Digital Commons Network^™

Single-Cell Epigenomics Reveals Mechanisms Of Human Cortical Development, Ryan S Ziffra, Tychele N Turner, Et Al.

2020-Current year OA Pubs

During mammalian development, differences in chromatin state coincide with cellular differentiation and reflect changes in the gene regulatory landscape

Patient-Reported Reasons For Stopping Care Or Switching Clinics In Zambia: A Multisite, Regionally Representative Estimate Using A Multistage Sampling-Based Approach In Zambia, Izukanji Sikazwe, Ingrid Eshun-Wilson, Kombatende Sikombe, Laura K Beres, Paul Somwe, Aaloke Mody, Sandra Simbeza, Chama Bukankala, David V Glidden, Lloyd B Mulenga, Nancy Padian, Peter Ehrenkranz, Carolyn Bolton-Moore, Charles B Holmes, Elvin H Geng

2020-Current year OA Pubs

BACKGROUND: Understanding patient-reported reasons for lapses of retention in human immunodeficiency virus (HIV) treatment can drive improvements in the care cascade. A systematic assessment of outcomes among a random sample of patients lost to follow-up (LTFU) from 32 clinics in Zambia to understand the reasons for silent transfers and disengagement from care was undertaken.

METHODS: We traced a simple random sample of LTFU patients (>90 days from last scheduled visit) as determined from clinic-based electronic medical records from a probability sample of facilities. Among patients found in person, we solicited reasons for either stopping or switching care and predictors …

Epigenetic Dynamics Shaping Melanophore And Iridophore Cell Fate In Zebrafish, Hyo Sik Jang, Yujie Chen, Jiaxin Ge, Alicia N Wilkening, Yiran Hou, Hyung Joo Lee, You Rim Choi, Rebecca F Lowdon, Xiaoyun Xing, Daofeng Li, Charles K Kaufman, Stephen L Johnson, Ting Wang

2020-Current year OA Pubs

BACKGROUND: Zebrafish pigment cell differentiation provides an attractive model for studying cell fate progression as a neural crest progenitor engenders diverse cell types, including two morphologically distinct pigment cells: black melanophores and reflective iridophores. Nontrivial classical genetic and transcriptomic approaches have revealed essential molecular mechanisms and gene regulatory circuits that drive neural crest-derived cell fate decisions. However, how the epigenetic landscape contributes to pigment cell differentiation, especially in the context of iridophore cell fate, is poorly understood.

RESULTS: We chart the global changes in the epigenetic landscape, including DNA methylation and chromatin accessibility, during neural crest differentiation into melanophores and …

The Role Of Community Health Workers In The Surgical Cascade: A Scoping Review, Helen W Li, Michael L Scanlon, Nicholas Kisilu, Debra K Litzelman

2020-Current year OA Pubs

BACKGROUND: Community health workers (CHWs) can increase access to various primary healthcare services; however, their potential for improving surgical care is under-explored. We sought to assess the role of CHWs in the surgical cascade, defined as disease screening, linkage to operative care, and post-operative care. Given the well-described literature on CHWs and screening, we focused on the latter two steps of the surgical cascade.

METHODS: We conducted a scoping review of the peer-reviewed literature. We searched for studies published in any language from January 1, 2000 to May 1, 2020 using electronic literature databases including Pubmed/MEDLINE, Web of Science, SCOPUS, …

Aces: Analysis Of Conservation With An Extensive List Of Species, Evin M Padhi, Jeffrey K Ng, Elvisa Mehinovic, Eleanor I Sams, Tychele N Turner

2020-Current year OA Pubs

MOTIVATION: An abundance of new reference genomes is becoming available through large-scale sequencing efforts. While the reference FASTA for each genome is available, there is currently no automated mechanism to query a specific sequence across all new reference genomes.

