Digital Commons Network^™

Reproducibility Of Hospital Rankings Based On Centers For Medicare & Medicaid Services Hospital Compare Measures As A Function Of Measure Reliability, Laurent G. Glance, David R. Nerenz, Karen E. Joynt Maddox, Bruce L. Hall, Andrew W. Dick

Open Access Publications

Importance: Unreliable performance measures can mask poor-quality care and distort financial incentives in value-based purchasing.

Objective: To examine the association between test-retest reliability and the reproducibility of hospital rankings.

Design, Setting, and Participants: In a cross-sectional design, Centers for Medicare & Medicaid Services Hospital Compare data were analyzed for the 2017 (based on 2014-2017 data) and 2018 (based on 2015-2018 data) reporting periods. The study was conducted from December 13, 2020, to September 30, 2021. This analysis was based on 28 measures, including mortality (acute myocardial infarction, congestive heart failure, pneumonia, and coronary artery bypass grafting), readmissions (acute myocardial infarction, …

Infectious Disease Providers’ Knowledge Of And Engagement In Quality Improvement, Kathleen R. Sheridan, Michael A. Lane, Thomas J. Kim, Joshua C. Eby

Open Access Publications

No abstract provided.

Risk Factors And Medical Resource Utilization Of Respiratory Syncytial Virus, Human Metapneumovirus, And Influenza-Related Hospitalizations In Adults—A Global Study During The 2017–2019 Epidemic Seasons (Hospitalized Acute Respiratory Tract Infection [Harti] Study), Ann R. Falsey, Edward E. Walsh, Yannick Vandenijck, Xiaohui Ren, Sofia Keim, Diye Kang, Pascale Peeters, James Witek, Gabriela Ispas

Open Access Publications

No abstract provided.

A Randomized, Placebo-Controlled Trial Assessing The Effect Of Visbiome Es Probiotic In People With Hiv On Antiretroviral Therapy, Rachel M. Presti, Et Al

Open Access Publications

Background: A5350, a phase II, randomized, double-blind study, evaluated the safety and tolerability of the probiotic Visbiome Extra Strength (ES) over 24 weeks and measured effects on inflammation and intestinal barrier function.

Methods: The primary outcome was change in soluble CD14 (sCD14) levels; secondary outcomes included safety and tolerability, markers of inflammation and cellular activation, and microbiome. In a substudy, gut permeability was assessed by paired colonic biopsies measuring the area of lamina propria occupied by CD4+ cells, interleukin (IL)-17+ cells, and myeloperoxidase (MPO). Changes between arms were compared with the 2-sample

Results: Overall, 93 participants enrolled: 86% male, median …

Inhibitor Of Growth Protein 3 Epigenetically Silences Endogenous Retroviral Elements And Prevents Innate Immune Activation, Yanhua Song, Gaopeng Hou, Jonathan Diep, Yaw Shin Ooi, Natalia S. Akopyants, Stephen M. Beverley, Jan E. Carette, Harry B. Greenberg, Siyuan Ding

Open Access Publications

Endogenous retroviruses (ERVs) are subject to transcriptional repression in adult tissues, in part to prevent autoimmune responses. However, little is known about the epigenetic silencing of ERV expression. Here, we describe a new role for inhibitor of growth family member 3 (ING3), to add to an emerging group of ERV transcriptional regulators. Our results show that ING3 binds to several ERV promoters (for instance MER21C) and establishes an EZH2-mediated H3K27 trimethylation modification. Loss of ING3 leads to decreases of H3K27 trimethylation enrichment at ERVs, induction of MDA5-MAVS-interferon signaling, and functional inhibition of several virus infections. These data demonstrate an important …

The Genetic Architecture Of A Congenital Heart Defect Is Related To Its Fitness Cost, Ehiole Akhirome, Suk D Regmi, Rachel A Magnan, Nelson Ugwu, Yidan Qin, Claire E Schulkey, James M Cheverud, Patrick Y Jay

Open Access Publications

In newborns, severe congenital heart defects are rarer than mild ones. This epidemiological relationship between heart defect severity and incidence lacks explanation. Here, an analysis of ~10,000

Human B Cell Lineages Associated With Germinal Centers Following Influenza Vaccination Are Measurably Evolving, Kenneth B. Hoehn, Jackson S. Turner, Frederick I. Miller, Ruoyi Jiang, Oliver G. Pybus, Ali H. Ellebedy, Steven H. Kleinstein

