Digital Commons Network^™

In Vivo Evolution Of Biopsy-Proven Inflammatory Demyelination Quantified By R2t* Mapping, Biao Xiang, Jie Wen, Hsiang-Chih Lu, Robert E Schmidt, Dmitriy A Yablonskiy, Anne H Cross

Open Access Publications

A 35-year-old man with an enhancing tumefactive brain lesion underwent biopsy, revealing inflammatory demyelination. We used quantitative Gradient-Recalled-Echo (qGRE) MRI to visualize and measure tissue damage in the lesion. Two weeks after biopsy, qGRE showed significant R2t* reduction in the left optic radiation and surrounding tissue, consistent with the histopathological and clinical findings. qGRE was repeated 6 and 14 months later, demonstrating partially recovered optic radiation R2t*, in concert with improvement of the hemianopia to ultimately involve only the lower right visual quadrant. These results support qGRE metrics as in vivo biomarkers for tissue damage and longitudinal monitoring of demyelinating …

Antibiotic Prescription Practices In Primary Care In Low- And Middle-Income Countries: A Systematic Review And Meta-Analysis, Giorgia Sulis, Pierrick Adam, Vaidehi Nafade, Genevieve Gore, Benjamin Daniels, Amrita Daftary, Jishnu Das, Sumanth Gandra, Madhukar Pai

Open Access Publications

BACKGROUND: The widespread use of antibiotics plays a major role in the development and spread of antimicrobial resistance. However, important knowledge gaps still exist regarding the extent of their use in low- and middle-income countries (LMICs), particularly at the primary care level. We performed a systematic review and meta-analysis of studies conducted in primary care in LMICs to estimate the prevalence of antibiotic prescriptions as well as the proportion of such prescriptions that are inappropriate.

METHODS AND FINDINGS: We searched PubMed, Embase, Global Health, and CENTRAL for articles published between 1 January 2010 and 4 April 2019 without language restrictions. …

Oliceridine And Its Potential To Revolutionize Gi Endoscopy Sedation, Basavana Goudra, Preet Mohinder Singh

Open Access Publications

Providing sedation to patients undergoing gastrointestinal (GI) endoscopy is a controversial and emotive issue. The mainstay of sedation is propofol, whose administration is within the sole jurisdiction of anesthesia providers, at least in the USA. Attempts have been made to seize the authority by the GI community. One of the first attempts was the use of the prodrug of propofol -fospropofol. However, as the drug has a similar adverse effect profile as propofol in terms of respiratory depression, the FDA did not approve its use by providers other than those trained in airway management. Sedasys

Conformational Distributions Of Isolated Myosin Motor Domains Encode Their Mechanochemical Properties, Justin R. Porter, Artur Meller, Maxwell I. Zimmerman, Michael J. Greenberg, Gregory R. Bowman

Open Access Publications

Myosin motor domains perform an extraordinary diversity of biological functions despite sharing a common mechanochemical cycle. Motors are adapted to their function, in part, by tuning the thermodynamics and kinetics of steps in this cycle. However, it remains unclear how sequence encodes these differences, since biochemically distinct motors often have nearly indistinguishable crystal structures. We hypothesized that sequences produce distinct biochemical phenotypes by modulating the relative probabilities of an ensemble of conformations primed for different functional roles. To test this hypothesis, we modeled the distribution of conformations for 12 myosin motor domains by building Markov state models (MSMs) from an …

Plasmodium Falciparum Translational Machinery Condones Polyadenosine Repeats, Slavica Pavlovic Djuranovic, Jessey Erath, Ryan J. Andrews, Peter O. Bayguinov, Joyce J. Chung, Douglas L. Chalker, James A.J. Fitzpatrick, Walter N. Moss, Pawel Szczesny, Sergej Djuranovic

Open Access Publications

No abstract provided.