RESULTS: We developed ACES (Analysis of Conservation with an Extensive list of Species) as a computational workflow to query specific sequences of interest (e.g., enhancers, promoters, exons) against reference genomes with an available reference FASTA. This automated workflow generates BLAST hits against each of the reference genomes, a multiple sequence alignment file, a graphical fragment assembly file, and a phylogenetic tree …

Ceftolozane/Tazobactam Probability Of Target Attainment And Outcomes In Participants With Augmented Renal Clearance From The Randomized Phase 3 Aspect-Np Trial, Andrew F Shorr, Christopher J Bruno, Zufei Zhang, Erin Jensen, Wei Gao, Hwa-Ping Feng, Jennifer A Huntington, Brian Yu, Elizabeth G Rhee, Carisa De Anda, Sumit Basu, Marin H Kollef

2020-Current year OA Pubs

BACKGROUND: The randomized, double-blind, phase 3 ASPECT-NP trial evaluated the efficacy of 3 g of ceftolozane/tazobactam (C/T) versus 1 g of meropenem infused every 8 h for 8 to 14 days for treatment of adults with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). We assessed the probability of target attainment and compared efficacy outcomes from ASPECT-NP in participants with augmented renal clearance (ARC) versus those with normal renal function.

METHODS: Baseline renal function was categorized as normal renal function (creatinine clearance 80-130 mL/min) or ARC (creatinine clearance > 130 mL/min). Population pharmacokinetic models informed Monte Carlo simulations to assess …

A Human Ipsc-Derived Inducible Neuronal Model Of Niemann-Pick Disease, Type C1, Anika V Prabhu, Insung Kang, Raffaella De Pace, Christopher A Wassif, Hideji Fujiwara, Pamela Kell, Xuntian Jiang, Daniel S Ory, Juan S Bonifacino, Michael E Ward, Forbes D Porter

2020-Current year OA Pubs

BACKGROUND: Niemann-Pick disease, type C (NPC) is a childhood-onset, lethal, neurodegenerative disorder caused by autosomal recessive mutations in the genes NPC1 or NPC2 and characterized by impaired cholesterol homeostasis, a lipid essential for cellular function. Cellular cholesterol levels are tightly regulated, and mutations in either NPC1 or NPC2 lead to deficient transport and accumulation of unesterified cholesterol in the late endosome/lysosome compartment, and progressive neurodegeneration in affected individuals. Previous cell-based studies to understand the NPC cellular pathophysiology and screen for therapeutic agents have mainly used patient fibroblasts. However, these do not allow modeling the neurodegenerative aspect of NPC disease, highlighting …

Clinical Trial And Postmarketing Safety Of Onasemnogene Abeparvovec Therapy, John W Day, Jerry R Mendell, Eugenio Mercuri, Richard S Finkel, Kevin A Strauss, Aaron Kleyn, Sitra Tauscher-Wisniewski, Francis Fonyuy Tukov, Sandra P Reyna, Deepa H Chand

2020-Current year OA Pubs

INTRODUCTION: This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy.

OBJECTIVE: We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data.

METHODS: Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign …

Chyloptysis As A Delayed Sequela Of Penetrating Thoracic Trauma, Kyle G Mitchell, Hope Feldman, Bryan F Meyers, Mara B Antonoff

2020-Current year OA Pubs

No abstract provided.

Friends And Foes: Extracellular Vesicles In Aging And Rejuvenation, Brian V Lananna, Shin-Ichiro Imai

2020-Current year OA Pubs

Extracellular vesicles (EVs) are released by many different cell types throughout the body and play a role in a diverse range of biological processes. EVs circulating in blood as well as in other body fluids undergo dramatic alterations over an organism's lifespan that are only beginning to be elucidated. The exact nature of these changes is an area of active and intense investigation, but lacks clear consensus due to the substantial heterogeneity in EV subpopulations and insufficiencies in current technologies. Nonetheless, emerging evidence suggests that EVs regulate systemic aging as well as the pathophysiology of age-related diseases. Here, we review …

