Medicine and Health Sciences Commons^™

Recurrent Adrenergic Stress Provokes Persistent Myocarditis In Pd-1-Deficient Mice, Tomohiro Hayashi, Kenji Rowel Q Lim, Attila Kovacs, Douglas L Mann

2020-Current year OA Pubs

It is unclear how the immune system initiates effective tissue repair responses without also simultaneously activating adaptive immune responses to self-antigens released by damaged or necrotic cells. We studied the role of repetitive adrenergic mediated stress on cardiac injury wild-type and programmed death-1-deficient (PD-1

Beyond The Single-Outcome Approach: A Comparison Of Outcome-Wide Analysis Methods For Exposome Research, Augusto Anguita-Ruiz, Chongliang Luo, Et Al.

2020-Current year OA Pubs

Outcome-wide analysis can offer several benefits, including increased power to detect weak signals and the ability to identify exposures with multiple effects on health, which may be good targets for preventive measures. Recently, advanced statistical multivariate techniques for outcome-wide analysis have been developed, but they have been rarely applied to exposome analysis. In this work, we provide an overview of a selection of methods that are well-suited for outcome-wide exposome analysis and are implemented in the R statistical software. Our work brings together six different methods presenting innovative solutions for typical problems arising from outcome-wide approaches in the context of …

Idasanutlin And Navitoclax Induce Synergistic Apoptotic Cell Death In T-Cell Acute Lymphoblastic Leukemia, Kimberly B Johansson, Megan S Zimmerman, Iryna V Dmytrenko, Feng Gao, Daniel C Link

2020-Current year OA Pubs

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy in which activating mutations in the Notch pathway are thought to contribute to transformation, in part, by activating c-Myc. Increased c-Myc expression induces oncogenic stress that can trigger apoptosis through the MDM2-p53 tumor suppressor pathway. Since the great majority of T-ALL cases carry inactivating mutations upstream in this pathway but maintain wildtype MDM2 and TP53, we hypothesized that T-ALL would be selectively sensitive to MDM2 inhibition. Treatment with idasanutlin, an MDM2 inhibitor, induced only modest apoptosis in T-ALL cells but upregulated the pro-apoptotic BH3 domain genes BAX and BBC3, prompting …

Neurofibromin 1 Mutations Impair The Function Of Human Induced Pluripotent Stem Cell-Derived Microglia, Leonard D Kuhrt, Edyta Motta, Nirmeen Elmadany, Hannah Weidling, Raphaela Fritsche-Guenther, Ibrahim E Efe, Olivia Cobb, Jit Chatterjee, Lucy G Boggs, Marina Schnauß, Sebastian Diecke, Marcus Semtner, Corina Anastasaki, David H Gutmann, Helmut Kettenmann

2020-Current year OA Pubs

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by germline mutations in the neurofibromin 1 (NF1) gene. Children with NF1 are prone to the development of multiple nervous system abnormalities, including autism and brain tumors, which could reflect the effect of NF1 mutation on microglia function. Using heterozygous Nf1-mutant mice, we previously demonstrated that impaired purinergic signaling underlies deficits in microglia process extension and phagocytosis in situ. To determine whether these abnormalities are also observed in human microglia in the setting of NF1, we leveraged an engineered isogenic series of human induced pluripotent stem cells to generate human …

What Can The Plasma Proteome Tell Us About Platelets And (Vice Versa)?, Steven Bruzek, Marisol Betensky, Jorge Di Paola, Thomas Diacovo, Neil Goldenberg, Vera Ignjatovic

2020-Current year OA Pubs

Multi-omics approaches are being used increasingly to study physiological and pathophysiologic processes. Proteomics specifically focuses on the study of proteins as functional elements and key contributors to, and markers of the phenotype, as well as targets for diagnostic and therapeutic approaches. Depending on the condition, the plasma proteome can mirror the platelet proteome, and hence play an important role in elucidating both physiologic and pathologic processes. In fact, both plasma and platelet protein signatures have been shown to be important in the setting of thrombosis-prone disease states such as atherosclerosis and cancer. Plasma and platelet proteomes are increasingly being studied …

