Digital Commons Network^™

Treatment Patterns And Blood Counts In Patients With Polycythemia Vera Treated With Hydroxyurea In The United States: An Analysis From The Reveal Study, Michael R Grunwald, David J Kuter, Ivy Altomare, John M Burke, Aaron T Gerds, Mark A Walshauser, Michael R Savona, Brady Stein, Stephen T Oh, Philomena Colucci, Shreekant Parasuraman, Dilan Paranagama, Ruben Mesa

Open Access Publications

BACKGROUND: Polycythemia vera (PV) is associated with increased blood cell counts, risk of thrombosis, and symptoms including fatigue and pruritus. National guidelines support the use of hydroxyurea (HU) in high-risk patients or those with some other clinical indication for cytoreduction.

PATIENTS AND METHODS: REVEAL is a prospective, observational study designed to collect data pertaining to demographics, disease burden, clinical management, patient-reported outcomes, and health care resource utilization of patients with PV in the United States. In this analysis, HU treatment patterns and outcomes were assessed from 6 months prior to enrollment to the time of discontinuation, death, or data cutoff. …

Association Between Preoperative Obstructive Sleep Apnea And Preoperative Positive Airway Pressure With Postoperative Intensive Care Unit Delirium, Christopher R. King, Bradley A. Fritz, Krisztina Escallier, Yo-El S. Ju, Nan Lin, Sherry Mckinnon, Michael S. Avidan, Ben Julian Palanca

Open Access Publications

Importance: Obstructive sleep apnea has been associated with postoperative delirium, which predisposes patients to major adverse outcomes. Positive airway pressure may be an effective intervention to reduce delirium in this population.

Objectives: To determine if preoperative obstructive sleep apnea is associated with postoperative incident delirium in the intensive care unit and if preoperative positive airway pressure adherence modifies the association.

Design, Setting, and Participants: A retrospective single-center cohort study was conducted at a US tertiary hospital from November 1, 2012, to August 31, 2016, among 7792 patients admitted to an intensive care unit who underwent routine Confusion Assessment Method for …

Incomplete Vesicular Docking Limits Synaptic Strength Under High Release Probability Conditions, Gerardo Malagon, Takafumi Miki, Van Tran, Laura C. Gomez, Alain Marty

Open Access Publications

Central mammalian synapses release synaptic vesicles in dedicated structures called docking/release sites. It has been assumed that when voltage-dependent calcium entry is sufficiently large, synaptic output attains a maximum value of one synaptic vesicle per action potential and per site. Here we use deconvolution to count synaptic vesicle output at single sites (mean site number per synapse: 3.6). When increasing calcium entry with tetraethylammonium in 1.5 mM external calcium concentration, we find that synaptic output saturates at 0.22 vesicle per site, not at 1 vesicle per site. Fitting the results with current models of calcium-dependent exocytosis indicates that the 0.22 …

The Design And Development Of A Multicentric Protocol To Investigate The Impact Of Adjunctive Doxycycline On The Management Of Peripheral Lymphoedema Caused By Lymphatic Filariasis And Podoconiosis, John Horton, Philip J Budge, Gary Weil, Et Al

Open Access Publications

BACKGROUND: As new lymphatic filariasis infections are eliminated through mass chemotherapy, previously affected individuals are left with the sequellae, especially chronic progressive lymphoedema. Currently this is managed by careful attention to limb hygiene to prevent infection. Studies over the past 15 years have suggested that the incorporation of doxycycline treatment may arrest or even reverse progression of lymphoedema. Most of this work has been observational or based on small studies, and if this intervention is effective, studies need to be conducted on a larger scale and under diverse geographical and social conditions before it can be incorporated into treatment policy. …

The Sterlet Sturgeon Genome Sequence And The Mechanisms Of Segmental Rediploidization, Kang Du, Chad Tomlinson, Et Al

Open Access Publications

Sturgeons seem to be frozen in time. The archaic characteristics of this ancient fish lineage place it in a key phylogenetic position at the base of the ~30,000 modern teleost fish species. Moreover, sturgeons are notoriously polyploid, providing unique opportunities to investigate the evolution of polyploid genomes. We assembled a high-quality chromosome-level reference genome for the sterlet, Acipenser ruthenus. Our analysis revealed a very low protein evolution rate that is at least as slow as in other deep branches of the vertebrate tree, such as that of the coelacanth. We uncovered a whole-genome duplication that occurred in the Jurassic, early …

Perspectives On Program Mis-Implementation Among U.S. Local Public Health Departments, Peg Allen, Rebekah R Jacob, Renee G Parks, Stephanie Mazzucca, Hengrui Hu, Mackenzie Robinson, Maureen Dobbins, Debra Dekker, Margaret Padek, Ross C Brownson

Open Access Publications

BACKGROUND: Public health resources are limited and best used for effective programs. This study explores associations of mis-implementation in public health (ending effective programs or continuing ineffective programs) with organizational supports for evidence-based decision making among U.S. local health departments.