The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, And Rezafungin, Martin Hoenigl, Rosanne Sprute, Matthias Egger, Amir Arastehfar, Oliver A Cornely, Robert Krause, Cornelia Lass-Flörl, Juergen Prattes, Andrej Spec, George R Thompson 3rd, Nathan Wiederhold, Jeffrey D Jenks

2020-Current year OA Pubs

The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug-drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a …

How To Screen For Monoclonal Gammopathy In Patients With A Suspected Amyloidosis, Samuel M Rubinstein, Keith Stockerl-Goldstein

2020-Current year OA Pubs

No abstract provided.

Somatic Pik3r1 Variation As A Cause Of Vascular Malformations And Overgrowth, Catherine E Cottrell, Jonathan W Heusel, Meagan Corliss, Michael J Evenson, Carrie C Coughlin, Et Al.

2020-Current year OA Pubs

PURPOSE: Somatic activating variants in the PI3K-AKT pathway cause vascular malformations with and without overgrowth. We previously reported an individual with capillary and lymphatic malformation harboring a pathogenic somatic variant in PIK3R1, which encodes three PI3K complex regulatory subunits. Here, we investigate PIK3R1 in a large cohort with vascular anomalies and identify an additional 16 individuals with somatic mosaic variants in PIK3R1.

METHODS: Affected tissue from individuals with vascular lesions and overgrowth recruited from a multisite collaborative network was studied. Next-generation sequencing targeting coding regions of cell-signaling and cancer-associated genes was performed followed by assessment of variant pathogenicity.

RESULTS: The …

Impact Of Covid-19 On Gastroenterology Fellowship Training: A Multicenter Analysis Of Endoscopy Volumes, Swathi Paleti, Anas Gremida, Et Al.

2020-Current year OA Pubs

No abstract provided.

Estimating The Effects Of Race And Social Vulnerability On Hospital Admission And Mortality From Covid-19, Joshua M Landman, Karen Steger-May, Karen E Joynt Maddox, Gmerice Hammond, Aditi Gupta, Adriana M Rauseo, Min Zhao, Randi E Foraker

2020-Current year OA Pubs

OBJECTIVE: To estimate the risk of hospital admission and mortality from COVID-19 to patients and measure the association of race and area-level social vulnerability with those outcomes.

MATERIALS AND METHODS: Using patient records collected at a multisite hospital system from April 2020 to October 2020, the risk of hospital admission and the risk of mortality were estimated for patients who tested positive for COVID-19 and were admitted to the hospital for COVID-19, respectively, using generalized estimating equations while controlling for patient race, patient area-level social vulnerability, and time course of the pandemic.

RESULTS: Black individuals were 3.57 as likely (95% …

Combined Thoracic Endovascular Aortic Repair And Endovascular Aneurysm Repair And The Long-Term Consequences Of Altered Cardiovascular Haemodynamics On Morbidity And Mortality: Case Series And Literature Review, Sherif Sultan, Yogesh Acharya, Mohiey Hazima, Hiba Salahat, Juan Carlos Parodi, Niamh Hynes

2020-Current year OA Pubs

BACKGROUND: Thoracic and abdominal aortic stent grafts are firmer and more rigid than the native aorta. Aortic implanted devices have been implicated in the development of acute systolic hypertension, elevated pulse pressure, and reduced coronary perfusion.

CASE SUMMARY: We report four cases of staged thoracic endovascular aortic repair (TEVAR) and then endovascular aneurysm repair (EVAR). All patients had TEVAR first for thoracic aortic aneurysm and later on developed infra-renal abdominal aortic aneurysm (AAA) that required EVAR. There were three males and one female with a median age of 74.5 years (range 67.5-78.5). None of the patients developed aortic-related major clinical …

Ct Findings And Patterns Of E-Cigarette Or Vaping Product Use-Associated Lung Injury: A Multicenter Cohort Of 160 Cases, Seth J Kligerman, Constantine A Raptis, Kaitlin M Marquis, Et Al.