Open Access Publications

The poor efficacy of seasonal influenza virus vaccines is often attributed to pre-existing immunity interfering with the persistence and maturation of vaccine-induced B cell responses. We previously showed that a subset of vaccine-induced B cell lineages are recruited into germinal centers (GCs) following vaccination, suggesting that affinity maturation of these lineages against vaccine antigens can occur. However, it remains to be determined whether seasonal influenza vaccination stimulates additional evolution of vaccine-specific lineages, and previous work has found no significant increase in somatic hypermutation among influenza-binding lineages sampled from the blood following seasonal vaccination in humans. Here, we investigate this issue …

Toxoplasma Bradyzoites Exhibit Physiological Plasticity Of Calcium And Energy Stores Controlling Motility And Egress, Yong Fu, Kevin M. Brown, Nathaniel G. Jones, Silvia N.J. Moreno, L. David Sibley

Open Access Publications

No abstract provided.

Flexor Tendon Injury And Repair: The Influence Of Synovial Environment On The Early Healing Response In A Canine Mode, Hua Shen, Susumu Yoneda, Shelly E Sakiyama-Elbert, Qiang Zhang, Stavros Thomopoulos, Richard H Gelberman

Open Access Publications

BACKGROUND: Environmental conditions strongly influence the healing capacity of connective tissues. Well-vascularized extrasynovial tendons typically undergo a robust wound-healing process following transection and repair. In contrast, avascular intrasynovial tendons do not mount an effective repair response. The current study tests the hypothesis that flexor tendons, as a function of their synovial environment, exhibit unique inflammatory, angiogenic, and metabolic responses to injury and repair.

METHODS: Flexor tendons present a distinct opportunity to test the study hypothesis, as they have proximal regions that are extrasynovial and distal regions that are intrasynovial. In an internally controlled study design, the second and fifth forepaw …

Isolation And Characterization Of A Novel Bacteriophage Wo From Allonemobius Socius Crickets In Missouri, Jonah Kupritz, John Martin, Kerstin Fischer, Kurt C. Curtis, Joseph R. Fauver, Yuefang Huang, Young-Jun Choi, Wandy L. Beatty, Makedonka Mitreva, Peter U. Fischer

Open Access Publications

Wolbachia are endosymbionts of numerous arthropod and some nematode species, are important for their development and if present can cause distinct phenotypes of their hosts. Prophage DNA has been frequently detected in Wolbachia, but particles of Wolbachia bacteriophages (phage WO) have been only occasionally isolated. Here, we report the characterization and isolation of a phage WO of the southern ground cricket, Allonemobius socius, and provided the first whole-genome sequence of phage WO from this arthropod family outside of Asia. We screened A. socius abdomen DNA extracts from a cricket population in eastern Missouri by quantitative PCR for Wolbachia surface protein …

Identifying The Impact Of Intimate Partner Violence In Humanitarian Settings: Using An Ecological Framework To Review 15 Years Of Evidence, Melissa Meinhart, Ilana Seff, Katrina Troy, Samantha Mcnelly, Luissa Vahedi, Catherine Poulton, Lindsay Stark

Open Access Publications

Intimate partner violence (IPV) is a pervasive form of gender-based violence that exacerbates in humanitarian settings. This systematic review examined the myriad IPV impacts and the quality of existing evidence of IPV in humanitarian settings. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) procedures, a total of 51 articles were included from the 3924 screened. We identified the impact of IPV across two levels of the ecological framework: individual and microsystem. Our findings corroborated previous evidence that indicated IPV to be associated with adverse physical and mental health for survivors. Our findings also uniquely synthesized the intergenerational …

Investigation Of Convergent And Divergent Genetic Influences Underlying Schizophrenia And Alcohol Use Disorder, Emma C Johnson, Alexander S Hatoum, Sarah Hartz, Arpana Agrawal, Et Al

Open Access Publications

BACKGROUND: Alcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and large-scale genome-wide association studies (GWAS) have identified significant genetic correlations between these disorders.

METHODS: We used the largest published GWAS for AUD (total cases = 77 822) and SCZ (total cases = 46 827) to identify genetic variants that influence both disorders (with either the same or opposite direction of effect) and those that are disorder specific.

