Medicine and Health Sciences Commons^™

Information Theoretic Measures For Quantifying Sequence-Ensemble Relationships Of Intrinsically Disordered Proteins, Megan C Cohan, Kiersten M Ruff, Rohit V Pappu

2010-2019 OA Pubs

Intrinsically disordered proteins (IDPs) contribute to a multitude of functions. De novo design of IDPs should open the door to modulating functions and phenotypes controlled by these systems. Recent design efforts have focused on compositional biases and specific sequence patterns as the design features. Analysis of the impact of these designs on sequence-function relationships indicates that individual sequence/compositional parameters are insufficient for describing sequence-function relationships in IDPs. To remedy this problem, we have developed information theoretic measures for sequence-ensemble relationships (SERs) of IDPs. These measures rely on prior availability of statistically robust conformational ensembles derived from all atom simulations. We …

Safety Of Paclitaxel-Coated Balloon Angioplasty For Femoropopliteal Peripheral Artery Disease, Kenneth Ouriel, Mark A. Adelman, Kenneth Rosenfield, Dierk Scheinert, Marianne Brodmann, Constantino Peña, Patrick Geraghty, Arthur Lee, Roseann White, Daniel G. Clair

2010-2019 OA Pubs

OBJECTIVES: The aim of this study was to assess safety outcomes of femoropopliteal drug-coated balloon (DCB) angioplasty using patient-level data from the Lutonix clinical program.

BACKGROUND: A recent systematic review and meta-analysis of heterogenous trials and summary-level data identified increased long-term mortality in patients treated with paclitaxel-coated balloons and stents.

METHODS: We evaluated DCB angioplasty (n = 1,093) and uncoated balloon angioplasty (percutaneous transluminal angioplasty [PTA]) (n = 250) outcomes in LEVANT 1 (The Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis), LEVANT 2 (Moxy Drug Coated Balloon vs. Standard Balloon Angioplasty for the Treatment of Femoropopliteal Arteries), and …

Rapid And Sustained Response To Immune Checkpoint Inhibition In Cutaneous Squamous Cell Carcinoma After Allogenic Hematopoietic Cell Transplant For Sézary Syndrome, Karam Khaddour, Amy Musiek, Lynn A Cornelius, Farrokh Dehdashti, Peter Westervelt, Ryan Fields, George Ansstas

2010-2019 OA Pubs

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is not uncommon in association with indolent malignancies that were treated with prior radiotherapy and after allogenic bone marrow transplantation. On the other hand, cutaneous T-cell lymphoma (CTCL) is a subtype of non-Hodgkin's lymphoma which is characterized by an indolent course, with relative refractoriness to conventional chemotherapies and radiotherapy, and occasionally referred for allogeneic hematopoietic cell transplantation (allo-HCT). Recently, the use of immune checkpoint inhibitors has gained attention in the treatment of both cutaneous squamous cell carcinoma and hematological malignancies. However, many patients with hematological malignancies eventually undergo allo-HCT, raising the concern of potential …

Phenotypic And Genotypic Characterization Of Linezolid-Resistant Enterococcus Faecium From The Usa And Pakistan, Kate E Wardenburg, Robert F Potter, Alaric W D'Souza, Tahir Hussain, Meghan A Wallace, Saadia Andleeb, Carey-Ann D Burnham, Gautam Dantas

2010-2019 OA Pubs

OBJECTIVES: Linezolid is an important therapeutic option for the treatment of infections caused by VRE. Linezolid is a synthetic antimicrobial and resistance to this antimicrobial agent remains relatively rare. As a result, data on the comparative genomics of linezolid resistance determinants in Enterococcus faecium are relatively sparse.

METHODS: To address this knowledge gap in E. faecium, we deployed phenotypic antibiotic susceptibility testing and Illumina WGS on hospital surface (environmental) and clinical isolates from the USA and Pakistan.

RESULTS: We found complete concordance between isolate source country and mechanism of linezolid resistance, with all the US isolates possessing a 23S rRNA …

The Community Structure Of Functional Brain Networks Exhibits Scale-Specific Patterns Of Inter- And Intra-Subject Variability, Richard F Betzel, Maxwell A Bertolero, Evan M Gordon, Caterina Gratton, Nico U F Dosenbach, Danielle S Bassett

2010-2019 OA Pubs

The network organization of the human brain varies across individuals, changes with development and aging, and differs in disease. Discovering the major dimensions along which this variability is displayed remains a central goal of both neuroscience and clinical medicine. Such efforts can be usefully framed within the context of the brain's modular network organization, which can be assessed quantitatively using computational techniques and extended for the purposes of multi-scale analysis, dimensionality reduction, and biomarker generation. Although the concept of modularity and its utility in describing brain network organization is clear, principled methods for comparing multi-scale communities across individuals and time …

Immune Globulin Subcutaneous, Human - Klhw 20% For Primary Humoral Immunodeficiency: An Open-Label, Phase Iii Study, John W Sleasman, William R Lumry, Iftikhar Hussain, H James Wedner, James B Harris, Kecia L Courtney, Elsa Mondou, Jiang Lin, Mark R Stein

2010-2019 OA Pubs

No abstract provided.