2020-Current year OA Pubs

BACKGROUND: e-Cigarette or vaping-induced lung injury (EVALI) causes a spectrum of CT lung injury patterns. Relative frequencies and associations with vaping behavior are unknown.

RESEARCH QUESTION: What are the frequencies of imaging findings and CT patterns in EVALI and what is the relationship to vaping behavior?

STUDY DESIGN AND METHODS: CT scans of 160 subjects with EVALI from 15 institutions were retrospectively reviewed. CT findings and patterns were defined and agreed on via consensus. The parenchymal organizing pneumonia (OP) pattern was defined as regional or diffuse ground-glass opacity (GGO) ± consolidation without centrilobular nodules (CNs). An airway-centered OP pattern was …

Evaluation Of Patient-Reported Delays And Affordability-Related Barriers To Care In Head And Neck Cancer, Nicholas R Lenze, Jeannette T Bensen, Laura Farnan, Siddharth Sheth, Jose P Zevallos, Wendell G Yarbrough, Adam M Zanation

2020-Current year OA Pubs

OBJECTIVE: To examine the prevalence and predictors of patient-reported barriers to care among survivors of head and neck squamous cell carcinoma and the association with health-related quality of life (HRQOL) outcomes.

STUDY DESIGN: Retrospective cohort study.

SETTING: Outpatient oncology clinic at an academic tertiary care center.

METHODS: Data were obtained from the UNC Health Registry/Cancer Survivorship Cohort. Barriers to care included self-reported delays in care and inability to obtain needed care due to cost. HRQOL was measured with validated questionnaires: general (PROMIS) and cancer specific (FACT-GP).

RESULTS: The sample included 202 patients with head and neck squamous cell carcinoma with …

Neutralisation Of Sars-Cov-2 Lineage P.1 By Antibodies Elicited Through Natural Sars-Cov-2 Infection Or Vaccination With An Inactivated Sars-Cov-2 Vaccine: An Immunological Study, William M Souza, Michael S Diamond, Et Al.

2020-Current year OA Pubs

BACKGROUND: Mutations accrued by SARS-CoV-2 lineage P.1-first detected in Brazil in early January, 2021-include amino acid changes in the receptor-binding domain of the viral spike protein that also are reported in other variants of concern, including B.1.1.7 and B.1.351. We aimed to investigate whether isolates of wild-type P.1 lineage SARS-CoV-2 can escape from neutralising antibodies generated by a polyclonal immune response.

METHODS: We did an immunological study to assess the neutralising effects of antibodies on lineage P.1 and lineage B isolates of SARS-CoV-2, using plasma samples from patients previously infected with or vaccinated against SARS-CoV-2. Two specimens (P.1/28 and P.1/30) …

White Matter Plasticity In Healthy Older Adults: The Effects Of Aerobic Exercise, Andrea Mendez Colmenares, Michelle W Voss, Jason Fanning, Elizabeth A Salerno, Neha P Gothe, Michael L Thomas, Edward Mcauley, Arthur F Kramer, Agnieszka Z Burzynska

2020-Current year OA Pubs

White matter deterioration is associated with cognitive impairment in healthy aging and Alzheimer's disease. It is critical to identify interventions that can slow down white matter deterioration. So far, clinical trials have failed to demonstrate the benefits of aerobic exercise on the adult white matter using diffusion Magnetic Resonance Imaging. Here, we report the effects of a 6-month aerobic walking and dance interventions (clinical trial NCT01472744) on white matter integrity in healthy older adults (n = 180, 60-79 years) measured by changes in the ratio of calibrated T1- to T2-weighted images (T1w/T2w). Specifically, the aerobic walking and social dance interventions …