Correlating Deep Learning-Based Automated Reference Kidney Histomorphometry With Patient Demographics And Creatinine, Nicholas Lucarelli, Brandon Ginley, Jarcy Zee, Sayat Mimar, Anindya S. Paul, Sanjay Jain, Seung Seok Han, Luis Rodrigues, Tezcan Ozrazgat-Baslanti, Michelle L. Wong, Girish Nadkarni, William L. Clapp, Kuang-Yu Jen, Pinaki Sarder

2020-Current year OA Pubs

KEY POINTS: The authors leverage the unique benefits of panoptic segmentation to perform the largest ever quantitation of reference kidney morphometry. Kidney features vary with age and sex; and glomeruli size may intricately link to creatinine, defying prior notions.

BACKGROUND: Reference histomorphometric data of healthy human kidneys are largely lacking because of laborious quantitation requirements. Correlating histomorphometric features with clinical parameters through machine learning approaches can provide valuable information about natural population variance. To this end, we leveraged deep learning (DL), computational image analysis, and feature analysis to associate the relationship of histomorphometry with patient age, sex, serum creatinine (SCr), …

Trajectories Of Host-Response Subphenotypes In Patients With Covid-19 Across The Spectrum Of Respiratory Support, Michael Lu, Janet S Lee, Et Al.

2020-Current year OA Pubs

BACKGROUND: Hospitalized patients with severe COVID-19 follow heterogeneous clinical trajectories, requiring different levels of respiratory support and experiencing diverse clinical outcomes. Differences in host immune responses to SARS-CoV-2 infection may account for the heterogeneous clinical course, but we have limited data on the dynamic evolution of systemic biomarkers and related subphenotypes. Improved understanding of the dynamic transitions of host subphenotypes in COVID-19 may allow for improved patient selection for targeted therapies.

RESEARCH QUESTION: We examined the trajectories of host-response profiles in severe COVID-19 and evaluated their prognostic impact on clinical outcomes.

STUDY DESIGN AND METHODS: In this prospective observational study, …

Blockade Of Il-6r Prevents Preterm Birth And Adverse Neonatal Outcomes, Marcelo Farias-Jofre, Valeria Garcia-Flores, Nardhy Gomez-Lopez, Et Al.

2020-Current year OA Pubs

BACKGROUND: Preterm birth preceded by spontaneous preterm labour often occurs in the clinical setting of sterile intra-amniotic inflammation (SIAI), a condition that currently lacks treatment.

METHODS: Proteomic and scRNA-seq human data were analysed to evaluate the role of IL-6 and IL-1α in SIAI. A C57BL/6 murine model of SIAI-induced preterm birth was developed by the ultrasound-guided intra-amniotic injection of IL-1α. The blockade of IL-6R by using an aIL-6R was tested as prenatal treatment for preterm birth and adverse neonatal outcomes. QUEST-MRI evaluated brain oxidative stress in utero. Targeted transcriptomic profiling assessed maternal, foetal, and neonatal inflammation. Neonatal biometrics and neurodevelopment …

Camkk2 And Chk1 Phosphorylate Human Stn1 In Response To Replication Stress To Protect Stalled Forks From Aberrant Resection, Rishi Kumar Jaiswal, Kai-Hang Lei, Megan Chastain, Yuan Wang, Olga Shiva, Shan Li, Zhongsheng You, Peter Chi, Weihang Chai

2020-Current year OA Pubs

Keeping replication fork stable is essential for safeguarding genome integrity; hence, its protection is highly regulated. The CTC1-STN1-TEN1 (CST) complex protects stalled forks from aberrant MRE11-mediated nascent strand DNA degradation (NSD). However, the activation mechanism for CST at forks is unknown. Here, we report that STN1 is phosphorylated in its intrinsic disordered region. Loss of STN1 phosphorylation reduces the replication stress-induced STN1 localization to stalled forks, elevates NSD, increases MRE11 access to stalled forks, and decreases RAD51 localization at forks, leading to increased genome instability under perturbed DNA replication condition. STN1 is phosphorylated by both the ATR-CHK1 and the calcium-sensing …

Intravenous Levothyroxine For Unstable Brain-Dead Heart Donors, Rajat Dhar, Gary F Marklin, W Dean Klinkenberg, Jinli Wang, Charles W Goss, Abhijit V Lele, Clark D Kensinger, Paul A Lange, Daniel J Lebovitz

2020-Current year OA Pubs

BACKGROUND: Hemodynamic instability and myocardial dysfunction are major factors preventing the transplantation of hearts from organ donors after brain death. Intravenous levothyroxine is widely used in donor care, on the basis of observational data suggesting that more organs may be transplanted from donors who receive hormonal supplementation.