METHODS: The national U.S. sample for this cross-sectional study was stratified by local health department jurisdiction population size. One person was invited from each randomly selected local health department: the leader in chronic disease, or the director. Of 600 selected, 579 had valid email addresses; 376 completed the survey (64.9% response). Survey items assessed frequency of and reasons for mis-implementation. …

Unc-4 Acts To Promote Neuronal Identity And Development Of The Take-Off Circuit In The Drosophila Cns, Haluk Lacin, W. Ryan Williamson, Gwyneth M. Card, James B. Skeath, James W. Truman

Open Access Publications

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Loss Of H3k36 Methyltransferase Setd2 Impairs V(D)J Recombination During Lymphoid Development, S Haihua Chu, Putzer J Hung, Et Al

Open Access Publications

Repair of DNA double-stranded breaks (DSBs) during lymphocyte development is essential for V(D)J recombination and forms the basis of immunoglobulin variable region diversity. Understanding of this process in lymphogenesis has historically been centered on the study of RAG1/2 recombinases and a set of classical non-homologous end-joining factors. Much less has been reported regarding the role of chromatin modifications on this process. Here, we show a role for the non-redundant histone H3 lysine methyltransferase, Setd2, and its modification of lysine-36 trimethylation (H3K36me3), in the processing and joining of DNA ends during V(D)J recombination. Loss leads to mis-repair of Rag-induced DNA DSBs, …

Single Cell Transcriptomics Identifies Focal Segmental Glomerulosclerosis Remission Endothelial Biomarker, Rajasree Menon, Sanjay Jain, Et Al

Open Access Publications

To define cellular mechanisms underlying kidney function and failure, the KPMP analyzes biopsy tissue in a multicenter research network to build cell-level process maps of the kidney. This study aimed to establish a single cell RNA sequencing strategy to use cell-level transcriptional profiles from kidney biopsies in KPMP to define molecular subtypes in glomerular diseases. Using multiple sources of adult human kidney reference tissue samples, 22,268 single cell profiles passed KPMP quality control parameters. Unbiased clustering resulted in 31 distinct cell clusters that were linked to kidney and immune cell types using specific cell markers. Focusing on endothelial cell phenotypes, …

Cd137 Signaling Regulates Acute Colitis Via Raldh2-Expressing Cd11b−Cd103+ Dcs, Jing Jin, In-Hyuk Jung, Se-Jin Jeong, Et Al

Open Access Publications

CD137, a potent costimulatory receptor for CD8

Development Of A Hybrid Magnetic Resonance/Computed Tomography-Compatible Phantom For Magnetic Resonance Guided Radiotherapy, Min-Joo Kim, Seu-Ran Lee, Kyu-Ho Song, Hyeon-Man Baek, Bo-Young Choe, Tae Suk Suh

Open Access Publications

The purpose of the present study was to develop a hybrid magnetic resonance/computed tomography (MR/CT)-compatible phantom and tissue-equivalent materials for each MR and CT image. Therefore, the essential requirements necessary for the development of a hybrid MR/CT-compatible phantom were determined and the development process is described. A total of 12 different tissue-equivalent materials for each MR and CT image were developed from chemical components. The uniformity of each sample was calculated. The developed phantom was designed to use 14 plugs that contained various tissue-equivalent materials. Measurement using the developed phantom was performed using a 3.0-T scanner with 32 channels and …

Long Non-Coding Rna Graslnd Enhances Chondrogenesis Via Suppression Of The Interferon Type Ii Signaling Pathway, Nguyen P.T. Huynh, Catherine C. Gloss, Jeremiah Lorentz, Ruhang Tang, Jonathan M. Brunger, Audrey Mcalinden, Bo Zhang, Farshid Guilak

Open Access Publications

The roles of long noncoding RNAs (lncRNAs) in musculoskeletal development, disease, and regeneration remain poorly understood. Here, we identified the novel lncRNA

Inflammatory Osteolysis Is Regulated By Site-Specific Isgylation Of The Scaffold Protein Nemo, Naga Suresh Adapala, Gaurav Swarnkar, Manoj Arra, Jie Shen, Gabriel Mbalaviele, Ke Ke, Yousef Abu-Amer