E-Cadherin Expression And Blunted Interferon Response In Blastic Plasmacytoid Dendritic Cell Neoplasm, Luisa Lorenzi, Silvia Lonardi, Donatella Vairo, Andrea Bernardelli, Michela Tomaselli, Mattia Bugatti, Sara Licini, Mariachiara Arisi, Lorenzo Cerroni, Alessandra Tucci, William Vermi, Silvia Clara Giliani, Fabio Facchetti

2020-Current year OA Pubs

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive neoplasm derived from plasmacytoid dendritic cells (pDCs). In this study, we investigated by immunohistochemical analysis the expression of E-cadherin (EC) on pDCs in reactive lymph nodes and tonsils, bone marrow, and in BPDCN. We compared the expression of EC in BPDCN to that in leukemia cutis (LC) and cutaneous lupus erythematosus (CLE), the latter typically featuring pDC activation. In BPDCN, we also assessed the immunomodulatory activity of malignant pDCs through the expression of several type I interferon (IFN-I) signaling effectors and downstream targets, PD-L1/CD274, and determined the extent of tumor infiltration …

Preparing Nursing Homes For A Second Wave Of Coronavirus Disease 2019 (Covid-19), A Rekha Murthy, Hilary Babcock, Et Al.

2020-Current year OA Pubs

No abstract provided.

Multicenter, Double-Blind, Placebo-Controlled Trial Of Seviprotimut-L Polyvalent Melanoma Vaccine In Patients With Post-Resection Melanoma At High Risk Of Recurrence, Craig L Slingluff, Leonel Hernandez-Aya, Et Al

2020-Current year OA Pubs

BACKGROUND: Most patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here.

METHODS: Patients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For …

Implementing An Application Programming Interface For Promis Measures At Three Medical Centers, Michael Bass, Christian Oncken, Allison W. Mcintyre, Chris Dasilva, Joshua Spuhl, Nan E. Rothrock

2020-Current year OA Pubs

BACKGROUND: There is an increasing body of literature advocating for the collection of patient-reported outcomes (PROs) in clinical care. Unfortunately, there are many barriers to integrating PRO measures, particularly computer adaptive tests (CATs), within electronic health records (EHRs), thereby limiting access to advances in PRO measures in clinical care settings.

OBJECTIVE: To address this obstacle, we created and evaluated a software integration of an Application Programming Interface (API) service for administering and scoring Patient-Reported Outcomes Measurement Information System (PROMIS) measures with the EHR system.

METHODS: We created a RESTful API and evaluated the technical feasibility and impact on clinical workflow …

Inpatient Versus Outpatient Intravenous Diuresis For The Acute Exacerbation Of Chronic Heart Failure, Ilia G Halatchev, Wen-Chin Wu, Paul A Heidenreich, Elma Djukic, Sumitra Balasubramanian, Kelly B Ohlms, Jay R Mcdonald

2020-Current year OA Pubs

BACKGROUND: We established an IV outpatient diuresis (IVOiD) clinic and conducted a quality improvement project to evaluate safety, effectiveness and costs associated with outpatient versus inpatient diuresis for patients presenting with acute decompensated heart failure (ADHF) to the emergency department (ED).

METHODS: Patients who were clinically diagnosed with ADHF in the ED, but did not have high-risk features, were either diuresed in the hospital or in the outpatient IVOiD clinic. The dose of IV diuretic was based on their home maintenance diuretic dose. The outcomes measured were the effects of diuresis (urine output, weight, hemodynamic and laboratory abnormalities), 30-90 day …

Gut Microbiota-Derived Short-Chain Fatty Acids Protect Against The Progression Of Endometriosis, Sangappa B Chadchan, Pooja Popli, Chandrasekhar R Ambati, Eric Tycksen, Sang Jun Han, Serdar E Bulun, Nagireddy Putluri, Scott W Biest, Ramakrishna Kommagani

