Digital Commons Network^™

Mortality In Pediatric Oncology And Stem Cell Transplant Patients With Bloodstream Infections, Daniel N Willis, Mary Claire Mcglynn, Patrick J Reich, Robert J Hayashi

2020-Current year OA Pubs

BACKGROUND: Bloodstream infections (BSI) continue to represent a significant source of morbidity for pediatric oncology patients, however less is known regarding this population's risk of death. We sought to evaluate the risk of BSI and death at a large pediatric cancer center.

METHODS: We retrospectively collected inpatient data from pediatric oncology and hematopoietic stem cell transplant (HSCT) patients over a 9-year period. We performed univariate and multivariable modeling to assess risk of BSI and mortality examining the following variables: demographics, underlying malignancy, history of HSCT, central line type, and febrile neutropenia (FN).

RESULTS: During the study period, 6763 admissions from …

Do The Expert Recommendations For Implementing Change (Eric) Strategies Adequately Address Sustainment?, Nicole Nathan, Byron J Powell, Rachel C Shelton, Celia V Laur, Luke Wolfenden, Maji Hailemariam, Sze Lin Yoong, Rachel Sutherland, Melanie Kingsland, Thomas J Waltz, Alix Hall

2020-Current year OA Pubs

BACKGROUND: Sustainability science is an emerging area within implementation science. There is limited evidence regarding strategies to best support the continued delivery and sustained impact of evidence-based interventions (EBIs). To build such evidence, clear definitions, and ways to operationalize strategies specific and/or relevant to sustainment are required. Taxonomies and compilations such as the Expert Recommendations for Implementing Change (ERIC) were developed to describe and organize implementation strategies. This study aimed to adapt, refine, and extend the ERIC compilation to incorporate an explicit focus on sustainment. We also sought to classify the specific phase(s) of implementation when the ERIC strategies could …

Low Risk For Developing Diabetes Among The Offspring Of Individuals With Exceptional Longevity And Their Spouses, Iva Miljkovic, Ryan Cvejkus, Ping An, Bharat Thyagarajan, Kaare Christensen, Mary Wojczynski, Nicole Schupf, Joseph M Zmuda

2020-Current year OA Pubs

Little is known about the risk of type 2 diabetes (T2D) among the offspring of individuals with exceptional longevity. We determined the incidence of and potential risk and protective factors for T2D among the offspring of probands and offspring's spouses (mean age=60 years, range 32-88 years) in the Long Life Family Study (LLFS), a multicenter cohort study of 583 two-generation families with a clustering of healthy aging and exceptional longevity. Incident T2D was defined as fasting serum glucose ≥126 mg/dl, or HbA1c of ≥6.5%, or self-reported with doctor diagnosis of T2D, or the use of anti-diabetic medication during a mean …

Case Report: Real-World Experience Using A Personalized Cancer-Specific Circulating Tumor Dna Assay In Different Metastatic Melanoma Scenarios, Karam Khaddour, Alice Zhou, Omar H Butt, Griffin Budde, Allyson Koyen Malashevich, George Ansstas

2020-Current year OA Pubs

Circulating-tumor DNA (ctDNA) has emerged as an important biomarker for monitoring disease status in cancer patients. Different ctDNA testing platforms have shown promising results in the early detection of disease, monitoring response to treatment, and prognostication in metastatic melanoma. However, several challenges exist, including the reduced shedding of ctDNA into the bloodstream in the metastatic setting, differences in sensitivity among various ctDNA assays, and the inherent inability to distinguish tumor-specific mutations from other mutations that are not related to the cancer of interest. Using a ctDNA assay that is designed to detect multiple single-nucleotide variants (SNVs) that are specific to …

Use Of Leishmania Major Parasites Expressing A Recombinant Trypanosoma Cruzi Antigen As Live Vaccines Against Chagas Disease, Catherine W Cai, Anne O'Shea, Christopher S Eickhoff, Hongjie Guo, Warren G Lewis, Stephen M Beverley, Daniel F Hoft

2020-Current year OA Pubs

INTRODUCTION:

METHODS: We generated recombinant

RESULTS: We demonstrate that mice inoculated with these recombinant TS-expressing

DISCUSSION: Altogether, these data indicate that

Multi-Omics Insights Into The Biological Mechanisms Underlying Statistical Gene-By-Lifestyle Interactions With Smoking And Alcohol Consumption, Timothy D Majarian, Mary F Feitosa, Michael Province, Dabeeru C Rao, Karen Schwander, Yun Ju Sung, C Charles Gu, Et Al.