METHODS: In this trial involving 15 organ-procurement organizations in the United States, we randomly assigned hemodynamically unstable potential heart donors within 24 hours after declaration of death according to neurologic criteria to open-label infusion of intravenous levothyroxine (30 μg per hour for a minimum of 12 hours) or saline placebo. The primary outcome …

Clinical Situations For Which 3d Printing Is Considered An Appropriate Representation Or Extension Of Data Contained In A Medical Imaging Examination: Vascular Conditions, Joonhyuk Lee, Seetharam C Chadalavada, Anish Ghodadra, Arafat Ali, Elsa M Arribas, Leonid Chepelev, Ciprian N Ionita, Prashanth Ravi, Justin R Ryan, Lumarie Santiago, Nicole Wake, Adnan M Sheikh, Frank J Rybicki, David H Ballard

2020-Current year OA Pubs

BACKGROUND: Medical three-dimensional (3D) printing has demonstrated utility and value in anatomic models for vascular conditions. A writing group composed of the Radiological Society of North America (RSNA) Special Interest Group on 3D Printing (3DPSIG) provides appropriateness recommendations for vascular 3D printing indications.

METHODS: A structured literature search was conducted to identify all relevant articles using 3D printing technology associated with vascular indications. Each study was vetted by the authors and strength of evidence was assessed according to published appropriateness ratings.

RESULTS: Evidence-based recommendations for when 3D printing is appropriate are provided for the following areas: aneurysm, dissection, extremity vascular …

Blobcut: A Contrastive Learning Method To Support Small Blob Detection In Medical Imaging, Teng Li, Yanzhe Xu, Teresa Wu, Jennifer R Charlton, Kevin M Bennett, Firas Al-Hindawi

2020-Current year OA Pubs

Medical imaging-based biomarkers derived from small objects (e.g., cell nuclei) play a crucial role in medical applications. However, detecting and segmenting small objects (a.k.a. blobs) remains a challenging task. In this research, we propose a novel 3D small blob detector called BlobCUT. BlobCUT is an unpaired image-to-image (I2I) translation model that falls under the Contrastive Unpaired Translation paradigm. It employs a blob synthesis module to generate synthetic 3D blobs with corresponding masks. This is incorporated into the iterative model training as the ground truth. The I2I translation process is designed with two constraints: (1) a convexity consistency constraint that relies …

A Youth-Centred Approach To Improving Engagement In Hiv Services: Human-Centred Design Methods And Outcomes In A Research Trial In Kisumu County, Kenya, Eliud Omondi Akama, Thomas Odeny, Ingrid Eshun-Wilson, Elvin H Geng, Et Al.

2020-Current year OA Pubs

UNLABELLED: IntroductionInnovative interventions are needed to improve HIV outcomes among adolescents and young adults (AYAs) living with HIV. Engaging AYAs in intervention development could increase effectiveness and youth acceptance, yet research is limited. We applied human-centred design (HCD) to refine adherence-support interventions pretrial and assessed HCD workshop acceptability.

METHODS: We applied an iterative, four-phased HCD process in Kenya that included: (1) systematic review of extant knowledge, (2) prioritisation of design challenges, (3) a co-creation workshop and (4) translation tables to pair insights with trial intervention adaptations. The co-creation workshop was co-led by youth facilitators employing participatory activities to inform intervention …

Functional Analysis Of Recurrent Cdc20 Promoter Variants In Human Melanoma, Paula M Godoy, Abimbola Oyedeji, Jacqueline L Mudd, Vasilios A Morikis, Anna P Zarov, Gregory D Longmore, Ryan C Fields, Charles K Kaufman