Pharmacokinetics Of Once-Daily Extended-Release Tacrolimus Tablets Versus Twice-Daily Capsules In De Novo Liver Transplant, Derek A Dubay, Lewis Teperman, Kimi Ueda, Andrew Silverman, William Chapman, Angel E Alsina, Carmelina Tyler, Daniel R Stevens

2010-2019 OA Pubs

The pharmacokinetics of once-daily extended-release tacrolimus tablets (LCPT) in de novo liver transplantation have not been previously reported. In this phase II, randomized, open-label study, de novo liver transplant recipients were randomized to LCPT 0.07-0.13 mg/kg/day (taken once daily; n = 29) or twice-daily immediate-release tacrolimus capsules (IR-Tac) at 0.10-0.15 mg/kg/day (divided twice daily; n = 29). Subsequent doses of both drugs were adjusted to maintain tacrolimus trough concentrations of 5 to 20 ng/mL through day 90, and 5-15 ng/mL thereafter. Twenty-four-hour pharmacokinetic profiles were obtained on days 1, 7, and 14, with trough concentration and efficacy/safety monitoring through year …

Molecular Game Theory For A Toxin-Dominant Food Chain Model, Bowen Li, Jonathan R Silva, Jianmin Cui, Et Al.

2010-2019 OA Pubs

Animal toxins that are used to subdue prey and deter predators act as the key drivers in natural food chains and ecosystems. However, the predators of venomous animals may exploit feeding adaptation strategies to overcome toxins their prey produce. Much remains unknown about the genetic and molecular game process in the toxin-dominant food chain model. Here, we show an evolutionary strategy in different trophic levels of scorpion-eating amphibians, scorpions and insects, representing each predation relationship in habitats dominated by the paralytic toxins of scorpions. For scorpions preying on insects, we found that the scorpion α-toxins irreversibly activate the skeletal muscle …

Systemic And Local Immunity Following Adoptive Transfer Of Ny-Eso-1 Spear T Cells In Synovial Sarcoma, Indu Ramachandran, Brian A Van Tine, Et Al

2010-2019 OA Pubs

BACKGROUND: Gene-modified autologous T cells expressing NY-ESO-1

METHODS: Four cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay.

RESULTS: Responses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients …

Cis-Regulatory Basis Of Sister Cell Type Divergence In The Vertebrate Retina, Daniel P Murphy, Andrew Eo Hughes, Karen A Lawrence, Connie A Myers, Joseph C Corbo

2010-2019 OA Pubs

Multicellular organisms evolved via repeated functional divergence of transcriptionally related sister cell types, but the mechanisms underlying sister cell type divergence are not well understood. Here, we study a canonical pair of sister cell types, retinal photoreceptors and bipolar cells, to identify the key

Keep The Cat, Change The Care Pathway: A Transformational Approach To Managing Fel D 1, The Major Cat Allergen, Ebenezer Satyaraj, Harold James Wedner, Jean Bousquet

2010-2019 OA Pubs

BACKGROUND: Allergies to cats are the most common animal-origin allergy, and affect approximately 1 in 5 adults worldwide. The prevalence of allergy to furry animals has been increasing, and allergy to cats is a major risk factor for the development of asthma and rhinitis. The diagnosis of cat allergy is now well established. The exact significance of component-resolved diagnosis in the diagnosis of cat allergy remains to be fully understood. Allergen avoidance is effective but often has a psychologic impact. Allergen immunotherapy is not well demonstrated. There is a need for innovative approaches to better manage cat allergens. Next-generation care …

Long-Term Results Of The Delivery For Pulmonary Arterial Hypertension Trial, Mardi Gomberg-Maitland, Murali M Chakinala, Et Al

2010-2019 OA Pubs

BACKGROUND: The DelIVery for Pulmonary Arterial Hypertension clinical trial was a multi-center, prospective, single arm, Investigational Device Exemption study utilizing a fully implantable, programmable intravascular delivery system consisting of a pump and a catheter for intravenous treprostinil. The study met its primary endpoint and demonstrated that the intravascular delivery system significantly reduced catheter related complications at 22,000 subject-days of follow-up compared with a predefined objective performance criterion. Here we summarize the results obtained during a 6.4-year follow-up period.