Consensus Guideline For The Diagnosis And Treatment Of Tetrahydrobiopterin (Bh4) Deficiencies, Thomas Opladen, Toni S Pearson, Et Al

Open Access Publications

BACKGROUND: Tetrahydrobiopterin (BH

CONCLUSION: Although the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH

Bone Density Of First And Second Segments Of Normal And Dysmorphic Sacra, Joseph M Radley, Brian W Hill, Daemeon A Nicolaou, Stephen B Huebner, Kelby B Napier, Dane H Salazar

Open Access Publications

BACKGROUND: Iliosacral screw fixation is safe and effective but can be complicated by loss of fixation, particularly in patients with osteopenic bone. Sacral morphology dictates where iliosacral screws may be placed when stabilizing pelvic ring injuries. In dysmorphic sacra, the safe osseous corridor of the upper sacral segment (S1) is smaller and lacks a transsacral corridor, increasing the need for fixation in the second sacral segment (S2). Previous evidence suggests that S2 is less dense than S1. The aim of this cross-sectional study is to further evaluate bone mineral density (BMD) of the S1 and S2 iliosacral osseous pathways through …

Targeting Mitochondrial Fusion And Fission Proteins For Cardioprotection, Sauri Hernandez-Resendiz, Fabrice Prunier, Henrique Girao, Gerald Dorn, Derek J Hausenloy, Eu-Cardioprotection Cost Action (Ca16225)

Open Access Publications

New treatments are needed to protect the myocardium against the detrimental effects of acute ischaemia/reperfusion (IR) injury following an acute myocardial infarction (AMI), in order to limit myocardial infarct (MI) size, preserve cardiac function and prevent the onset of heart failure (HF). Given the critical role of mitochondria in energy production for cardiac contractile function, prevention of mitochondrial dysfunction during acute myocardial IRI may provide novel cardioprotective strategies. In this regard, the mitochondrial fusion and fissions proteins, which regulate changes in mitochondrial morphology, are known to impact on mitochondrial quality control by modulating mitochondrial biogenesis, mitophagy and the mitochondrial unfolded …

Coronary Heart Disease And Mortality Following A Breast Cancer Diagnosis, Aixia Guo, Kathleen W Zhang, Kristi Reynolds, Randi E Foraker

Open Access Publications

BACKGROUND: Coronary heart disease (CHD) is a leading cause of morbidity and mortality for breast cancer survivors, yet the joint effect of adverse cardiovascular health (CVH) and cardiotoxic cancer treatments on post-treatment CHD and death has not been quantified.

METHODS: We conducted statistical and machine learning approaches to evaluate 10-year risk of these outcomes among 1934 women diagnosed with breast cancer during 2006 and 2007. Overall CVH scores were classified as poor, intermediate, or ideal for 5 factors, smoking, body mass index, blood pressure, glucose/hemoglobin A1c, and cholesterol from clinical data within 5 years prior to the breast cancer diagnosis. …

Radiation Induces Iatrogenic Immunosuppression By Indirectly Affecting Hematopoiesis In Bone Marrow, Vaishali Kapoor, Andrea Collins, Kaylan Griffith, Subhajit Ghosh, Nathan Wong, Xiaowei Wang, Grant A. Challen, Joseph Krambs, Dan Link, Dennis E. Hallahan, Dinesh Thotala

Open Access Publications

The immune system plays a vital role in cancer therapy, especially with the advent of immunotherapy. Radiation therapy induces iatrogenic immunosuppression referred to as radiation-induced lymphopenia (RIL). RIL correlates with significant decreases in the overall survival of cancer patients. Although the etiology and severity of lymphopenia are known, the mechanism(s) of RIL are largely unknown. We found that irradiation not only had direct effects on circulating lymphocytes but also had indirect effects on the spleen, thymus, and bone marrow. We found that irradiated cells traffic to the bone marrow and bring about the reduction of hematopoietic stem cells (HSC) and …

Mentored Training And Its Association With Dissemination And Implementation Research Output: A Quasi-Experimental Evaluation, Rebekah R Jacob, Angeline Gacad, Margaret Padek, Graham A Colditz, Karen M Emmons, Jon F Kerner, David A Chambers, Ross C Brownson

Open Access Publications

BACKGROUND: There is a continued need to evaluate training programs in dissemination and implementation (D&I) research. Scientific products yielded from trainees are an important and objective measure to understand the capacity growth within the D&I field. This study evaluates our mentored training program in terms of scientific productivity among applicants.

