Digital Commons Network^™

Satb2 Induction Of A Neural Crest Mesenchyme-Like Program Drives Melanoma Invasion And Drug Resistance, Maurizio Fazio, Charles K. Kaufman, Et Al

Open Access Publications

Recent genomic and scRNA-seq analyses of melanoma demonstrated a lack of recurrent genetic drivers of metastasis, while identifying common transcriptional states correlating with invasion or drug resistance. To test whether transcriptional adaptation can drive melanoma progression, we made use of a zebrafish mitfa:

The Effect Of The Covid-19 Pandemic On Hip And Knee Arthroplasty Patients In The United States: A Multicenter Update To The Previous Survey, Timothy S Brown, Christopher A Anthony, Et Al

Open Access Publications

Background: In March 2020, elective total hip and knee arthroplasty (THA and TKA) were suspended across the United States in response to the COVID-19 pandemic. We had previously published the results of a survey to the affected patients from 6 institutions. We now present the results of a larger distribution of this survey, through May and June 2020, to electively scheduled patients representing different regions of the United States.

Methods: Fifteen centers identified through the American Association of Hip and Knee Surgeons Research Committee participated in a survey study of THA and TKA patients. Patients scheduled for primary elective THA …

Ccr5 Inhibition In Critical Covid-19 Patients Decreases Inflammatory Cytokines, Increases Cd8 T-Cells, And Decreases Sars-Cov2 Rna In Plasma By Day 14, Bruce K Patterson, Philip A Mudd, Et Al

Open Access Publications

OBJECTIVE: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now a global pandemic. Emerging results indicate a dysregulated immune response. Given the role of CCR5 in immune cell migration and inflammation, we investigated the impact of CCR5 blockade via the CCR5-specific antibody leronlimab on clinical, immunological, and virological parameters in severe COVID-19 patients.

METHODS: In March 2020, 10 terminally ill, critical COVID-19 patients received two doses of leronlimab via individual emergency use indication. We analyzed changes in clinical presentation, immune cell populations, inflammation, as well as SARS-CoV-2 plasma viremia before and 14 days after treatment.

RESULTS: Over the …

Global, Cell Non-Autonomous Gene Regulation Drives Individual Lifespan Among Isogenic C. Elegans, Holly E. Kinser, Matthew C. Mosley, Isaac B. Plutzer, Zachary Pincus

Open Access Publications

Across species, lifespan is highly variable among individuals within a population. Even genetically identical

Progress Towards Onchocerciasis Elimination In Côte D'Ivoire: A Geospatial Modelling Study, Obiora A. Eneanya, Benjamin G. Koudou, Meite Aboulaye, Aba Ange Elvis, Yeo Souleymane, Marie-Madeleine Kouakou, Gary J. Weil, Peter U. Fischer

Open Access Publications

BACKGROUND: Côte d'Ivoire has had 45 years of intervention for onchocerciasis by vector control (from 1975 to 1991), ivermectin mass drug administration (MDA) (from 1992 to 1994) and community directed treatment with ivermectin (CDTi) from 1995 to the present. We modeled onchocerciasis endemicity during two time periods that correspond to the scale up of vector control and ivermectin distribution, respectively. This analysis illustrates progress towards elimination during these periods, and it has identified potential hotspots areas that are at risk for ongoing transmission.

METHODS AND FINDINGS: The analysis used Ministry of Health skin snip microfilaria (MF) prevalence and intensity data …

Capsule Carbohydrate Structure Determines Virulence In Acinetobacter Baumannii, Yuli Talyansky, Travis B. Nielsen, Jun Yan, Ulrike Carlino-Macdonald, Gisela Di Venanzio, Somnath Chakravorty, Amber Ulhaq, Mario F. Feldman, Thomas A. Russo, Evgeny Vinogradov, Brian Luna, Meredith S. Wright, Mark D. Adams, Brad Spellberg

Open Access Publications

Acinetobacter baumannii is a highly antibiotic-resistant bacterial pathogen for which novel therapeutic approaches are needed. Unfortunately, the drivers of virulence in A. baumannii remain uncertain. By comparing genomes among a panel of A. baumannii strains we identified a specific gene variation in the capsule locus that correlated with altered virulence. While less virulent strains possessed the intact gene gtr6, a hypervirulent clinical isolate contained a spontaneous transposon insertion in the same gene, resulting in the loss of a branchpoint in capsular carbohydrate structure. By constructing isogenic gtr6 mutants, we confirmed that gtr6-disrupted strains were protected from phagocytosis in vitro and …