2020-Current year OA Pubs

Though both genetic and lifestyle factors are known to influence cardiometabolic outcomes, less attention has been given to whether lifestyle exposures can alter the association between a genetic variant and these outcomes. The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium's Gene-Lifestyle Interactions Working Group has recently published investigations of genome-wide gene-environment interactions in large multi-ancestry meta-analyses with a focus on cigarette smoking and alcohol consumption as lifestyle factors and blood pressure and serum lipids as outcomes. Further description of the biological mechanisms underlying these statistical interactions would represent a significant advance in our understanding of gene-environment …

Implicating Genes, Pleiotropy, And Sexual Dimorphism At Blood Lipid Loci Through Multi-Ancestry Meta-Analysis, Stavroula Kanoni, Adam E. Locke, E Warwick Daw, Mary F. Feitosa, Mary K. Wojczynski, Bernhard Banas, Carsten A. Boger, Bettina Jung, D C. Rao, Michael A. Province, Et Al.

2020-Current year OA Pubs

No abstract provided.

A Promising Genetic Target For A Deadly Disease: Single Immunoglobulin Interleukin 1 (Sigirr) Mutations In Necrotizing Enterocolitis, Misty Good, Camilia R Martin

2020-Current year OA Pubs

No abstract provided.

Co-Clinical Fdg-Pet Radiomic Signature In Predicting Response To Neoadjuvant Chemotherapy In Triple-Negative Breast Cancer, Sudipta Roy, Timothy D Whitehead, Shunqiang Li, Foluso O Ademuyiwa, Richard L Wahl, Farrokh Dehdashti, Kooresh I Shoghi

2020-Current year OA Pubs

PURPOSE: We sought to exploit the heterogeneity afforded by patient-derived tumor xenografts (PDX) to first, optimize and identify robust radiomic features to predict response to therapy in subtype-matched triple negative breast cancer (TNBC) PDX, and second, to implement PDX-optimized image features in a TNBC co-clinical study to predict response to therapy using machine learning (ML) algorithms.

METHODS: TNBC patients and subtype-matched PDX were recruited into a co-clinical FDG-PET imaging trial to predict response to therapy. One hundred thirty-one imaging features were extracted from PDX and human-segmented tumors. Robust image features were identified based on reproducibility, cross-correlation, and volume independence. A …

Creation Of Philadelphia Chromosome By Crispr/Cas9-Mediated Double Cleavages On Bcr And Abl1 Genes As A Model For Initial Event In Leukemogenesis, Minori Tamai, Kenji Kamimoto, Kohei Omachi, Et Al.

2020-Current year OA Pubs

The Philadelphia (Ph) chromosome was the first translocation identified in leukemia. It is supposed to be generated by aberrant ligation between two DNA double-strand breaks (DSBs) at the BCR gene located on chromosome 9q34 and the ABL1 gene located on chromosome 22q11. Thus, mimicking the initiation process of translocation, we induced CRISPR/Cas9-mediated DSBs simultaneously at the breakpoints of the BCR and ABL1 genes in a granulocyte-macrophage colony-stimulating factor (GM-CSF) dependent human leukemia cell line. After transfection of two single guide RNAs (sgRNAs) targeting intron 13 of the BCR gene and intron 1 of the ABL1 gene, a factor-independent subline was …

Age Differences In The Association Between Sleep And Alzheimer's Disease Biomarkers In The Epad Cohort, Sharon L Naismith, Yue Leng, Jake R Palmer, Brendan P Lucey

2020-Current year OA Pubs

INTRODUCTION: We aimed to determine the independent association between sleep quality and Alzheimer's disease (AD) biomarkers, and whether the associations differ with age.

METHODS: We included 1240 individuals aged ≥50, without dementia from the

RESULTS: For the youngest age tertile, shorter sleep duration and higher sleep efficiency were associated with greater p-tau/Aβ42 ratio. For the oldest tertile, longer sleep latency was associated with greater p-tau/Aβ42.