METHODS: Post-doctoral and early-career cancer researchers were recruited and applied to the R25 Mentored Training for Dissemination and Implementation Research in Cancer (MT-DIRC) between 2014 and 2017. Using application details and publicly available bibliometric and funding data, we compared selected fellows with unsuccessful applicants (nonfellows). We extracted Scopus citations and …

A New Gorilla Adenoviral Vector With Natural Lung Tropism Avoids Liver Toxicity And Is Amenable To Capsid Engineering And Vector Retargeting, Zhi Hong Lu, Igor P. Dmitriev, Douglas E. Brough, Elena A. Kashentseva, Jie Li, David T. Curiel

Open Access Publications

Human adenoviruses have many attractive features for gene therapy applications. However, the high prevalence of preexisting immunity against these viruses in general populations worldwide has greatly limited their clinical utility. In addition, the most commonly used human adenovirus, human adenovirus subgroup C serotype 5 (HAd5), when systemically administered, triggers systemic inflammation and toxicity, with the liver being the most severely affected organ. Here, we evaluated the utility and safety of a new low-seroprevalence gorilla adenovirus (GAd; GC46) as a gene transfer vector in mice. Biodistribution studies revealed that systemically administered GAd had a selective and robust lung endothelial cell (EC) …

The Effects Of Vagus Nerve Stimulation On The Course And Outcomes Of Patients With Bipolar Disorder In A Treatment-Resistant Depressive Episode: A 5-Year Prospective Registry, R Hamish Mcallister-Williams, Soraia Sousa, Arun Kumar, Teresa Greco, Mark T Bunker, Scott T Aaronson, Charles R Conway, A John Rush

Open Access Publications

BACKGROUND: To compare illness characteristics, treatment history, response and durability, and suicidality scores over a 5-year period in patients with treatment-resistant bipolar depression participating in a prospective, multicenter, open-label registry and receiving Vagus Nerve Stimulation Therapy (VNS Therapy) plus treatment-as-usual (VNS + TAU) or TAU alone.

METHODS: Response was defined as ≥ 50% decrease from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score at 3, 6, 9, or 12 months post-baseline. Response was retained while MADRS score remained ≥ 40% lower than baseline. Time-to-events was estimated using Kaplan-Meier (KM) analysis and compared using log-rank test. Suicidality was assessed using the …

Effects Of Dopaminergic Drugs On Cognitive Control Processes Vary By Genotype, Daniella J Furman, Robert L White Iii, Jenna Naskolnakorn, Jean Ye, Andrew Kayser, Mark D'Esposito

Open Access Publications

Dopamine (DA) has been implicated in modulating multiple cognitive control processes, including the robust maintenance of task sets and memoranda in the face of distractors (cognitive stability) and, conversely, the ability to switch task sets or update the contents of working memory when it is advantageous to do so (cognitive flexibility). In humans, the limited specificity of available pharmacological probes has posed a challenge for understanding the mechanisms by which DA, acting on multiple receptor families across the PFC and striatum, differentially influences these cognitive processes. Using a within-subject, placebo-controlled design, we contrasted the impact of two mechanistically distinct DA …

Applying Two General Population Job Exposure Matrices To Predict Incident Carpal Tunnel Syndrome: A Cross-National Approach To Improve Estimation Of Workplace Physical Exposures, Marcus Yung, Bradley A Evanoff, Skye Buckner-Petty, Yves Roquelaure, Alexis Descatha, Ann Marie Dale

Open Access Publications

Objectives A job exposure matrix (JEM) is a tool to estimate workers' exposure to occupational physical risk factors. We evaluated the performance of two general population JEM (CONSTANCES and O*NET) to detect known exposure-disease relationships in an American prospective cohort study. We compared exposure estimates from three data sources and explored whether combining exposures from these two JEM, or combining exposure from each JEM with individual-level measures, improved prediction of carpal tunnel syndrome (CTS). Methods Using Cox proportional hazard models, we evaluated relationships between physical work exposure and incident CTS of 2393 workers using JEM-assigned and individual-level measure exposure information. …

Heterotopic Pregnancy Diagnosed With Point-Of-Care Ultrasound In The Emergency Department: A Case Report, Ian J Holley, Sean P Stickles

Open Access Publications

Introduction: Heterotopic pregnancies are rare. However, they are occurring with increasing frequency. Unfortunately, diagnosis is frequently delayed, with patients presenting in extremis.