2020-Current year OA Pubs

Small nucleotide variants in non-coding regions of the genome can alter transcriptional regulation, leading to changes in gene expression which can activate oncogenic gene regulatory networks. Melanoma is heavily burdened by non-coding variants, representing over 99% of total genetic variation, including the well-characterized TERT promoter mutation. However, the compendium of regulatory non-coding variants is likely still functionally under-characterized. We developed a pipeline to identify hotspots, i.e. recurrently mutated regions, in melanoma containing putatively functional non-coding somatic variants that are located within predicted melanoma-specific regulatory regions. We identified hundreds of statistically significant hotspots, including the hotspot containing the TERT promoter variants, …

Impact Of Circulating Lymphoma Cells At Diagnosis On Outcomes In Patients With Marginal Zone Lymphoma: A Multicenter Cohort Study, Kaitlin Annunzio, Marcus P Watkins, Nancy L Bartlett, Et Al.

2020-Current year OA Pubs

No abstract provided.

Relationship Between The Covid-19 Pandemic And Structural Inequalities Within The Pediatric Trauma Population, Christina Georgeades, Martin S Keller, Et Al.

2020-Current year OA Pubs

BACKGROUND: The COVID-19 pandemic disrupted social, political, and economic life across the world, shining a light on the vulnerability of many communities. The objective of this study was to assess injury patterns before and after implementation of stay-at-home orders (SHOs) between White children and children of color and across varying levels of vulnerability based upon children's home residence.

METHODS: A multi-institutional retrospective study was conducted evaluating patients < 18 years with traumatic injuries. A "Control" cohort from an averaged March-September 2016-2019 time period was compared to patients injured after SHO initiation-September 2020 ("COVID" cohort). Interactions between race/ethnicity or social vulnerability index (SVI), a marker of neighborhood vulnerability and socioeconomic status, and the COVID-19 timeframe with regard to the outcomes of interest were assessed using likelihood ratio Chi-square tests. Differences in injury intent, type, and mechanism were then stratified and explored by race/ethnicity and SVI separately.

RESULTS: A total of 47,385 patients met study inclusion. Significant interactions existed between race/ethnicity and the COVID-19 SHO period for intent (p < 0.001) and mechanism of injury (p < 0.001). There was also significant interaction between SVI and the COVID-19 SHO period for mechanism of injury (p = 0.01). Children of color experienced a significant increase in intentional (COVID 16.4% vs. Control 13.7%, p = 0.03) and firearm (COVID 9.0% vs. Control 5.2%, p < 0.001) injuries, but no change was seen among White children. Children from the most vulnerable neighborhoods suffered an increase in firearm injuries (COVID 11.1% vs. Control 6.1%, p = 0.001) with children from the least vulnerable neighborhoods having no change. All-terrain vehicle (ATV) and bicycle crashes increased for children of color (COVID 2.0% vs. Control 1.1%, p = 0.04 for ATV; COVID 6.7% vs. Control 4.8%, p = 0.02 for bicycle) and White children (COVID 9.6% vs. Control 6.2%, p < 0.001 for ATV; COVID 8.8% vs. Control 5.8%, p < 0.001 for bicycle).

CONCLUSIONS: In contrast to White children and children from neighborhoods of …

Sex-Associated Differences In Frequencies And Prognostic Impact Of Recurrent Genetic Alterations In Adult Acute Myeloid Leukemia (Alliance, Amlcg), Michael Ozga, Geoffrey L Uy, Et Al.

2020-Current year OA Pubs

Clinical outcome of patients with acute myeloid leukemia (AML) is associated with demographic and genetic features. Although the associations of acquired genetic alterations with patients' sex have been recently analyzed, their impact on outcome of female and male patients has not yet been comprehensively assessed. We performed mutational profiling, cytogenetic and outcome analyses in 1726 adults with AML (749 female and 977 male) treated on frontline Alliance for Clinical Trials in Oncology protocols. A validation cohort comprised 465 women and 489 men treated on frontline protocols of the German AML Cooperative Group. Compared with men, women more often had normal …

Essential Content For Teaching Implementation Practice In Healthcare: A Mixed-Methods Study Of Teams Offering Capacity-Building Initiatives, Jessica Reszel, Beth E Crowner, Et Al.