DISCUSSION: Differential relationships between sleep and AD pathology depend on age. Short sleep duration and sleep efficiency are relevant in middle age whereas time taken to fall asleep is more closely linked to AD biomarkers …

White Matter Abnormalities In The Hdc Knockout Mouse, A Model Of Tic And Ocd Pathophysiology, Kantiya Jindachomthong, Chengran Yang, Yuegao Huang, Daniel Coman, Maximiliano Rapanelli, Fahmeed Hyder, Joseph Dougherty, Luciana Frick, Christopher Pittenger

2020-Current year OA Pubs

INTRODUCTION: An inactivating mutation in the

MATERIALS AND METHODS: We performed exploratory RNA-seq to identify pathological alterations in several brain regions in

RESULTS: Exploratory RNA-Seq analysis revealed, unexpectedly, that genes associated with oligodendrocytes and with myelin production are upregulated in the dorsal striatum of these mice. This was confirmed by qPCR, immunostaining, and immunoblotting. These results suggest an abnormality in myelination in the striatum. To test this in an intact mouse brain, we performed whole-brain

DISCUSSION: While the DTI literature in individuals with TS is sparse, these results are consistent with findings of disrupted descending cortical projections in patients with …

Clinical And Molecular Characteristics Of A Novel Rare De Novo Variant In Ppp2ca In A Patient With A Developmental Disorder, Autism, And Epilepsy, Iris Verbinnen, Sara S Procknow, Lisa Lenaerts, Sara Reynhout, Aujan Mehregan, Chris Ulens, Veerle Janssens, Katherine A King

2020-Current year OA Pubs

PP2A-related (neuro) developmental disorders are a family of genetic diseases caused by a heterozygous alteration in one of several genes encoding a subunit of type 2A protein phosphatases. Reported affected genes, so far, are

The Enigma Stroke Recovery Working Group: Big Data Neuroimaging To Study Brain-Behavior Relationships After Stroke, Sook-Lei Liew, Catherine E Lang, Anup K Bhattacharya, Et Al.

2020-Current year OA Pubs

The goal of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Stroke Recovery working group is to understand brain and behavior relationships using well-powered meta- and mega-analytic approaches. ENIGMA Stroke Recovery has data from over 2,100 stroke patients collected across 39 research studies and 10 countries around the world, comprising the largest multisite retrospective stroke data collaboration to date. This article outlines the efforts taken by the ENIGMA Stroke Recovery working group to develop neuroinformatics protocols and methods to manage multisite stroke brain magnetic resonance imaging, behavioral and demographics data. Specifically, the processes for scalable data intake and preprocessing, multisite data …

Women And Ethnoracial Minorities With Poor Cardiovascular Health Measures Associated With A Higher Risk Of Developing Mood Disorder, Aixia Guo, Kari A Stephens, Yosef M Khan, James R Langabeer, Randi E Foraker

2020-Current year OA Pubs

BACKGROUND: Mood disorders (MDS) are a type of mental health illness that effects millions of people in the United States. Early prediction of MDS can give providers greater opportunity to treat these disorders. We hypothesized that longitudinal cardiovascular health (CVH) measurements would be informative for MDS prediction.

METHODS: To test this hypothesis, the American Heart Association's Guideline Advantage (TGA) dataset was used, which contained longitudinal EHR from 70 outpatient clinics. The statistical analysis and machine learning models were employed to identify the associations of the MDS and the longitudinal CVH metrics and other confounding factors.