Polygenic Burden Has Broader Impact On Health, Cognition, And Socioeconomic Outcomes Than Most Rare And High-Risk Copy Number Variants, Elmo Christian Saarentaus, Lei Chen, Ira M Hall, Et Al

Open Access Publications

Copy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on …

Suspected Metal Allergy And Femoral Loosening After Total Knee Arthroplasty: A Diagnostic Dilemma, Elizabeth G Lieberman, Robert L Barrack, Thomas P Schmalzried

Open Access Publications

Metal sensitivity is increasingly prevalent and is associated with negative outcomes after total knee arthroplasty (TKA). Currently, there is no consensus on diagnostic criteria for TKA failure from immune reaction. We present a patient who had pain and aseptic effusion 2 years after TKA. Radiographs were concerning femoral loosening. Lymphocyte transformation testing showed nickel sensitivity. During revision surgery, the femoral component was loose. The histologic aseptic lymphocyte-dominated vasculitis-associated lesion score was 4 with elevated CD4+ lymphocytes, consistent with sensitization. Nickel-free revision implants were used. One year after surgery, the patient is symptom-free. This case has features suggestive of an immune …

The Role Of Endometrial Sampling For Surveillance Of Recurrence In Postmenopausal Patients With Medically Inoperable Stage I Endometrial Cancer, Angelina Carey-Love, Mary M Mullen, Abigail Zamorano, Stephanie Markovina, Andrea R Hagemann, Katherine C Fuh, Premal H Thaker, David G Mutch, Matthew A Powell, Lindsay M Kuroki

Open Access Publications

It is unclear if surveillance for postmenopausal women with medically inoperable stage 1 endometrial cancer (EC) should differ depending on their management strategy. Thus, we investigated the utility of surveillance endometrial sampling among 53 postmenopausal women with medically inoperable, clinical stage I, grade 1 endometrioid EC who received either progestin therapy or radiation between 2009 and 2018, at a single academic institution. Frequency and results of endometrial sampling, as well as recurrence and survival rates were studied. Of 53 patients, 18 (34.0%) received progestin therapy and 35 (66.0%) radiation. Medically managed patients were treated with megestrol acetate (27.7%), a levonorgestrel …

Evaluating Cognitive Relationships With Resting-State And Task-Driven Blood Oxygen Level-Dependent Variability, Peter R Millar, Beau M Ances, Brian A Gordon, Tammie L S Benzinger, John C Morris, David A Balota

Open Access Publications

Recent functional magnetic resonance imaging studies have reported that moment-to-moment variability in the blood oxygen level-dependent (BOLD) signal is positively associated with task performance and, thus, may reflect a behaviorally sensitive signal. However, it is not clear whether estimates of resting-state and task-driven BOLD variability are differentially related to cognition, as they may be driven by distinct sources of variance in the BOLD signal. Moreover, other studies have suggested that age differences in resting-state BOLD variability may be particularly sensitive to individual differences in cardiovascular, rather than neural, factors. In this study, we tested relationships between measures of behavioral task …

Investigating Rare Pathogenic/Likely Pathogenic Exonic Variation In Bipolar Disorder, Xiaoming Jia, Fernando S Goes, Adam E Locke, Duncan Palmer, Weiqing Wang, Et Al

Open Access Publications

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes …

Genomic Characterization Of Emerging Bacterial Uropathogen Neisseria Meningitidis, Which Was Misidentified As Neisseria Gonorrhoeae By Nucleic Acid Amplification Testing, Kimberley V Sukhum, Sophonie Jean, Meghan Wallace, Neil Anderson, C A Burnham, Gautam Dantas

Open Access Publications

No abstract provided.

Central Venous Catheter Adverse Events Are Not Associated With Crowding Indicators, Daniel L Theodoro, Niraj Vyas, Enyo Ablordeppey, Brian Bausano, Stephanie Charshafian, Phillip Asaro, Richard T Griffey

Open Access Publications

OBJECTIVE: Crowding in the emergency department (ED) impacts a number of important quality and safety metrics. We studied ED crowding measures associated with adverse events (AE) resulting from central venous catheters (CVC) inserted in the ED, as well as the relationship between crowding and the frequency of CVC insertions in an ED cohort admitted to the intensive care unit (ICU).