2020-Current year OA Pubs

BACKGROUND: Applying the knowledge gained through implementation science can support the uptake of research evidence into practice; however, those doing and supporting implementation (implementation practitioners) may face barriers to applying implementation science in their work. One strategy to enhance individuals' and teams' ability to apply implementation science in practice is through training and professional development opportunities (capacity-building initiatives). Although there is an increasing demand for and offerings of implementation practice capacity-building initiatives, there is no universal agreement on what content should be included. In this study we aimed to explore what capacity-building developers and deliverers identify as essential training content …

Single-Cell Multiomics Of The Human Retina Reveals Hierarchical Transcription Factor Collaboration In Mediating Cell Type-Specific Effects Of Genetic Variants On Gene Regulation, Jun Wang, Xuesen Cheng, Qingnan Liang, Leah A Owen, Jiaxiong Lu, Yiqiao Zheng, Meng Wang, Shiming Chen, Margaret M Deangelis, Yumei Li, Rui Chen

2020-Current year OA Pubs

BACKGROUND: Systematic characterization of how genetic variation modulates gene regulation in a cell type-specific context is essential for understanding complex traits. To address this question, we profile gene expression and chromatin accessibility in cells from healthy retinae of 20 human donors through single-cell multiomics and genomic sequencing.

RESULTS: We map eQTL, caQTL, allelic-specific expression, and allelic-specific chromatin accessibility in major retinal cell types. By integrating these results, we identify and characterize regulatory elements and genetic variants effective on gene regulation in individual cell types. The majority of identified sc-eQTLs and sc-caQTLs display cell type-specific effects, while the cis-elements containing genetic …

Clinical Situations For Which 3d Printing Is Considered An Appropriate Representation Or Extension Of Data Contained In A Medical Imaging Examination: Neurosurgical And Otolaryngologic Conditions, Arafat Ali, Jonathan M Morris, Summer J Decker, Yu-Hui Huang, Nicole Wake, Frank J Rybicki, David H Ballard

2020-Current year OA Pubs

BACKGROUND: Medical three dimensional (3D) printing is performed for neurosurgical and otolaryngologic conditions, but without evidence-based guidance on clinical appropriateness. A writing group composed of the Radiological Society of North America (RSNA) Special Interest Group on 3D Printing (SIG) provides appropriateness recommendations for neurologic 3D printing conditions.

METHODS: A structured literature search was conducted to identify all relevant articles using 3D printing technology associated with neurologic and otolaryngologic conditions. Each study was vetted by the authors and strength of evidence was assessed according to published guidelines.

RESULTS: Evidence-based recommendations for when 3D printing is appropriate are provided for diseases of …

Formative Evaluation And Adaptation Of A Hypertension Extension For Community Health Outcomes Program For Healthcare Workers Within The Federal Capital Territory, Nigeria, Abigail S Baldridge, Nadia Goldstar, Grace C Bellinger, Abigail T Denoma, Ikechukwu A Orji, Gabriel L Shedul, Rosemary C B Okoli, Nanna R Ripiye, Adaora Odukwe, Olabisi Dabiri, L Nneka Mobisson, Dike B Ojji, Mark D Huffman, Namratha R Kandula, Lisa R Hirschhorn

2020-Current year OA Pubs

BACKGROUND: The Extension for Community Health Outcomes (ECHO) model has been used extensively to link care providers in rural communities with experts with the aim of improving local patient care.

OBJECTIVE: The aim of this qualitative research study was to assess the feasibility, acceptability, perceived needs, and contextual factors to guide implementation of a hypertension focused ECHO program for Community Health Extension Workers (CHEWs) in the Federal Capital Territory, Nigeria.