RESULTS: Patients diagnosed with MDS …

A Next Generation Sequencing-Based Protocol For Screening Of Variants Of Concern In Autism Spectrum Disorder, Jie Huang, Jun Liu, Ruiyi Tian, Kevin Liu, Patrick Zhuang, Hannah Tayla Sherman, Christoph Budjan, Michelle Fong, Min-Seo Jeong, Xue-Jun Kong

2020-Current year OA Pubs

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with strong genetic influences. There is an increasing demand for ASD genetic testing beyond the traditionally recommended microarray and syndromic autism testing; however, the current whole genome sequencing (WGS) and whole exome sequencing (WES) methods are lacking an academic standard for WGS variant annotation, reporting, and interpretation, tailored towards patients with ASD and offer very limited interpretation for clinical significance. Using WGS data from six family trios, we demonstrate the clinical feasibility and technical implementation of an evidence-based, fully transparent bioinformatics pipeline and report framework for an ASD-focused WGS genetic report. We …

Emerging Themes In The Molecular Pathogenesis Of Enterotoxigenic Escherichia Coli, James M Fleckenstein, Alaullah Sheikh

2020-Current year OA Pubs

Enterotoxigenic Escherichia coli (ETEC) are ubiquitous diarrheal pathogens that thrive in areas lacking basic human needs of clean water and sanitation. These genetically plastic organisms cause tremendous morbidity among disadvantaged young children, in the form of both acute diarrheal illness and sequelae of malnutrition and growth impairment. The recent discovery of additional plasmid-encoded virulence factors and elucidation of their critical role in the molecular pathogenesis of ETEC may inform new approaches to the development of broadly protective vaccines. Although the pathogens have been closely linked epidemiologically with nondiarrheal sequelae, these conditions remain very poorly understood. Similarly, while canonical effects of …

A Review Of Dna Risk Alleles To Determine Epigenetic Repair Of Mrna Expression To Prove Therapeutic Effectiveness In Reward Deficiency Syndrome (Rds): Embracing "Precision Behavioral Management", Kenneth Blum, Bruce Steinberg, Marjorie C Gondre-Lewis, David Baron, Edward J Modestino, Rajendra D Badgaiyan, B William Downs, Debasis Bagchi, Raymond Brewer, Thomas Mclaughlin, Abdalla Bowirrat, Mark Gold

2020-Current year OA Pubs

This is a review of research on "Precision Behavioral Management" of substance use disorder (SUD). America is experiencing a high prevalence of substance use disorder, primarily involving legal and illegal opioid use. A 3000% increase in treatment for substance abuse has occurred between 2000 and 2016. Unfortunately, present day treatment of opioid abuse involves providing replacement therapy with powerful opioids to, at best, induce harm reduction, not prophylaxis. These interventions do not enhance gene expression and restore the balance of the brain reward system's neurotransmitters. We are proposing a generalized approach called "Precision Behavioral Management". This approach includes 1) using …

Stat3 Inhibitor Mitigates Cerebral Amyloid Angiopathy And Parenchymal Amyloid Plaques While Improving Cognitive Functions And Brain Networks, Jogender Mehla, Itender Singh, Deepti Diwan, James W Nelson, Molly Lawrence, Eunjae Lee, Adam Q Bauer, David M Holtzman, Gregory J Zipfel

2020-Current year OA Pubs

Previous reports indicate a potential role for signal transducer and activator of transcription 3 (STAT3) in amyloid-β (Aβ) processing and neuritic plaque pathogenesis. In the present study, the impact of STAT3 inhibition on cognition, cerebrovascular function, amyloid pathology, oxidative stress, and neuroinflammation was studied using in vitro and in vivo models of Alzheimer's disease (AD)-related pathology. For in vitro experiments, human brain vascular smooth muscle cells (HBVSMC) and human brain microvascular endothelial cells (HBMEC) were used, and these cultured cells were exposed to Aβ peptides followed by measurement of activated forms of STAT3 expression and reactive oxygen species (ROS) generation. …

Transcriptional Reprogramming Differentiates Active From Inactive Esr1 Fusions In Endocrine Therapy-Refractory Metastatic Breast Cancer, Xuxu Gou, Shunqiang Li, Et Al.