METHODS: We conducted a retrospective observational study from 2008-2010 in an academic tertiary care center. Participants undergoing CVC in the ED or admitted to an ICU were categorized by quartile based on the following: National Emergency Department Overcrowding Scale (NEDOCS); …

Naturalistic Language Input Is Associated With Resting-State Functional Connectivity In Infancy, Lucy S. King, M. Catalina Camacho, David F. Montez, Kathryn L. Humphreys, Ian H. Gotlib

Open Access Publications

The quantity and quality of the language input that infants receive from their caregivers affects their future language abilities; however, it is unclear how variation in this input relates to preverbal brain circuitry. The current study investigated the relation between naturalistic language input and the functional connectivity (FC) of language networks in human infancy using resting-state functional magnetic resonance imaging (rsfMRI). We recorded the naturalistic language environments of five- to eight-month-old male and female infants using the Linguistic ENvironment Analysis (LENA) system and measured the quantity and consistency of their exposure to adult words (AWs) and adult-infant conversational turns (CTs). …

Coxsackievirus B3 Infection Early In Pregnancy Induces Congenital Heart Defects Through Suppression Of Fetal Cardiomyocyte Proliferation, Vipul Sharma, Lisa S Goessling, Anoop K Brar, Chetanchandra S Joshi, Indira U Mysorekar, Pirooz Eghtesady

Open Access Publications

Background Coxsackievirus B (CVB) is the most common cause of viral myocarditis. It targets cardiomyocytes through coxsackie and adenovirus receptor, which is highly expressed in the fetal heart. We hypothesized CVB3 can precipitate congenital heart defects when fetal infection occurs during critical window of gestation. Methods and Results We infected C57Bl/6 pregnant mice with CVB3 during time points in early gestation (embryonic day [E] 5, E7, E9, and E11). We used different viral titers to examine possible dose-response relationship and assessed viral loads in various fetal organs. Provided viral exposure occurred between E7 and E9, we observed characteristic features of …

Death And Myocardial Infarction Following Initial Revascularization Versus Optimal Medical Therapy In Chronic Coronary Syndromes With Myocardial Ischemia: A Systematic Review And Meta-Analysis Of Contemporary Randomized Controlled Trials, Andrea Soares, William E Boden, Whady Hueb, Maria M Brooks, Helen E A Vlachos, Kevin O'Fee, Angela Hardi, David L Brown

Open Access Publications

Background In chronic coronary syndromes, myocardial ischemia is associated with a greater risk of death and nonfatal myocardial infarction (MI). We sought to compare the effect of initial revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) plus optimal medical therapy (OMT) with OMT alone in patients with chronic coronary syndrome and myocardial ischemia on long-term death and nonfatal MI. Methods and Results Ovid Medline, Embase, Scopus, and Cochrane Library databases were searched for randomized controlled trials of PCI or CABG plus OMT versus OMT alone for patients with chronic coronary syndromes. Studies were screened and data …

Designing And Undertaking Randomised Implementation Trials: Guide For Researchers, Luke Wolfenden, Robbie Foy, Justin Presseau, Jeremy Grimshaw, Noah Ivers, Byron Powell, Monica Taljaard, John Wiggers, Rachel Sutherland, Nicole Nathan, Christopher Williams, Melanie Kingsland, Andrew Milat, Rebecca Hodder, Sze Lin Yoong

Open Access Publications

No abstract provided.

Function Of Mammalian M-Cones Depends On The Level Of Cralbp In Müller Cells, Alexander V. Kolesnikov, Philip D. Kiser, Krzysztof Palczewski, Vladimir J. Kefalov

Open Access Publications

Cone photoreceptors mediate daytime vision in vertebrates. The rapid and efficient regeneration of their visual pigments following photoactivation is critical for the cones to remain photoresponsive in bright and rapidly changing light conditions. Cone pigment regeneration depends on the recycling of visual chromophore, which takes place via the canonical visual cycle in the retinal pigment epithelium (RPE) and the Müller cell-driven intraretinal visual cycle. The molecular mechanisms that enable the neural retina to regenerate visual chromophore for cones have not been fully elucidated. However, one known component of the two visual cycles is the cellular retinaldehyde-binding protein (CRALBP), which is …

Disrupted Association Of Sensory Neurons With Enveloping Satellite Glial Cells In Fragile X Mouse Model, Oshri Avraham, Pan-Yue Deng, Dario Maschi, Vitaly A Klyachko, Valeria Cavalli

