunnel syndrome (CTS) symptoms that are unresponsive to conservative treatment. Most patients experience symptomatic relief after CTR regardless of the surgical technique. However, direct comparisons of the safety and effectiveness between CTR surgical techniques are limited. The purpose of this randomized controlled trial is to compare the safety and effectiveness of CTR with ultrasound guidance (CTR-US) versus mini-open CTR (mOCTR) in subjects with symptomatic CTS.

DESIGN AND METHODS: TUTOR (Trial of Ultrasound guided CTR versus Traditional Open Release) is a randomized controlled trial in which 120 …

Predicting Postoperative Troponin In Patients Undergoing Elective Hip Or Knee Arthroplasty: A Comparison Of Five Cardiac Risk Prediction Tools, Merih T Tesfazghi, Anne R Bass, Noor Al-Hammadi, Scott C Woller, Scott M Stevens, Charles S Eby, Mitchell G Scott, Lindsey Snyder, Troy S Wildes, Brian F Gage

2020-Current year OA Pubs

BACKGROUND: Elderly patients undergoing hip or knee arthroplasty are at a risk for myocardial injury after noncardiac surgery (MINS). We evaluated the ability of five common cardiac risk scores, alone or combined with baseline high-sensitivity cardiac troponin I (hs-cTnI), in predicting MINS and postoperative day 2 (POD2) hs-cTnI levels in patients undergoing elective total hip or knee arthroplasty.

METHODS: This study is ancillary to the Genetics-InFormatics Trial (GIFT) of Warfarin Therapy to Prevent Deep Venous Thrombosis, which enrolled patients 65 years and older undergoing elective total hip or knee arthroplasty. The five cardiac risk scores evaluated were the atherosclerotic cardiovascular …

Impact Of The Covid-19 Pandemic On The Implementation Of Mobile Health To Improve The Uptake Of Hydroxyurea In Patients With Sickle Cell Disease: Mixed Methods Study, Sherif M Badawy, Lisa Dimartino, Donald Brambilla, Lisa Klesges, Ana Baumann, Ebony Burns, Terri Demartino, Sara Jacobs, Hamda Khan, Chinonyelum Nwosu, Nirmish Shah, Jane S Hankins, Sickle Cell Disease Implementation Consortium

2020-Current year OA Pubs

BACKGROUND: Hydroxyurea therapy is effective for reducing complications related to sickle cell disease (SCD) and is recommended by National Health Lung and Blood Institute care guidelines. However, hydroxyurea is underutilized, and adherence is suboptimal. We wanted to test a multilevel mobile health (mHealth) intervention to increase hydroxyurea adherence among patients and improve prescribing among providers in a multicenter clinical trial. In the first 2 study sites, participants were exposed to the early phases of the COVID-19 pandemic, which included disruption to their regular SCD care.

OBJECTIVE: We aimed to describe the impact of the COVID-19 pandemic on the implementation of …

Personalized Structural Biology Reveals The Molecular Mechanisms Underlying Heterogeneous Epileptic Phenotypes Caused By De Novo Kcnc2 Variants, Souhrid Mukherjee, Jonathan H Sheehan, Et Al.

2020-Current year OA Pubs

Whole-exome sequencing (WES) in the clinic has identified several rare monogenic developmental and epileptic encephalopathies (DEE) caused by ion channel variants. However, WES often fails to provide actionable insight for rare diseases, such as DEEs, due to the challenges of interpreting variants of unknown significance (VUS). Here, we describe a "personalized structural biology" (PSB) approach that leverages recent innovations in the analysis of protein 3D structures to address this challenge. We illustrate this approach in an Undiagnosed Diseases Network (UDN) individual with DEE symptoms and a