METHODS: From September 2020 to December 2020, key informant interviews were performed with seven global organizations (hubs) providing ECHO training focused on cardiovascular disease or nephrology to identify contextual factors …

Awareness With Paralysis And Symptoms Of Post-Traumatic Stress Disorder Among Mechanically Ventilated Emergency Department Survivors (Ed-Awareness-2 Trial): Study Protocol For A Pragmatic, Multicenter, Stepped Wedge Cluster Randomized Trial, Brian M Fuller, Brian E Driver, Michael B Roberts, Christa A Schorr, Kathryn Thompson, Brett Faine, Julianne Yeary, Nicholas M Mohr, Ryan D Pappal, Robert J Stephens, Yan Yan, Nicholas J Johnson, Brian W Roberts

2020-Current year OA Pubs

BACKGROUND: Awareness with paralysis (AWP) is memory recall during neuromuscular blockade (NMB) and can cause significant psychological harm. Decades of effort and rigorous trials have been conducted to prevent AWP in the operating room, where prevalence is 0.1-0.2%. By contrast, AWP in mechanically ventilated emergency department (ED) patients is common, with estimated prevalence of 3.3-7.4% among survivors given NMB. Longer-acting NMB use is a critical risk for AWP, and we have shown an association between ED rocuronium use and increased AWP prevalence. As NMB are given to more than 90% of ED patients during tracheal intubation, this trial provides a …

Dynamical Control Enables The Formation Of Demixed Biomolecular Condensates, Andrew Z Lin, Kiersten M Ruff, Furqan Dar, Ameya Jalihal, Matthew R King, Jared M Lalmansingh, Ammon E Posey, Nadia A Erkamp, Ian Seim, Amy S Gladfelter, Rohit V Pappu

2020-Current year OA Pubs

Cellular matter can be organized into compositionally distinct biomolecular condensates. For example, in Ashbya gossypii, the RNA-binding protein Whi3 forms distinct condensates with different RNA molecules. Using criteria derived from a physical framework for explaining how compositionally distinct condensates can form spontaneously via thermodynamic considerations, we find that condensates in vitro form mainly via heterotypic interactions in binary mixtures of Whi3 and RNA. However, within these condensates, RNA molecules become dynamically arrested. As a result, in ternary systems, simultaneous additions of Whi3 and pairs of distinct RNA molecules lead to well-mixed condensates, whereas delayed addition of an RNA component results …

Association Between The Introduction Of A National Targeted Intervention Program And The Incidence Of Surgical Site Infections In Swiss Acute Care Hospitals, Marcus Eder, Rami Sommerstein, Arlette Szelecsenyi, Alexander Schweiger, Matthias Schlegel, Andrew Atkinson, Stefan P Kuster, Danielle Vuichard-Gysin, Nicolas Troillet, Andreas F Widmer, For Swissnoso

2020-Current year OA Pubs

BACKGROUND: In Switzerland, the national surgical site infection (SSI) surveillance program showed a modest decrease in SSI rates for different procedures over the last decade. The study aimed to determine whether a multimodal, targeted intervention program in addition to existing SSI surveillance is associated with decreased SSI rates in the participating hospitals.

METHODS: Prospective multicenter pre- and postintervention study conducted in eight Swiss acute care hospitals between 2013 and 2020. All consecutive patients > 18 years undergoing cardiac, colon, or hip/knee replacement surgery were included. The follow-up period was 30 days and one year for implant-related surgery. Patients with at least …

Genetic Separation Of Brca1 Functions Reveal Mutation-Dependent Polθ Vulnerabilities, John J Krais, Et Al.

2020-Current year OA Pubs

Homologous recombination (HR)-deficiency induces a dependency on DNA polymerase theta (Polθ/Polq)-mediated end joining, and Polθ inhibitors (Polθi) are in development for cancer therapy. BRCA1 and BRCA2 deficient cells are thought to be synthetic lethal with Polθ, but whether distinct HR gene mutations give rise to equivalent Polθ-dependence, and the events that drive lethality, are unclear. In this study, we utilized mouse models with separate Brca1 functional defects to mechanistically define Brca1-Polθ synthetic lethality. Surprisingly, homozygous Brca1 mutant, Polq

Evaluating 17 Methods Incorporating Biological Function With Gwas Summary Statistics To Accelerate Discovery Demonstrates A Tradeoff Between High Sensitivity And High Positive Predictive Value, Amy Moore, Jesse A Marks, Bryan C Quach, Yuelong Guo, Laura J Bierut, Nathan C Gaddis, Dana B Hancock, Grier P Page, Eric O Johnson