Open Access Publications

Among most prevalent deficits in individuals with Fragile X syndrome (FXS) is hypersensitivity to sensory stimuli and somatosensory alterations. Whether dysfunction in peripheral sensory system contributes to these deficits remains poorly understood. Satellite glial cells (SGCs), which envelop sensory neuron soma, play critical roles in regulating neuronal function and excitability. The potential contributions of SGCs to sensory deficits in FXS remain unexplored. Here we found major structural defects in sensory neuron-SGC association in the dorsal root ganglia (DRG), manifested by aberrant covering of the neuron and gaps between SGCs and the neuron along their contact surface. Single-cell RNAseq analyses demonstrated …

Parental Factors Associated With The Decision To Participate In A Neonatal Clinical Trial, Elliott Mark Weiss, Rakesh Rao, Et Al

Open Access Publications

Importance: It remains poorly understood how parents decide whether to enroll a child in a neonatal clinical trial. This is particularly true for parents from racial or ethnic minority populations. Understanding factors associated with enrollment decisions may improve recruitment processes for families, increase enrollment rates, and decrease disparities in research participation.

Objective: To assess differences in parental factors between parents who enrolled their infant and those who declined enrollment for a neonatal randomized clinical trial.

Design, Setting, and Participants: This survey study conducted from July 2017 to October 2019 in 12 US level 3 and 4 neonatal intensive care units …

Ron Signalling Promotes Therapeutic Resistance In Esr1 Mutant Breast Cancer, Derek Dustin, Shunqiang Li, Et Al

Open Access Publications

BACKGROUND: Oestrogen Receptor 1 (ESR1) mutations are frequently acquired in oestrogen receptor (ER)-positive metastatic breast cancer (MBC) patients who were treated with aromatase inhibitors (AI) in the metastatic setting. Acquired ESR1 mutations are associated with poor prognosis and there is a lack of effective therapies that selectively target these cancers.

METHODS: We performed a proteomic kinome analysis in ESR1 Y537S mutant cells to identify hyperactivated kinases in ESR1 mutant cells. We validated Recepteur d'Origine Nantais (RON) and PI3K hyperactivity through phospho-immunoblot analysis, organoid growth assays, and in an in vivo patient-derived xenograft (PDX) metastatic model.

RESULTS: We demonstrated that RON …

Impact Of New Unos Allocation Criteria On Heart Transplant Practices And Outcomes, Jason Liu, Bin Q. Yang, Akinobu Itoh, Mohammed Faraz Masood, Justin C. Hartupee, Joel D. Schilling

Open Access Publications

No abstract provided.

Dairy Intake During Adolescence And Risk Of Colorectal Adenoma Later In Life, Katharina Nimptsch, Yin Cao, Et Al

Open Access Publications

BACKGROUND: Higher dairy intake during adulthood has been associated with lower colorectal cancer risk. As colorectal carcinogenesis spans several decades, we hypothesised that higher dairy intake during adolescence is associated with lower risk of colorectal adenoma, a colorectal cancer precursor.

METHODS: In 27,196 females from the Nurses' Health Study 2, aged 25-42 years at recruitment (1989), who had completed a validated high school diet questionnaire in 1998 and undergone at least one lower bowel endoscopy between 1998 and 2011, logistic regression for clustered data was used to calculate odds ratios (ORs) and 95% confidence intervals (CI).

RESULTS: Colorectal adenomas were …

Tlr3 Controls Constitutive Ifn-Β Antiviral Immunity In Human Fibroblasts And Cortical Neurons, Daxing Gao, Michael S Diamond, Et Al

Open Access Publications

Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/β induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-β protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes …

Bland Embolization Of Benign Liver Tumors: Review Of The Literature And A Single Center Experience, Daniel Crawford, Sailen Naidu, Indravadan Patel, Grace Knuttinen, Sadeer Alzubaidi, Rahmi Oklu

Open Access Publications

Transarterial embolization has shown promise as a safe, effective, and less invasive treatment modality for benign liver lesions (hemangioma, focal nodular hyperplasia (FNH), and hepatic adenoma (HA)) with fewer complications compared to surgical intervention. There is no consensus regarding the most appropriate embolization material(s) for the treatment of benign liver tumors. The purpose of this study was to review the current literature regarding the transarterial embolization of benign liver tumors and to share our single center experience. This was a non-blinded, retrospective, single-institution review of the bland embolization of benign liver tumors. Clinical data and imaging before and after embolization …

Dosimetric Impact Of Range Uncertainty In Passive Scattering Proton Therapy, Ruirui Liu, Baozhou Sun, Tiezhi Zhang, Jeffery F Williamson, Joseph A O'Sullivan, Tianyu Zhao

Open Access Publications

PURPOSE: The objective of this study was to investigate the dosimetric impact of range uncertainty in a large cohort of patients receiving passive scatter proton therapy.