Case Report: We present a case of a heterotopic pregnancy diagnosed by point-of-care ultrasound (POCUS) in a woman presenting with lower abdominal pain, who had a documented normal first trimester ultrasound the day prior to presentation.

Discussion: Given the increasing rates of heterotopic pregnancies, we can no longer be reassured by the presence of an intra-uterine pregnancy (IUP) in a patient with concerning signs and symptoms of a ruptured ectopic pregnancy. A thorough POCUS evaluation of the uterus …

Cystic Fibrosis Foundation Consensus Guidelines For The Care Of Individuals With Advanced Cystic Fibrosis Lung Disease, Siddhartha G Kapnadak, Peter Michelson, Joan Zukosky, Et Al

Open Access Publications

BACKGROUND: Advanced cystic fibrosis lung disease (ACFLD) is common, is associated with reduced quality of life, and remains the most frequent cause of death in individuals with cystic fibrosis (CF). These consensus guidelines provide recommendations to the CF community on management of both common and unique issues that arise when individuals reach a state of ACFLD.

METHODS: The CF Foundation assembled a multidisciplinary expert panel consisting of three workgroups: Pulmonary management; Management of comorbid conditions; Symptom management and psychosocial issues. Topics were excluded if the management considerations did not differ in ACFLD from in the overall CF population or if …

Self-Care Research: How To Grow The Evidence Base?, T Jaarsma, A Strömberg, S B Dunbar, D Fitzsimons, C Lee, S Middleton, E Vellone, K E Freedland, B Riegel

Open Access Publications

BACKGROUND AND OBJECTIVE: The number of studies in the area of self-care is growing and international researchers are increasingly developing self-care interventions to improve outcomes of individual patients and communities. However, growth of the evidence is still slow due to challenges with designing and testing self-care interventions. In this article we address major methodological challenges with regard to the definition of self-care, use of theory, and research design, intended to provide guidance to researchers in this field.

METHOD: During the inaugural conference of the International Center for Self-Care Research held in Rome, Italy in June 2019 we identified important issues …

Targeting Usp1-Dependent Kdm4a Protein Stability As A Potential Prostate Cancer Therapy, Shu-Zhong Cui, Zi-Ying Lei, Tian-Pei Guan, Ling-Ling Fan, You-Qiang Li, Xin-Yan Geng, De-Xue Fu, Hao-Wu Jiang, Song-Hui Xu

Open Access Publications

The histone demethylase lysine-specific demethylase 4A (KDM4A) is reported to be overexpressed and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 or H3K36 methylation marks. However, the biological role and mechanism of KDM4A in prostate cancer (PC) remain unclear. Herein, we reported KDM4A expression was upregulation in phosphatase and tensin homolog knockout mouse prostate tissue. Depletion of KDM4A in PC cells inhibited their proliferation and survival in vivo and vitro. Further studies reveal that USP1 is a deubiquitinase that regulates KDM4A K48-linked deubiquitin and stability. Interestingly, we found c-Myc was a key downstream …

Seafood Graded Oral Food Challenge Outcomes In A Pediatric Tertiary Care Center, Zachary E Rubin, Hongjie Gu, Brooke I Polk

Open Access Publications

BACKGROUND: There are sparse data regarding the predictors of positive oral food challenges and reaction severity for seafood in children.

OBJECTIVE: Identify clinical characteristics in children with seafood allergy who were most likely to experience a negative oral food challenge (OFC).

METHODS: A retrospective chart review was performed for children who had a graded OFC to seafood at a pediatric tertiary care center from 2008 through 2019.