RESULTS: We identified 55 independent genome-wide significant single nucleotide polymorphisms with the same direction of effect on AUD and SCZ, 8 with robust effects in opposite directions, and 98 with disorder-specific effects. …

The Fidelity Of Dna Replication, Particularly On Gc-Rich Templates, Is Reduced By Defects Of The Fe-S Cluster In Dna Polymerase Δ, Denis A. Kiktev, Margaret Dominska, Tony Zhang, Joseph Dahl, Elena I. Stepchenkova, Piotr Mieczkowski, Peter M. Burgers, Scott Lujan, Adam Burkholder, Thomas A. Kunkel, Thomas D. Petes

Open Access Publications

Iron-sulfur clusters (4Fe-4S) exist in many enzymes concerned with DNA replication and repair. The contribution of these clusters to enzymatic activity is not fully understood. We identified the MET18 (MMS19) gene of Saccharomyces cerevisiae as a strong mutator on GC-rich genes. Met18p is required for the efficient insertion of iron-sulfur clusters into various proteins. met18 mutants have an elevated rate of deletions between short flanking repeats, consistent with increased DNA polymerase slippage. This phenotype is very similar to that observed in mutants of POL3 (encoding the catalytic subunit of Pol δ) that weaken binding of the iron-sulfur cluster. Comparable mutants …

Chronic Nerve Injuries And Delays In Surgical Treatment Negatively Impact Patient-Reported Quality Of Life, John M. Felder, Ivica Ducic

Open Access Publications

No abstract provided.

Models Of Distal Arthrogryposis And Lethal Congenital Contracture Syndrome, Julia Whittle, Aaron Johnson, Matthew B Dobbs, Christina A Gurnett

Open Access Publications

Distal arthrogryposis and lethal congenital contracture syndromes describe a broad group of disorders that share congenital limb contractures in common. While skeletal muscle sarcomeric genes comprise many of the first genes identified for Distal Arthrogyposis, other mechanisms of disease have been demonstrated, including key effects on peripheral nerve function. While Distal Arthrogryposis and Lethal Congenital Contracture Syndromes display superficial similarities in phenotype, the underlying mechanisms for these conditions are diverse but overlapping. In this review, we discuss the important insights gained into these human genetic diseases resulting from in vitro molecular studies and in vivo models in fruit fly, zebrafish, …

Protein Phosphatase 4 Controls Circadian Clock Dynamics By Modulating Clock/Bmal1 Activity, Sabrina Klemz, Thomas Wallach, Sandra Korge, Mechthild Rosing, Roman Klemz, Bert Maier, Nicholas C Fiorenza, Irem Kaymak, Anna K Fritzsche, Erik D Herzog, Ralf Stanewsky, Achim Kramer

Open Access Publications

In all organisms with circadian clocks, post-translational modifications of clock proteins control the dynamics of circadian rhythms, with phosphorylation playing a dominant role. All major clock proteins are highly phosphorylated, and many kinases have been described to be responsible. In contrast, it is largely unclear whether and to what extent their counterparts, the phosphatases, play an equally crucial role. To investigate this, we performed a systematic RNAi screen in human cells and identified protein phosphatase 4 (PPP4) with its regulatory subunit PPP4R2 as critical components of the circadian system in both mammals and

Developmental Variation In Testosterone: Cortisol Ratio Alters Cortical- And Amygdala-Based Cognitive Processes, Jimin Lew, Sherri Lee Jones, Christina Caccese, Isobel Orfi, Charlotte Little, Kelly N Botteron, James T Mccracken, Tuong-Vi Nguyen

Open Access Publications

Testosterone (T) and cortisol (C) are the end products of neuroendocrine axes that interact with the process of shaping brain structure and function. Relative levels of T:C (TC ratio) may alter prefrontal-amygdala functional connectivity in adulthood. What remains unclear is whether TC-related effects are rooted to childhood and adolescence. We used a healthy cohort of 4-22-year-olds to test for associations between TC ratios, brain structure (amygdala volume, cortical thickness (CTh), and their coordinated growth), as well as cognitive and behavioral development. We found greater TC ratios to be associated with the growth of specific brain structures: 1) parietal CTh; 2) …

Bioactivation Of Isoxazole-Containing Bromodomain And Extra-Terminal Domain (Bet) Inhibitors, Noah R Flynn, Michael D Ward, Mary A Schleiff, Corentine M C Laurin, Rohit Farmer, Stuart J Conway, Gunnar Boysen, S Joshua Swamidass, Grover P Miller