Open Access Publications

Inflammatory osteolysis is governed by exacerbated osteoclastogenesis. Ample evidence points to central role of NF-κB in such pathologic responses, yet the precise mechanisms underpinning specificity of these responses remain unclear. We propose that motifs of the scaffold protein IKKγ/NEMO partly facilitate such functions. As proof-of-principle, we used site-specific mutagenesis to examine the role of NEMO in mediating RANKL-induced signaling in mouse bone marrow macrophages, known as osteoclast precursors. We identified lysine (K)270 as a target regulating RANKL signaling as K270A substitution results in exuberant osteoclastogenesis in vitro and murine inflammatory osteolysis in vivo. Mechanistically, we discovered that K270A mutation disrupts …

Chromatin-Binding Protein Phf6 Regulates Activity-Dependent Transcriptional Networks To Promote Hunger Response, Linhua Gan, Cheng Cheng, Azad Bonni, Et Al

Open Access Publications

Understanding the mechanisms of activity-dependent gene transcription underlying adaptive behaviors is challenging at neuronal-subtype resolution. Using cell-type specific molecular analysis in agouti-related peptide (AgRP) neurons, we reveal that the profound hunger-induced transcriptional changes greatly depend on plant homeodomain finger protein 6 (PHF6), a transcriptional repressor enriched in AgRP neurons. Loss of PHF6 in the satiated mice results in a hunger-state-shifting transcriptional profile, while hunger fails to further induce a rapid and robust activity-dependent gene transcription in PHF6-deficient AgRP neurons. We reveal that PHF6 binds to the promoters of a subset of immediate-early genes (IEGs) and that this chromatin binding is …

Abnormally Increased Carotid Intima Media-Thickness And Elasticity In Patients With Morquio A Disease, Raymond Y Wang, Kyle D Rudser, Donald R Dengel, Nicholas Evanoff, Julia Steinberger, Nina Movsesyan, Robert Garrett, Katherine Christensen, Deborah Boylan, Stephen R Braddock, Marwan Shinawi, Qi Gan, Adriana M Montaño

Open Access Publications

BACKGROUND: Cardiovascular disease frequently causes morbidity and mortality in mucopolysaccharidoses (MPS); however, cardiovascular anatomy and dysfunction in MPS IVA (Morquio A disease) is not well described. Consequently, the study aimed to compare carotid artery structure and elasticity of MPS IVA patients with other MPS patients and healthy control subjects, and quantitate frequency of MPS IVA cardiac structural and functional abnormalities.

METHODS: Prospective, multi-center echocardiogram and carotid ultrasound evaluations of 12 Morquio A patients were compared with other MPS and healthy control subjects. Average differences between groups were adjusted for age, sex, and height with robust variance estimation for confidence intervals …

Cerebrospinal Fluid Phospho-Tau T217 Outperforms T181 As A Biomarker For The Differential Diagnosis Of Alzheimer's Disease And Pet Amyloid-Positive Patient Identification, Nicolas R Barthélemy, Randall J Bateman, Christophe Hirtz, Philippe Marin, François Becher, Chihiro Sato, Audrey Gabelle, Sylvain Lehmann

Open Access Publications

BACKGROUND: Cerebrospinal fluid biomarker profiles characterized by decreased amyloid-beta peptide levels and increased total and phosphorylated tau levels at threonine 181 (pT181) are currently used to discriminate between Alzheimer's disease and other neurodegenerative diseases. However, these changes are not entirely specific to Alzheimer's disease, and it is noteworthy that other phosphorylated isoforms of tau, possibly more specific for the disease process, have been described in the brain parenchyma of patients. The precise detection of these isoforms in biological fluids remains however a challenge.

METHODS: In the present study, we used the latest quantitative mass spectrometry approach, which achieves a sensitive …

Select Atrophied Regions In Alzheimer Disease (Sara): An Improved Volumetric Model For Identifying Alzheimer Disease Dementia, Lauren N Koenig, Gregory S Day, Amber Salter, Sarah Keefe, Laura M Marple, Justin Long, Pamela Lamontagne, Parinaz Massoumazada, B Joy Snider, Manasa Kanthamneni, Cyrus A Raji, Nupur Ghoshal, Brian A Gordon, Michelle Miller-Thomas, John C Morris, Joshua S Shimony, Tammie L S Benzinger, Alzheimer's Disease Neuroimaging Initiative (Adni) And The Dominantly Inherited Alzheimer Network (Dian)

Open Access Publications

INTRODUCTION: Volumetric biomarkers for Alzheimer disease (AD) are attractive due to their wide availability and ease of administration, but have traditionally shown lower diagnostic accuracy than measures of neuropathological contributors to AD. Our purpose was to optimize the diagnostic specificity of structural MRIs for AD using quantitative, data-driven techniques.