RESULTS: Sixty-three (60% male; average age 8 years; range 1-21 years) OFCs were performed, of which 21 were fish and 42 were shellfish. There were 10 (16%) positive OFCs and positive OFC rate …

Association Of Isolated Coronary Microvascular Dysfunction With Mortality And Major Adverse Cardiac Events: A Systematic Review And Meta-Analysis Of Aggregate Data, Mark A Gdowski, Venkatesh L Murthy, Michelle Doering, Andrea G Monroy-Gonzalez, Riemer Slart, David L Brown

Open Access Publications

Background The impact of coronary microvascular dysfunction (CMD), as diagnosed by reduced coronary flow reserve, on the outcomes of patients with symptoms of myocardial ischemia and nonobstructive coronary artery disease is poorly understood. We performed a systematic review and meta-analysis of observational studies to determine the association of CMD with outcomes. Methods and Results We searched online databases for studies where coronary flow reserve was measured invasively or noninvasively, clinical events were recorded after determination of coronary flow reserve, and the frequency of those events was reported for patients with and without CMD. The primary outcome was all-cause mortality. The …

Cd4+ T Cell Expression Of The Il-10 Receptor Is Necessary For Facial Motoneuron Survival After Axotomy, Elizabeth M Runge, Abhirami K Iyer, Deborah O Setter, Felicia M Kennedy, Virginia M Sanders, Kathryn J Jones

Open Access Publications

BACKGROUND: After peripheral nerve transection, facial motoneuron (FMN) survival depends on an intact CD4+ T cell population and a central source of interleukin-10 (IL-10). However, it has not been determined previously whether CD4+ T cells participate in the central neuroprotective IL-10 cascade after facial nerve axotomy (FNA).

METHODS: Immunohistochemical labeling of CD4+ T cells, pontine vasculature, and central microglia was used to determine whether CD4+ T cells cross the blood-brain barrier and enter the facial motor nucleus (FMNuc) after FNA. The importance of IL-10 signaling in CD4+ T cells was assessed by performing adoptive transfer of IL-10 receptor beta (IL-10RB)-deficient …

Reinforcement Biases Subsequent Perceptual Decisions When Confidence Is Low, A Widespread Behavioral Phenomenon, Armin Lak, Emily Hueske, Junya Hirokawa, Paul Masset, Torben Ott, Anne E. Urai, Tobias H. Donner, Matteo Carandini, Susumu Tonegawa, Naoshige Uchida, Adam Kepecs

Open Access Publications

Learning from successes and failures often improves the quality of subsequent decisions. Past outcomes, however, should not influence purely perceptual decisions after task acquisition is complete since these are designed so that only sensory evidence determines the correct choice. Yet, numerous studies report that outcomes can bias perceptual decisions, causing spurious changes in choice behavior without improving accuracy. Here we show that the effects of reward on perceptual decisions are principled: past rewards bias future choices specifically when previous choice was difficult and hence decision confidence was low. We identified this phenomenon in six datasets from four laboratories, across mice, …

Assessment Of Biological Role And Insight Into Druggability Of The Plasmodium Falciparum Protease Plasmepsin V, Alexander J Polino, Armiyaw S Nasamu, Jacquin C Niles, Daniel E Goldberg

Open Access Publications

Upon infecting a red blood cell (RBC), the malaria parasite

Cd300lf Is The Primary Physiologic Receptor Of Murine Norovirus But Not Human Norovirus, Vincent R. Graziano, Forrest C. Walker, Elizabeth A. Kennedy, Ebrahim Hassan, Arthur S. Kim, Megan T. Baldridge, Et Al.

Open Access Publications

Murine norovirus (MNoV) is an important model of human norovirus (HNoV) and mucosal virus infection more broadly. Viral receptor utilization is a major determinant of cell tropism, host range, and pathogenesis. The bona fide receptor for HNoV is unknown. Recently, we identified CD300lf as a proteinaceous receptor for MNoV. Interestingly, its paralogue CD300ld was also sufficient for MNoV infection in vitro. Here we explored whether CD300lf is the sole physiologic receptor in vivo and whether HNoV can use a CD300 ortholog as an entry receptor. We report that both CD300ld and CD300lf are sufficient for infection by diverse MNoV strains …