METHODS: Throughout study follow-up, participants had clinic visits and medication refills at least every 12 weeks (dependent on the subjects' dose). All …

Multispectral Tracing In Densely Labeled Mouse Brain With Ntracer, Douglas H Roossien, John M Webb, Cristina Mazuski, Erik D Herzog, Et Al.

2010-2019 OA Pubs

SUMMARY: This note describes nTracer, an ImageJ plug-in for user-guided, semi-automated tracing of multispectral fluorescent tissue samples. This approach allows for rapid and accurate reconstruction of whole cell morphology of large neuronal populations in densely labeled brains.

AVAILABILITY AND IMPLEMENTATION: nTracer was written as a plug-in for the open source image processing software ImageJ. The software, instructional documentation, tutorial videos, sample image and sample tracing results are available at https://www.cai-lab.org/ntracer-tutorial.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Elucidating Under-Studied Aspects Of The Link Between Obesity And Multiple Myeloma: Weight Pattern, Body Shape Trajectory, And Body Fat Distribution, Catherine R Marinac, Catherine A Suppan, Edward Giovannucci, Mingyang Song, Ane S Kværner, Mary K Townsend, Bernard A Rosner, Timothy R Rebbeck, Graham A Colditz, Brenda M Birmann

2010-2019 OA Pubs

BACKGROUND: Although obesity is an established modifiable risk factor for multiple myeloma (MM), several nuanced aspects of its relation to MM remain unelucidated, limiting public health and prevention messages.

METHODS: We analyzed prospective data from the Nurses' Health Study and Health Professionals Follow-Up Study to examine MM risk associated with 20-year weight patterns in adulthood, body shape trajectory from ages 5 to 60 years, and body fat distribution. For each aforementioned risk factor, we report hazard ratios (HRs) and 95% confidence intervals (CIs) for incident MM from multivariable Cox proportional-hazards models.

RESULTS: We documented 582 incident MM cases during 4 …

Apples To Apples? Neural Correlates Of Emotion Regulation Differences Between High- And Low-Risk Adolescents, Michael T Perino, João F Guassi Moreira, Ethan M Mccormick, Eva H Telzer

2010-2019 OA Pubs

Adolescence has been noted as a period of increased risk taking. The literature on normative neurodevelopment implicates aberrant activation of affective and regulatory regions as key to inhibitory failures. However, many of these studies have not included adolescents engaging in high rates of risky behavior, making generalizations to the most at-risk populations potentially problematic. We conducted a comparative study of nondelinquent community (n = 24, mean age = 15.8 years, 12 female) and delinquent adolescents (n = 24, mean age = 16.2 years, 12 female) who completed a cognitive control task during functional magnetic resonance imaging, where behavioral inhibition was …

Sexual Violation Of Patients By Physicians: A Mixed-Methods, Exploratory Analysis Of 101 Cases, James M Dubois, Heidi A Walsh, John T Chibnall, Emily E Anderson, Michelle R Eggers, Mobolaji Fowose, Hannah Ziobrowski

2010-2019 OA Pubs

A mixed-method, exploratory design was used to examine 101 cases of sexual violations in medicine. The study involved content analysis of cases to characterize the physicians, patient-victims, the practice setting, kinds of sexual violations, and consequences to the perpetrator. In each case, a criminal law framework was used to examine how motives, means, and opportunity combined to generate sexual misconduct. Finally, cross-case analysis was performed to identify clusters of causal factors that explain specific kinds of sexual misconduct. Most cases involved a combination of five factors: male physicians (100%), older than the age of 39 (92%), who were not board …

2019 Hrs/Ehra/Aphrs/Lahrs Expert Consensus Statement On Catheter Ablation Of Ventricular Arrhythmias, Edmond M Cronin, Phillip Cuculich, Et Al.

2010-2019 OA Pubs

Ventricular arrhythmias are an important cause of morbidity and mortality and come in a variety of forms, from single premature ventricular complexes to sustained ventricular tachycardia and fibrillation. Rapid developments have taken place over the past decade in our understanding of these arrhythmias and in our ability to diagnose and treat them. The field of catheter ablation has progressed with the development of new methods and tools, and with the publication of large clinical trials. Therefore, global cardiac electrophysiology professional societies undertook to outline recommendations and best practices for these procedures in a document that will update and replace the …

Neoadjuvant Folfirinox In Patients With Borderline Resectable Pancreatic Cancer: A Systematic Review And Patient-Level Meta-Analysis, Quisette P Janssen, Andrea Wang-Gillam, Et Al.