Open Access Publications

The 3,5-dimethylisoxazole motif has become a useful and popular acetyl-lysine mimic employed in isoxazole-containing bromodomain and extra-terminal (BET) inhibitors but may introduce the potential for bioactivations into toxic reactive metabolites. As a test, we coupled deep neural models for quinone formation, metabolite structures, and biomolecule reactivity to predict bioactivation pathways for 32 BET inhibitors and validate the bioactivation of select inhibitors experimentally. Based on model predictions, inhibitors were more likely to undergo bioactivation than reported non-bioactivated molecules containing isoxazoles. The model outputs varied with substituents indicating the ability to scale their impact on bioactivation. We selected OXFBD02, OXFBD04, and I-BET151 …

Rp11-362k2.2:Rp11-767i20.1 Genetic Variation Is Associated With Post-Reperfusion Therapy Parenchymal Hematoma. A Gwas Meta-Analysis, Elena Muiño, Laura Heitsch, Laura Ibañez, Carlos Cruchaga, Rajat Dhar, Jin-Moo Lee, Et Al

Open Access Publications

Stroke is one of the most common causes of death and disability. Reperfusion therapies are the only treatment available during the acute phase of stroke. Due to recent clinical trials, these therapies may increase their frequency of use by extending the time-window administration, which may lead to an increase in complications such as hemorrhagic transformation, with parenchymal hematoma (PH) being the more severe subtype, associated with higher mortality and disability rates. Our aim was to find genetic risk factors associated with PH, as that could provide molecular targets/pathways for their prevention/treatment and study its genetic correlations to find traits sharing …

Using Monozygotic Twins To Dissect Common Genes In Posttraumatic Stress Disorder And Migraine, Charlotte K Bainomugisa, Heidi G Sutherland, Richard Parker, Allan F Mcrae, Larisa M Haupt, Lyn R Griffiths, Andrew Heath, Elliot C Nelson, Margaret J Wright, Ian B Hickie, Nicholas G Martin, Dale R Nyholt, Divya Mehta

Open Access Publications

Epigenetic mechanisms have been associated with genes involved in Posttraumatic stress disorder (PTSD). PTSD often co-occurs with other health conditions such as depression, cardiovascular disorder and respiratory illnesses. PTSD and migraine have previously been reported to be symptomatically positively correlated with each other, but little is known about the genes involved. The aim of this study was to understand the comorbidity between PTSD and migraine using a monozygotic twin disease discordant study design in six pairs of monozygotic twins discordant for PTSD and 15 pairs of monozygotic twins discordant for migraine. DNA from peripheral blood was run on Illumina EPIC …

Mri Radiomic Signature Of White Matter Hyperintensities Is Associated With Clinical Phenotypes, Martin Bretzner, Laura Heitsch, Chia-Ling Phuah, Et Al

Open Access Publications

Objective: Neuroimaging measurements of brain structural integrity are thought to be surrogates for brain health, but precise assessments require dedicated advanced image acquisitions. By means of quantitatively describing conventional images, radiomic analyses hold potential for evaluating brain health. We sought to: (1) evaluate radiomics to assess brain structural integrity by predicting white matter hyperintensities burdens (WMH) and (2) uncover associations between predictive radiomic features and clinical phenotypes.

Methods: We analyzed a multi-site cohort of 4,163 acute ischemic strokes (AIS) patients with T2-FLAIR MR images with total brain and WMH segmentations. Radiomic features were extracted from normal-appearing brain tissue (brain mask-WMH …

Disentangling The Complexity Of The Rumen Microbial Diversity Through Fractionation Using A Sucrose Density Gradient, Ruth Hernández, Hugo Jimenez, Cesar Vargas-Garcia, Alejandro Caro-Quintero, Alejandro Reyes

Open Access Publications

The ruminal microbial community is an important element in health, nutrition, livestock productivity, and climate impact. Despite the historic and current efforts to characterize this microbial diversity, many of its members remain unidentified, making it challenging to associate microbial groups with functions. Here we present a low-cost methodology for rumen sample treatment that separates the microbial community based on cell size, allowing for the identification of subtle compositional changes. In brief, the sample is centrifuged through a series of sucrose density gradients, and cells migrate to their corresponding density fraction. From each fraction, DNA is extracted and

Functional Disruptions Of The Brain In Low Back Pain: A Potential Imaging Biomarker Of Functional Disability, Bidhan Lamichhane, Dinal Jayasekera, Rachel Jakes, Wilson Z Ray, Eric C Leuthardt, Ammar H Hawasli