2020-Current year OA Pubs

Worldwide, ∼196 million are afflicted with endometriosis, a painful disease in which endometrial tissue implants and proliferates on abdominal peritoneal surfaces. Theories on the origin of endometriosis remained inconclusive. Whereas up to 90% of women experience retrograde menstruation, only 10% develop endometriosis, suggesting that factors that alter peritoneal environment might contribute to endometriosis. Herein, we report that whereas some gut bacteria promote endometriosis, others protect against endometriosis by fermenting fiber to produce short-chain fatty acids. Specifically, we found that altered gut microbiota drives endometriotic lesion growth and feces from mice with endometriosis contained less of short-chain fatty acid and n-butyrate …

Thrombolytic Enzymes Of Microbial Origin: A Review, Deepti Diwan, Zeba Usmani, Minaxi Sharma, James W Nelson, Vijay Kumar Thakur, Graham Christie, Gustavo Molina, Vijai Kumar Gupta

2020-Current year OA Pubs

Enzyme therapies are attracting significant attention as thrombolytic drugs during the current scenario owing to their great affinity, specificity, catalytic activity, and stability. Among various sources, the application of microbial-derived thrombolytic and fibrinolytic enzymes to prevent and treat vascular occlusion is promising due to their advantageous cost-benefit ratio and large-scale production. Thrombotic complications such as stroke, myocardial infarction, pulmonary embolism, deep venous thrombosis, and peripheral occlusive diseases resulting from blood vessel blockage are the major cause of poor prognosis and mortality. Given the ability of microbial thrombolytic enzymes to dissolve blood clots and prevent any adverse effects, their use as …

Cxcl17 Is Dispensable During Hypervirulent Mycobacterium Tuberculosis Hn878 Infection In Mice, José Alberto Choreño-Parra, Micah D Dunlap, Rosemary Swanson, Luis A Jiménez-Álvarez, Marcela Muñoz-Torrico, Silvia Guzmán-Beltrán, Joaquín Zúñiga, Shabaana A Khader

2020-Current year OA Pubs

CXCL17 is a novel mucosal chemokine that mediates myeloid cell recruitment and bactericidal activity and highly expressed in the respiratory tract. However, its role in tuberculosis (TB) immunopathogenesis or protection remains unknown. In this study, we evaluated the function of CXCL17 in a mouse model of aerosol infection with the clinical W-Beijing lineage

A Novel Mitragynine Analog With Low-Efficacy Mu Opioid Receptor Agonism Displays Antinociception With Attenuated Adverse Effects, Soumen Chakraborty, Abdelfattah Faouzi, Sarah M Bernhard, Nitin Nuthikattu, Rahul Jilakara, Satyanarayana M Chintala, Tao Che, Susruta Majumdar, Et Al

2020-Current year OA Pubs

Mitragynine and 7-hydroxymitragynine (7OH) are the major alkaloids mediating the biological actions of the psychoactive plant kratom. To investigate the structure-activity relationships of mitragynine/7OH templates, we diversified the aromatic ring of the indole at the C9, C10, and C12 positions and investigated their G-protein and arrestin signaling mediated by mu opioid receptors (MOR). Three synthesized lead C9 analogs replacing the 9-OCH

Metformin Selectively Dampens The Acute Inflammatory Response Through An Ampk-Dependent Mechanism, Thomas S Postler, Vincent Peng, Dev M Bhatt, Sankar Ghosh

2020-Current year OA Pubs

Metformin is a first-line drug in the treatment of type-2 diabetes mellitus (T2DM). In addition to its antigluconeogenic and insulin-sensitizing properties, metformin has emerged as a potent inhibitor of the chronic inflammatory response of macrophages. In particular, metformin treatment has been shown to reduce expression of interleukin (IL-) 1β during long-term exposure to the pro-inflammatory stimulus lipopolysaccharide (LPS) through a reduction in reactive oxygen species (ROS), which decreases the levels of the hypoxia-inducible factor (HIF) 1-α, and through enhanced expression of IL-10. However, the effect of metformin on the acute inflammatory response, before significant levels of ROS accumulate in the …