2010-2019 OA Pubs

BACKGROUND: FOLFIRINOX is a standard treatment for metastatic pancreatic cancer patients. The effectiveness of neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer (BRPC) remains debated.

METHODS: We performed a systematic review and patient-level meta-analysis on neoadjuvant FOLFIRINOX in patients with BRPC. Studies with BRPC patients who received FOLFIRINOX as first-line neoadjuvant treatment were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival, resection rate, R0 resection rate, and grade III-IV adverse events. Patient-level survival outcomes were obtained from authors of the included studies and analyzed using the Kaplan-Meier method.

RESULTS: We included 24 studies …

The Current State Of Animal Models And Genomic Approaches Towards Identifying And Validating Molecular Determinants Of Mycobacterium Tuberculosis Infection And Tuberculosis Disease, Allison N Bucsan, Smriti Mehra, Shabaana A Khader, Deepak Kaushal

2010-2019 OA Pubs

Animal models are important in understanding both the pathogenesis of and immunity to tuberculosis (TB). Unfortunately, we are beginning to understand that no animal model perfectly recapitulates the human TB syndrome, which encompasses numerous different stages. Furthermore, Mycobacterium tuberculosis infection is a very heterogeneous event at both the levels of pathogenesis and immunity. This review seeks to establish the current understanding of TB pathogenesis and immunity, as validated in the animal models of TB in active use today. We especially focus on the use of modern genomic approaches in these models to determine the mechanism and the role of specific …

How To Implant A Phrenic Nerve Stimulator For Treatment Of Central Sleep Apnea?, Ralph S Augostini, Timothy W Smith, Et Al.

2010-2019 OA Pubs

BACKGROUND: Central sleep apnea (CSA) is a breathing disorder caused by the intermittent absence of central respiratory drive. Transvenous phrenic nerve stimulation is a new therapeutic option, recently approved by the FDA , for the treatment of CSA.

OBJECTIVE: To describe the technique used to implant the transvenous phrenic nerve stimulation system (the remedē System, Respicardia, Inc).

METHODS: The remedē System is placed in the pectoral region, typically on the right side. A single stimulation lead is placed in either the left pericardiophrenic vein (PPV) or the right brachiocephalic vein (RBC). A sensing lead is placed into the azygous vein …

Discovery Of Selective Toxoplasma Gondii Dihydrofolate Reductase Inhibitors For The Treatment Of Toxoplasmosis, Allen T Hopper, Adam Brockman, Andy Wise, Julie Gould, Jennifer Barks, Joshua B Radke, L. David Sibley, Yongmao Zou, Stephen Thomas

2010-2019 OA Pubs

A safer treatment for toxoplasmosis would be achieved by improving the selectivity and potency of dihydrofolate reductase (DHFR) inhibitors, such as pyrimethamine (1), for Toxoplasma gondii DHFR ( TgDHFR) relative to human DHFR ( hDHFR). We previously reported on the identification of meta-biphenyl analog 2, designed by in silico modeling of key differences in the binding pocket between TgDHFR and hDHFR. Compound 2 improves TgDHFR selectivity 6.6-fold and potency 16-fold relative to 1. Here, we report on the optimization and structure-activity relationships of this arylpiperazine series leading to the discovery of 5-(4-(3-(2-methoxypyrimidin-5-yl)phenyl)piperazin-1-yl)pyrimidine-2,4-diamine 3. Compound 3 has a TgDHFR IC

Gen-1 Immunotherapy For The Treatment Of Ovarian Cancer, Premal H Thaker, Nicholas Borys, Jason Fewell, Khursheed Anwer

2010-2019 OA Pubs

GEN-1 is a gene-based immunotherapy, comprising a human IL-12 gene expression plasmid and a synthetic plasmid delivery system, delivered intraperitoneally (ip.) to produce local and persistent levels of a pleiotropic immunocytokine, IL-12, at the tumor site in patients with advanced ovarian cancer. The goal of local and persistent IL-12 delivery is to remodel the highly immunosuppressive tumor microenvironment to favor immune stimulation while avoiding serious systemic toxicities, a major limitation of recombinant IL-12 therapy. Safe and sustained local production of IL-12 and related immunocytokines at the tumor site could produce potentially more favorable immunological changes in the tumor microenvironment and …

White Matter Damage, Neuroinflammation, And Neuronal Integrity In Hand, Aljoharah Alakkas, David B Clifford, Et Al.