2020-Current year OA Pubs

Genomic analysis has recently identified multiple

Minimally Invasive Postmortem Intestinal Tissue Sampling In Malnourished And Acutely Ill Children Is Feasible And Informative, Erika Feutz, Wieger Voskuijl, Peter J Finch, Ta-Chiang Liu, Robert H J Bandsma, Phillip I Tarr, Christopher Alan Moxon, Kelley Vanbuskirk, Sarah Lawrence, Grace Umutesi, Kirkby D Tickell, James A Berkley, Judd L Walson, Steve Kamiza, Donna M Denno

2020-Current year OA Pubs

BACKGROUND: Intestinal disorders such as environmental enteric dysfunction (EED) are prevalent in low- and middle-income countries (LMICs) and important contributors to childhood undernutrition and mortality. Autopsies are rarely performed in LMICs but minimally invasive tissue sampling is increasingly deployed as a more feasible and acceptable procedure, although protocols have been devoid of intestinal sampling to date. We sought to determine (1) the feasibility of postmortem intestinal sampling, (2) whether autolysis precludes enteric biopsies' utility, and (3) histopathologic features among children who died during hospitalization with acute illness or undernutrition.

METHODS: Transabdominal needle and endoscopic forceps upper and lower intestinal sampling …

Overexpression Screen Of Interferon-Stimulated Genes Identifies Rarres3 As A Restrictor Of Toxoplasma Gondii Infection, Nicholas Rinkenberger, Michael E Abrams, Sumit K Matta, John W Schoggins, Neal M Alto, L David Sibley

2020-Current year OA Pubs

No abstract provided.

Electronically Available Patient Claims Data Improve Models For Comparing Antibiotic Use Across Hospitals: Results From 576 Us Facilities, Katherine E Goodman, Lisa Pineles, Laurence S Magder, Deverick J Anderson, Elizabeth Dodds Ashley, Ronald E Polk, Hude Quan, William E Trick, Keith F Woeltje, Surbhi Leekha, Sara E Cosgrove, Anthony D Harris

2020-Current year OA Pubs

BACKGROUND: The Centers for Disease Control and Prevention (CDC) uses standardized antimicrobial administration ratios (SAARs)-that is, observed-to-predicted ratios-to compare antibiotic use across facilities. CDC models adjust for facility characteristics when predicting antibiotic use but do not include patient diagnoses and comorbidities that may also affect utilization. This study aimed to identify comorbidities causally related to appropriate antibiotic use and to compare models that include these comorbidities and other patient-level claims variables to a facility model for risk-adjusting inpatient antibiotic utilization.

METHODS: The study included adults discharged from Premier Database hospitals in 2016-2017. For each admission, we extracted facility, claims, and …

Ogden Type I To Iii Tibial Tubercle Fractures In Skeletally Immature Patients: Is Routine Anterior Compartment Fasciotomy Of The Leg Indicated?, Corey Brown, Brian A. Kelly, Kirsten Brouillet, Scott J. Luhmann

2020-Current year OA Pubs

PURPOSE: Determine the frequency of compartment syndrome of the leg after displaced, operatively treated modified Ogden I to III tibial tubercle fractures (TTFxs), evaluate the preoperative assessment and use of advanced imaging, and need for prophylactic fasciotomies.

METHODS: Retrospective analysis of operatively treated, displaced modified Ogden I to III TTFxs, at our level 1 paediatric trauma centre between 2007 and 2019. Modified Ogden Type IV and V fracture patterns were excluded. Fracture patterns were determined by plain radiographs.

RESULTS: There were 49 modified Ogden I to III TTFxs in 48 patients. None had signs nor symptoms of vascular compromise, compartment …

Increased Mitochondrial Activity Upon Catsper Channel Activation Is Required For Mouse Sperm Capacitation, Juan J Ferreira, Adriana Cassina, Pilar Irigoyen, Mariana Ford, Santiago Pietroroia, Nikita Peramsetty, Rafael Radi, Celia M Santi, Rossana Sapiro

2020-Current year OA Pubs

To fertilize an oocyte, sperm must undergo several biochemical and functional changes known as capacitation. A key event in capacitation is calcium influx through the cation channel of sperm (CatSper). However, the molecular mechanisms of capacitation downstream of this calcium influx are not completely understood. Capacitation is also associated with an increase in mitochondrial oxygen consumption, and several lines of evidence indicate that regulated calcium entry into mitochondria increases the efficiency of oxidative respiration. Thus, we hypothesized that calcium influx through CatSper during capacitation increases mitochondrial calcium concentration and mitochondrial efficiency and thereby contributes to sperm hyperactivation and fertilization capacity. …