METHODS: This retrospective study assembled several non-overlapping cohorts (total n = 1287) with publicly available data and clinical patients from Barnes-Jewish Hospital (data gathered 1990-2018). The Normal Aging Cohort (n = 383) contained amyloid biomarker negative, cognitively normal (CN) participants, and provided a basis for determining age-related atrophy in other cohorts. …

T Cell Response Kinetics Determines Neuroinfection Outcomes During Murine Hsv Infection, Aisha G Lee, Jason M Scott, Maria Rita Fabbrizi, Xiaoping Jiang, Dorothy K Sojka, Mark J Miller, Megan T Baldridge, Wayne M Yokoyama, Haina Shin

Open Access Publications

Herpes simplex virus-2 (HSV-2) and HSV-1 both can cause genital herpes, a chronic infection that establishes a latent reservoir in the nervous system. Clinically, the recurrence frequency of HSV-1 genital herpes is considerably less than HSV-2 genital herpes, which correlates with reduced neuronal infection. The factors dictating the disparate outcomes of HSV-1 and HSV-2 genital herpes are unclear. In this study, we show that vaginal infection of mice with HSV-1 leads to the rapid appearance of mature DCs in the draining lymph node, which is dependent on an early burst of NK cell-mediated IFN-γ production in the vagina that occurs …

Cooperative Synaptic And Intrinsic Plasticity In A Disynaptic Limbic Circuit Drive Stress-Induced Anhedonia And Passive Coping In Mice, Marco Pignatelli, Hugo A Tejeda, Et Al

Open Access Publications

Stress promotes negative affective states, which include anhedonia and passive coping. While these features are in part mediated by neuroadaptations in brain reward circuitry, a comprehensive framework of how stress-induced negative affect may be encoded within key nodes of this circuit is lacking. Here, we show in a mouse model for stress-induced anhedonia and passive coping that these phenomena are associated with increased synaptic strength of ventral hippocampus (VH) excitatory synapses onto D1 medium spiny neurons (D1-MSNs) in the nucleus accumbens medial shell (NAcmSh), and with lateral hypothalamus (LH)-projecting D1-MSN hyperexcitability mediated by decreased inwardly rectifying potassium channel (IRK) function. …

Barrier-To-Autointegration Factor 1 Protects Against A Basal Cgas-Sting Response, Hongming Ma, Wei Qian, Monika Bambouskova, Patrick L Collins, Sofia I Porter, Andrea K Byrum, Rong Zhang, Maxim Artyomov, Eugene M Oltz, Nima Mosammaparast, Jonathan J Miner, Michael S Diamond

Open Access Publications

Although the pathogen recognition receptor pathways that activate cell-intrinsic antiviral responses are well delineated, less is known about how the host regulates this response to prevent sustained signaling and possible immune-mediated damage. Using a genome-wide CRISPR-Cas9 screening approach to identify host factors that modulate interferon-stimulated gene (ISG) expression, we identified the DNA binding protein Barrier-to-autointegration factor 1 (Banf1), a previously described inhibitor of retrovirus integration, as a modulator of basal cell-intrinsic immunity. Ablation of Banf1 by gene editing resulted in chromatin activation near host defense genes with associated increased expression of ISGs, including

Mesh Sprayer Device With Liquefied Mesh Delivery System: Proposed Alternative For Currently Available Meshes In Hernia Repair And Supplement To Abdominal Closure, Alireza Hamidian Jahromi, David H Ballard, F Dean Griffen

Open Access Publications

No abstract provided.

Genome-Wide Association Study In Two Cohorts From A Multi-Generational Mouse Advanced Intercross Line Highlights The Difficulty Of Replication Due To Study-Specific Heterogeneity, Xinzhu Zhou, Celine L St Pierre, Natalia M Gonzales, Jennifer Zou, Riyan Cheng, Apurva S Chitre, Greta Sokoloff, Abraham A Palmer

Open Access Publications

There has been extensive discussion of the "Replication Crisis" in many fields, including genome-wide association studies (

Awareness And Bispectral Index (Bis) Monitoring In Mechanically Ventilated Patients In The Emergency Department And Intensive Care Unit: A Systematic Review Protocol, Ryan D Pappal, Brian W Roberts, Winston Winkler, Lauren H Yaegar, Robert J Stephens, Brian M Fuller

Open Access Publications

INTRODUCTION: Accidental awareness with recall is one of the most feared complications for patients undergoing general anaesthesia and can lead to post-traumatic stress disorder in up to 70% of patients experiencing it. To reduce the incidence of awareness with recall, the bispectral index monitor is recommended for patients receiving total intravenous anaesthetics, especially those receiving neuromuscular blockers. While extensive investigation into awareness and bispectral index monitoring has occurred for operating room patients, this has not extended to other clinical arenas where sedated and mechanically ventilated patients are cared for, namely the intensive care unit and emergency department. The purpose of …