Open Access Publications

Chronic low back pain (LBP) is one of the leading causes of disability worldwide. While LBP research has largely focused on the spine, many studies have demonstrated a restructuring of human brain architecture accompanying LBP and other chronic pain states. Brain imaging presents a promising source for discovering noninvasive biomarkers that can improve diagnostic and prognostication outcomes for chronic LBP. This study evaluated graph theory measures derived from brain resting-state functional connectivity (rsFC) as prospective noninvasive biomarkers of LBP. We also proposed and tested a hybrid feature selection method (Enet-subset) that combines Elastic Net and an optimal subset selection method. …

Pattern And Degree Of Individual Brain Atrophy Predicts Dementia Onset In Dominantly Inherited Alzheimer's Disease, Ophir Keret, Randal J Bateman, Tammie L S Benzinger, John C Morris, Beau M Ances, Nelly Joseph-Mathurin, Richard J Perrin, Brian A Gordon, Dominantly Inherited Alzheimer Network, Et Al

Open Access Publications

Introduction: Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment.

Methods: We created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally.

Results: Our risk score separated asymptomatic versus demented …

Predicting Self-Intercepted Medication Ordering Errors Using Machine Learning, Christopher Ryan King, Joanna Abraham, Bradley A. Fritz, Zhicheng Cui, William Galanter, Yixin Chen, Thomas Kannampallil

Open Access Publications

Current approaches to understanding medication ordering errors rely on relatively small manually captured error samples. These approaches are resource-intensive, do not scale for computerized provider order entry (CPOE) systems, and are likely to miss important risk factors associated with medication ordering errors. Previously, we described a dataset of CPOE-based medication voiding accompanied by univariable and multivariable regression analyses. However, these traditional techniques require expert guidance and may perform poorly compared to newer approaches. In this paper, we update that analysis using machine learning (ML) models to predict erroneous medication orders and identify its contributing factors. We retrieved patient demographics (race/ethnicity, …

Structure-Guided Microbial Targeting Of Antistaphylococcal Prodrugs, Justin J. Miller, Ishaan T. Shah, Jayda Hatten, Yasaman Barekatain, Elizabeth A. Mueller, Ahmed M. Moustafa, Rachel L. Edwards, Cynthia S. Dowd, Paul J. Planet, Florian L. Muller, Joseph M. Jez, Audrey R. Odom John

Open Access Publications

Carboxy ester prodrugs are widely employed to increase oral absorption and potency of phosphonate antibiotics. Prodrugging can mask problematic chemical features that prevent cellular uptake and may enable tissue-specific compound delivery. However, many carboxy ester promoieties are rapidly hydrolyzed by serum esterases, limiting their therapeutic potential. While carboxy ester-based prodrug targeting is feasible, it has seen limited use in microbes as microbial esterase-specific promoieties have not been described. Here we identify the bacterial esterases, GloB and FrmB, that activate carboxy ester prodrugs in

Glembatumumab Vedotin For Patients With Metastatic, Gpnmb Overexpressing, Triple-Negative Breast Cancer (“Metric”): A Randomized Multicenter Study, Linda T. Vahdat, Cynthia Ma, Et Al.

Open Access Publications

No abstract provided.

Tailoring Of Arteriovenous Graft‑To‑Vein Anastomosis Angle To Attenuate Pathological Flow Fields, Dillon Williams, Eric C. Leuthardt, Guy M. Genin, Mohamed Zayed

Open Access Publications

No abstract provided.

Visceral Obesity And Insulin Resistance Associate With Cd36 Deletion In Lymphatic Endothelial Cells, Vincenza Cifarelli, Sila Appak-Baskoy, Vivek S. Peche, Andrew Kluzak, Trevor Shew, Ramkumar Narendran, Kathryn M. Pietka, Marina Cella, Curtis W. Walls, Rafael Czepielewski, Stoyan Ivanov, Gwendalyn J. Randolph, Hellmut G. Augustin, Nada A. Abumrad

Open Access Publications

No abstract provided.

Deep Learning The Structural Determinants Of Protein Biochemical Properties By Comparing Structural Ensembles With Diffnets, Michael D. Ward, Maxwell I. Zimmerman, Artur Meller, Moses Chung, S.J. Swamidass, Gregory R. Bowman

Open Access Publications

No abstract provided.