METHODS: A cohort of 120 patients were reviewed in this study retrospectively, of which 61 were brain, 39 lung, and 20 prostate patients. Range uncertainties of ±3.5% (overshooting and undershooting by 3.5%, respectively) were added and recalculated on the original plans, which had been planned according to our clinical planning protocol while keeping beamlines, apertures, compensators, and dose grids intact. Changes in the coverage on CTV and DVH for critical organs were compared and …

Taking Account Of Asymptomatic Infections: A Modeling Study Of The Covid-19 Outbreak On The Diamond Princess Cruise Ship, Li-Shan Huang, Li Li, Lucia Dunn, Mai He

Open Access Publications

The COVID-19 outbreak on the Diamond Princess (DP) cruise ship has provided empirical data to study the transmission potential of COVID-19 with the presence of pre/asymptomatic cases. We studied the changes in R0 on DP from January 21 to February 19, 2020 based on chain binomial models under two scenarios: no quarantine assuming a random mixing condition, and quarantine of passengers in cabins-passengers may get infected either by an infectious case in a shared cabin or by pre/asymptomatic crew who continued to work. Estimates of R0 at the beginning of the epidemic were 3.27 (95% CI, 3.02-3.54) and 3.78 (95% …

Broadly Neutralizing Monoclonal Antibodies Protect Against Multiple Tick-Borne Flaviviruses, Laura A. Vanblargan, John M. Errico, Natasha M. Kafai, Prashant N. Jethva, Christopher A. Nelson, David Wang, Scott A. Handley, Michael L. Gross, Daved H. Fremont, Michael S. Diamond, Et Al

Open Access Publications

Although Powassan virus (POWV) is an emerging tick-transmitted flavivirus that causes severe or fatal neuroinvasive disease in humans, medical countermeasures have not yet been developed. Here, we developed a panel of neutralizing anti-POWV mAbs recognizing six distinct antigenic sites. The most potent of these mAbs bind sites within domain II or III of the envelope (E) protein and inhibit postattachment viral entry steps. A subset of these mAbs cross-react with other flaviviruses. Both POWV type-specific and cross-reactive neutralizing mAbs confer protection in mice against POWV infection when given as prophylaxis or postexposure therapy. Several cross-reactive mAbs mapping to either domain …

Mechanical Dysfunction Of The Sarcomere Induced By A Pathogenic Mutation In Troponin T Drives Cellular Adaptation, Sarah R. Clippinger, Paige E. Cloonan, Wei Wang, Lina Greenberg, W. Tom Stump, Paweorn Angsutararux, Jeanne M. Nerbonne, Michael J. Greenberg

Open Access Publications

Familial hypertrophic cardiomyopathy (HCM), a leading cause of sudden cardiac death, is primarily caused by mutations in sarcomeric proteins. The pathogenesis of HCM is complex, with functional changes that span scales, from molecules to tissues. This makes it challenging to deconvolve the biophysical molecular defect that drives the disease pathogenesis from downstream changes in cellular function. In this study, we examine an HCM mutation in troponin T, R92Q, for which several models explaining its effects in disease have been put forward. We demonstrate that the primary molecular insult driving disease pathogenesis is mutation-induced alterations in tropomyosin positioning, which causes increased …

Variables Associated With Intravenous Rehydration And Hospitalization In Children With Acute Gastroenteritis: A Secondary Analysis Of 2 Randomized Clinical Trials, Naveen Poonai, Philip Tarr, Et Al

Open Access Publications

Importance: Despite guidelines endorsing oral rehydration therapy, intravenous fluids are commonly administered to children with acute gastroenteritis in high-income countries.

Objective: To identify factors associated with intravenous fluid administration and hospitalization in children with acute gastroenteritis.

Design, Setting, and Participants: This study is a planned secondary analysis of the Pediatric Emergency Research Canada (PERC) and Pediatric Emergency Care Applied Research Network (PECARN) probiotic trials. Participants include children aged 3 to 48 months with 3 or more watery stools in 24 hours between November 5, 2013, and April 7, 2017, for the PERC study and July 8, 2014, and June 23, …