Variant R94c In Tnnt2‐Encoded Troponin T Predisposes To Pediatric Restrictive Dardiomyopathy And Sudden Death Through Impaired Thin Filament Relaxation Resulting In Myocardial Diastolic Dysfunction, Jordan E Ezekian, Sarah R Clippinger, Jaquelin M Garcia, Qixin Yang, Susan Denfield, Aamir Jeewa, William J Dreyer, Wenxin Zou, Yuxin Fan, Hugh D Allen, Jeffrey J Kim, Michael J Greenberg, Andrew P Landstrom

Open Access Publications

Background Pediatric-onset restrictive cardiomyopathy (RCM) is associated with high mortality, but underlying mechanisms of disease are under investigated. RCM-associated diastolic dysfunction secondary to variants in

Defining Stage-Specific Activity Of Potent New Inhibitors Of Cryptosporidium Parvum Growth In Vitro, Lisa J Funkhouser-Jones, Soumya Ravindran, L. David Sibley

Open Access Publications

No abstract provided.

Acetate Coordinates Neutrophil And Ilc3 Responses Against C. Difficile Through Ffar2, José Luís Fachi, Cristiane Sécca, Blanda Di Luccia, Marco Colonna, Et Al

Open Access Publications

Antibiotic-induced dysbiosis is a key predisposing factor for Clostridium difficile infections (CDIs), which cause intestinal disease ranging from mild diarrhea to pseudomembranous colitis. Here, we examined the impact of a microbiota-derived metabolite, short-chain fatty acid acetate, on an acute mouse model of CDI. We found that administration of acetate is remarkably beneficial in ameliorating disease. Mechanistically, we show that acetate enhances innate immune responses by acting on both neutrophils and ILC3s through its cognate receptor free fatty acid receptor 2 (FFAR2). In neutrophils, acetate-FFAR2 signaling accelerates their recruitment to the inflammatory sites, facilitates inflammasome activation, and promotes the release of …

Operative Versus Nonoperative Treatment Of Acute Achilles Tendon Ruptures: A Pilot Economic Decision Analysis, Alvin W Su, Ljiljana Bogunovic, Jeffrey Johnson, Sandra Klein, Matthew J Matava, Jeremy Mccormick, Matthew V Smith, Rick W Wright, Robert H Brophy

Open Access Publications

Background: The operative treatment of Achilles tendon ruptures has been associated with lower rerupture rates and better function but also a risk of surgery-related complications compared with nonoperative treatment, which may provide improved outcomes with accelerated rehabilitation protocols. However, economic decision analyses integrating the updated costs of both treatment options are limited in the literature.

Purpose: To compare the cost-effectiveness of operative and nonoperative treatment of acute Achilles tendon tears.

Study Design: Economic and decision analysis; Level of evidence, 2.

Methods: An economic decision model was built to assess the cost-utility ratio (CUR) of open primary repair versus nonoperative treatment …

Antibody-Mediated Rejection After Lung Transplantation, Amit I. Bery, Ramsey R. Hachem

Open Access Publications

Antibody-mediated rejection (AMR) has been identified as a significant form of acute allograft dysfunction in lung transplantation. The development of consensus diagnostic criteria has created a uniform definition of AMR; however, significant limitations of these criteria have been identified. Treatment modalities for AMR have been adapted from other areas of medicine and data on the effectiveness of these therapies in AMR are limited. AMR is often refractory to these therapies, and graft failure and death are common. AMR is associated with increased rates of chronic lung allograft dysfunction (CLAD) and poor long-term survival. In this review, we discuss the history …

5 Challenges In Understanding The Role Of The Virome In Health And Disease, David Wang

Open Access Publications

No abstract provided.

Proteoclade: A Taxonomic Toolkit For Multi-Species And Metaproteomic Analysis, Arshag D. Mooradian, Sjoerd Van Der Post, Kristen M. Naegle, Jason M. Held

Open Access Publications

We present ProteoClade, a Python toolkit that performs taxa-specific peptide assignment, protein inference, and quantitation for multi-species proteomics experiments. ProteoClade scales to hundreds of millions of protein sequences, requires minimal computational resources, and is open source, multi-platform, and accessible to non-programmers. We demonstrate its utility for processing quantitative proteomic data derived from patient-derived xenografts and its speed and scalability enable a novel de novo proteomic workflow for complex microbiota samples.