Clinical And Microbiological Outcomes Of Ceftazidime-Avibactam Treatment In Adults With Gram-Negative Bacteremia: A Subset Analysis From The Phase 3 Clinical Trial Program, John E Mazuski, Florian Wagenlehner, Antoni Torres, Yehuda Carmeli, Joseph W Chow, Dalia Wajsbrot, Gregory G Stone, Paurus Irani, David Bharucha, Karen Cheng, Margaret Tawadrous

2020-Current year OA Pubs

INTRODUCTION: This exploratory analysis assessed efficacy and safety outcomes in patients with Gram-negative bacteremia treated with ceftazidime-avibactam or comparator across five phase 3, randomized, controlled, multi-center trials in adults with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI)/pyelonephritis, hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP).

METHODS: In each trial, RECLAIM and RECLAIM 3 (cIAI; NCT01499290/NCT01726023), REPRISE (cIAI/cUTI; NCT01644643), RECAPTURE (cUTI; NCT01595438/NCT01599806), and REPROVE (HAP/VAP; NCT01808092), patients were randomized 1:1 to intravenous ceftazidime-avibactam (plus metronidazole for those with cIAI) or comparators (carbapenems in > 97% patients) for 5-21 days. Efficacy assessments included clinical and microbiological responses at the test-of-cure visit in …

Biochemical And Immuno-Histochemical Localization Of Type Iia Procollagen In Annulus Fibrosus Of Mature Bovine Intervertebral Disc, Audrey Mcalinden, David M Hudson, Aysel A Fernandes, Soumya Ravindran, Russell J Fernandes

2020-Current year OA Pubs

For next generation tissue-engineered constructs and regenerative medicine to succeed clinically, the basic biology and extracellular matrix composition of tissues that these repair techniques seek to restore have to be fully determined. Using the latest reagents coupled with tried and tested methodologies, we continue to uncover previously undetected structural proteins in mature intervertebral disc. In this study we show that the "embryonic" type IIA procollagen isoform (containing a cysteine-rich amino propeptide) was biochemically detectable in the annulus fibrosus of both calf and mature steer caudal intervertebral discs, but not in the nucleus pulposus where the type IIB isoform was predominantly …

Development Of A Qualified Clinical Data Registry For Emergency Medicine, Stephen K Epstein, Richard T Griffey, Michelle P Lin, James J Augustine, Pawan Goyal, Arjun K Venkatesh

2020-Current year OA Pubs

The passage of the Medicare Access and CHIP Reauthorization Act (MACRA) in 2015 marked a fundamental transition in physician payment by the Centers for Medicare and Medicaid Services (CMS) from traditional fee-for service to value-based models. MACRA led to the creation of the CMS Quality Payment Program (QPP), which bases the value of physician care in large part on physician quality reporting. The QPP enabled a shift away from legacy CMS-stewarded quality measures that had limited applicability to individual specialties toward specialty-specific quality measures developed and stewarded by physician specialty societies using Qualified Clinical Data Registries (QCDRs). This article describes …

Pharmacogenomics Insights Into Precision Pediatric Oncology, Kristie N. Ramos, David Gregornik, Kenneth S. Ramos

2020-Current year OA Pubs

PURPOSE OF REVIEW: Pharmacogenomic insights provide an opportunity to optimize medication dosing regimens and patient outcomes. However, the potential for interindividual genomic variability to guide medication dosing and toxicity monitoring is not yet standard of care. In this review, we present advances for the thiopurines, anthracyclines and vincristine and provide perspectives on the actionability of pharmacogenomic guidance in the future.

RECENT FINDINGS: The current guideline on thiopurines recommends that those with normal predicted thiopurine methyltransferase and NUDT15 expression receive standard-of-care dosing, while 'poor metabolizer' haplotypes receive a decreased 6-mercaptopurine starting dose to avoid bone marrow toxicity. Emerging evidence established significant …

A Pilot Study Of Urine Proteomics In Covid-19-Associated Acute Kidney Injury, Yinyin Ye, Madhurima Kaushal, Diane Salamon, Amanda Knoten, Laura Marks, Joseph P Gaut, Anitha Vijayan, Philip A Mudd, Jane A O'Halloran, Sanjay Jain, Et Al.

2020-Current year OA Pubs

No abstract provided.