2010-2019 OA Pubs

HIV-associated neurocognitive disorders (HANDs) persist even with virologic suppression on combination antiretroviral therapy (cART), and the underlying pathophysiological mechanisms are not well understood. We performed structural magnetic resonance imaging and MR spectroscopy (MRS) in HIV+ individuals without major neurocognitive comorbidities. Study participants were classified as neurocognitively unimpaired (NU), asymptomatic (ANI), mild neurocognitive disorder (MND), or HIV-associated dementia (HAD). Using structural MRI, we measured volumes of cortical and subcortical gray matter and total and abnormal white matter (aWM). Using single-voxel MRS, we estimated metabolites in frontal gray matter (FGM) and frontal white matter (FWM) and basal ganglia (BG) regions. Adjusted odds …

Association Between Reductions Of Number Of Cigarettes Smoked Per Day And Mortality Among Older Adults In The United States, Maki Inoue-Choi, Patricia Hartge, Yikyung Park, Christian C Abnet, Neal D Freedman

2010-2019 OA Pubs

Many smokers do not quit but instead reduce the number of cigarettes they smoke per day (CPD) over their lifetime. Yet the associations of such changes in CPD with health risks are unclear. We examined the association of changes in CPD with subsequent death in the period 2004-2011 among 253,947 participants of the National Institutes of Health-AARP Diet and Health Study. Using a questionnaire assessing responders' history of smoking cigarettes, we identified cigarette smokers who quit, decreased, maintained, or increased their CPD between ages 25-29 and 50-59 years. Hazard ratios and 95% confidence intervals were obtained from multivariable adjusted Cox …

Developing And Assessing The Feasibility Of A Home-Based Preexposure Prophylaxis Monitoring And Support Program, Aaron J Siegler, Kenneth H Mayer, Albert Y Liu, Rupa R Patel, Lauren M Ahlschlager, Colleen S Kraft, Rossi Fish, Sarah E Wiatrek, Patrick S Sullivan

2010-2019 OA Pubs

We piloted PrEP@Home, a preexposure prophylaxis system of remote laboratory and behavioral monitoring designed to replace routine quarterly follow-up visits with home care to reduce the patient and provider burden. The system was highly acceptable and in-demand for future use, and more than one-third of participants reported greater likelihood of persisting in care if available.

Reward Improves Response Inhibition By Enhancing Attentional Capture, Yanqing Wang, Todd S Braver, Shouhang Yin, Xueping Hu, Xiangpeng Wang, Antao Chen

2010-2019 OA Pubs

Reward plays a crucial role in enhancing response inhibition. While it is generally assumed that the process of response inhibition involves attentional capture and the stopping of action, it is unclear whether this reflects a direct impact of reward on response inhibition or rather an indirect mediation via attentional capture. Here, we employed a revised stop-signal task (SST) that separated these two cognitive elements, by including a continue signal that required the same motor response as in go trials, but also attention to a cue, as in stop trials. We first confirmed the engagement of the right inferior frontal gyrus …

Crocodylian Head Width Allometry And Phylogenetic Prediction Of Body Size In Extinct Crocodyliforms, Haley D O'Brien, Leigha M Lynch, Kent A Vliet, John Brueggen, Gregory M Erickson, Paul M Gignac

2010-2019 OA Pubs

Body size and body-size shifts broadly impact life-history parameters of all animals, which has made accurate body-size estimates for extinct taxa an important component of understanding their paleobiology. Among extinct crocodylians and their precursors (e.g., suchians), several methods have been developed to predict body size from suites of hard-tissue proxies. Nevertheless, many have limited applications due to the disparity of some major suchian groups and biases in the fossil record. Here, we test the utility of head width (HW) as a broadly applicable body-size estimator in living and fossil suchians. We use a dataset of sexually mature male and female …

Cdek: Clinical Drug Experience Knowledgebase, Rebekah H Griesenauer, Constantino Schillebeeckx, Michael S Kinch

2010-2019 OA Pubs

The Clinical Drug Experience Knowledgebase (CDEK) is a database and web platform of active pharmaceutical ingredients with evidence of clinical testing as well as the organizations involved in their research and development. CDEK was curated by disambiguating intervention and organization names from ClinicalTrials.gov and cross-referencing these entries with other prominent drug databases. Approximately 43% of active pharmaceutical ingredients in the CDEK database were sourced from ClinicalTrials.gov and cannot be found in any other prominent compound-oriented database. The contents of CDEK are structured around three pillars: active pharmaceutical ingredients (n = 22 292), clinical trials (n = 127 223) and organizations …