Care Of Patients With Pulmonary Arterial Hypertension During The Coronavirus (Covid-19) Pandemic, John J Ryan, Lana Melendres-Groves, Roham T Zamanian, Ronald J Oudiz, Murali Chakinala, Erika B Rosenzweig, Mardi Gomberg-Maitland

Open Access Publications

The COVID-19 pandemic presents many unique challenges when caring for patients with pulmonary hypertension. The COVID-19 pandemic has altered routine standard of care practice and the acute management particularly for those patients with pulmonary arterial hypertension, where pulmonary arterial hypertension-specific treatments are used. It is important to balance the ongoing care and evaluation of pulmonary arterial hypertension patients with "exposure risk" to COVID-19 for patients coming to clinic or the hospital. If there is a morbidity and mortality benefit from starting pulmonary arterial hypertension therapies, for example in a patient with high-likelihood of pulmonary arterial hypertension, then it remains important …

Glanzmann Thrombasthenia: Genetic Basis And Clinical Correlates, Juliana Perez Botero, Kristy Lee, Brian R. Branchford, Paul F. Bray, Kathleen Freson, Michele P. Lambert, Minjie Luo, Shruthi Mohan, Justyne E Ross, Wolfgang Bergmeier, Jorge Di Paola, Clingen Platelet Disorder Variant Curation Expert Panel

Open Access Publications

Glanzmann thrombasthenia (GT) is an autosomal recessive disorder of platelet aggregation caused by quantitative or qualitative defects in integrins αIIb and β3. These integrins are encoded by the

Assessing Clinical Research Coordinator Knowledge Of Good Clinical Practice: An Evaluation Of The State Of The Art And A Test Validation Study, James M Dubois, Jessica T Mozersky, Alison L Antes, Kari Baldwin, Michelle Jenkerson

Open Access Publications

This paper describes the development and validation of a new 32-item test of knowledge of good clinical practice (GCP) administered to 625 clinical research coordinators. GCP training is mandated by study sponsors including the US National Institutes of Health. The effectiveness of training is rarely assessed, and the lack of validated tests is an obstacle to assessment. The GCP knowledge test was developed following evaluation of two existing widely used GCP tests to ensure it accurately reflects the content of current training. The final GCP knowledge test demonstrated good reliability (

Analytical Performance Of An Immunoprofiling Assay Based On Rna Models, Ian Schillebeeckx, Jon R Armstrong, Jason T Forys, Jeffrey Hiken, Jon Earls, Kevin C Flanagan, Tiange Cui, Jarret I Glasscock, David N Messina, Eric J Duncavage

Open Access Publications

As immuno-oncology drugs grow more popular in the treatment of cancer, better methods are needed to quantify the tumor immune cell component to determine which patients are most likely to benefit from treatment. Methods such as flow cytometry can accurately assess the composition of infiltrating immune cells; however, they show limited use in formalin-fixed, paraffin-embedded (FFPE) specimens. This article describes a novel hybrid-capture RNA sequencing assay, ImmunoPrism, that estimates the relative percentage abundance of eight immune cell types in FFPE solid tumors. Immune health expression models were generated using machine learning methods and used to uniquely identify each immune cell …

Pre-Exposure Prophylaxis For Preventing Acquisition Of Hiv: A Cross-Sectional Study Of Patients, Prescribers, Uptake, And Spending In The United States, 2015-2016, Stephanie S. Chan, Andre R. Chappel, Karen E. Joynt Maddox, Karen W. Hoover, Ya-Lin A. Huang, Weiming Zhu, Stacy M. Cohen, Pamela W. Klein, Nancy De Lew

Open Access Publications

BACKGROUND: In 2015, there were approximately 40,000 new HIV diagnoses in the United States. Pre-exposure prophylaxis (PrEP) is an effective strategy that reduces the risk of HIV acquisition; however, uptake among those who can benefit from it has lagged. In this study, we 1) compared the characteristics of patients who were prescribed PrEP with individuals newly diagnosed with HIV infection, 2) identified the specialties of practitioners prescribing PrEP, 3) identified metropolitan statistical areas (MSAs) within the US where there is relatively low uptake of PrEP, and 4) reported median amounts paid by patients and third-party payors for PrEP.

METHODS AND …