2020-Current year OA Pubs

Where sufficiently large genome-wide association study (GWAS) samples are not currently available or feasible, methods that leverage increasing knowledge of the biological function of variants may illuminate discoveries without increasing sample size. We comprehensively evaluated 17 functional weighting methods for identifying novel associations. We assessed the performance of these methods using published results from multiple GWAS waves across each of five complex traits. Although no method achieved both high sensitivity and positive predictive value (PPV) for any trait, a subset of methods utilizing pleiotropy and expression quantitative trait loci nominated variants with high PPV (>75%) for multiple traits. Application …

Stratification Of Risk For Emergent Intracranial Abnormalities In Children With Headaches: A Pediatric Emergency Care Applied Research Network (Pecarn) Study Protocol, Daniel S Tsze, Kimberly S Quayle, Et Al.

2020-Current year OA Pubs

INTRODUCTION: Headache is a common chief complaint of children presenting to emergency departments (EDs). Approximately 0.5%-1% will have emergent intracranial abnormalities (EIAs) such as brain tumours or strokes. However, more than one-third undergo emergent neuroimaging in the ED, resulting in a large number of children unnecessarily exposed to radiation. The overuse of neuroimaging in children with headaches in the ED is driven by clinician concern for life-threatening EIAs and lack of clarity regarding which clinical characteristics accurately identify children with EIAs. The study objective is to derive and internally validate a stratification model that accurately identifies the risk of EIA …

Heterogeneous Cardiac Sympathetic Innervation Gradients Promote Arrhythmogenesis In Murine Dilated Cardiomyopathy, Al-Hassan J Dajani, Carla Valenzuela-Ripoll, Ali Javaheri, Et Al.

2020-Current year OA Pubs

Ventricular arrhythmias (VAs) in heart failure are enhanced by sympathoexcitation. However, radiotracer studies of catecholamine uptake in failing human hearts demonstrate a proclivity for VAs in patients with reduced cardiac sympathetic innervation. We hypothesized that this counterintuitive finding is explained by heterogeneous loss of sympathetic nerves in the failing heart. In a murine model of dilated cardiomyopathy (DCM), delayed PET imaging of sympathetic nerve density using the catecholamine analog [11C]meta-Hydroxyephedrine demonstrated global hypoinnervation in ventricular myocardium. Although reduced, sympathetic innervation in 2 distinct DCM models invariably exhibited transmural (epicardial to endocardial) gradients, with the endocardium being devoid of sympathetic nerve …

Dimerization Mechanism Of An Inverted-Topology Ion Channel In Membranes, Melanie Ernst, Esam A Orabi, Randy B Stockbridge, José D Faraldo-Gómez, Janice L Robertson

2020-Current year OA Pubs

Many ion channels are multisubunit complexes where oligomerization is an obligatory requirement for function as the binding axis forms the charged permeation pathway. However, the mechanisms of in-membrane assembly of thermodynamically stable channels are largely unknown. Here, we demonstrate a key advance by reporting the dimerization equilibrium reaction of an inverted-topology, homodimeric fluoride channel Fluc in lipid bilayers. While the wild-type channel is a long-lived dimer, we leverage a known mutation, N43S, that weakens Na

Engineering A Novel Modular Adenoviral Mrna Delivery Platform Based On Tag/Catcher Bioconjugation, Kexin Geng, Paul J Rice-Boucher, Elena A Kashentseva, Igor P Dmitriev, Zhi Hong Lu, S Peter Goedegebuure, William E Gillanders, David T Curiel

2020-Current year OA Pubs

mRNA vaccines have attracted widespread research attention with clear advantages in terms of molecular flexibility, rapid development, and potential for personalization. However, current mRNA vaccine platforms have not been optimized for induction of CD4/CD8 T cell responses. In addition, the mucosal administration of mRNA based on lipid nanoparticle technology faces challenges in clinical translation. In contrast, adenovirus-based vaccines induce strong T cell responses and have been approved for intranasal delivery. To leverage the inherent strengths of both the mRNA and adenovirus platforms, we developed a novel modular adenoviral mRNA delivery platform based on Tag/Catcher bioconjugation. Specifically, we engineered adenoviral vectors …