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Droplet Digital Pcr For Oncogenic Kmt2a Fusion Detection, Andrew L Young, Hannah C Davis, Grant A Challen
Droplet Digital Pcr For Oncogenic Kmt2a Fusion Detection, Andrew L Young, Hannah C Davis, Grant A Challen
2020-Current year OA Pubs
Acute myeloid leukemia (AML) is an aggressive blood cancer diagnosed in approximately 120,000 individuals worldwide each year. During treatment for AML, detecting residual disease is essential for prognostication and treatment decision-making. Currently, methods for detecting residual AML are limited to identifying approximately 1:100 to 1:1000 leukemic cells (morphology and DNA sequencing) or are difficult to implement (flow cytometry). AML arising after chemotherapy or radiation exposure is termed therapy-related AML (t-AML) and is exceptionally aggressive and treatment resistant. t-AML is often driven by oncogenic fusions that result from prior treatments that introduce double-strand DNA breaks. The most common t-AML-associated translocations affect …
Adverse Events And Complications After Primary Acl Reconstruction With Quadriceps Tendon Autograft: A Systematic Review, Garrett R Jackson, Enzo S Mameri, Trevor Tuthill, Morgan Wessels, Shaan Asif, Joan Sugrañes, Anjay K Batra, Johnathon R Mccormick, Obianuju A Obioha, Daniel J Kaplan, Derrick M Knapik, Nikhil N Verma, Jorge Chahla
Adverse Events And Complications After Primary Acl Reconstruction With Quadriceps Tendon Autograft: A Systematic Review, Garrett R Jackson, Enzo S Mameri, Trevor Tuthill, Morgan Wessels, Shaan Asif, Joan Sugrañes, Anjay K Batra, Johnathon R Mccormick, Obianuju A Obioha, Daniel J Kaplan, Derrick M Knapik, Nikhil N Verma, Jorge Chahla
2020-Current year OA Pubs
BACKGROUND: Anterior cruciate ligament reconstruction (ACLR) surgery with quadriceps tendon (QT) grafts, both with and without a patellar bone plug, have gained popularity in recent years in the primary and revision settings. Postoperative complications occur with the use of QT autografts.
PURPOSE: To systematically review the incidence of postoperative complications after primary ACLR QT autograft and compare complication rates in patients undergoing all-soft tissue QT grafts versus QT grafts with a patellar bone plug (QTPB).
STUDY DESIGN: Systematic review; Level of evidence, 4.
METHODS: A literature search using the 2020 PRISMA guidelines was performed by querying PubMed, Embase, and Scopus …
Optimized Strategy For Real-Time Qpcr Detection Of Onchocerca Volvulus Dna In Pooled Simulium Sp. Blackfly Vectors, Mary Doherty, Peter U. Fischer, Et Al.
Optimized Strategy For Real-Time Qpcr Detection Of Onchocerca Volvulus Dna In Pooled Simulium Sp. Blackfly Vectors, Mary Doherty, Peter U. Fischer, Et Al.
2020-Current year OA Pubs
BACKGROUND: Onchocerca volvulus is a filarial parasite that is a major cause of dermatitis and blindness in endemic regions primarily in sub-Saharan Africa. Widespread efforts to control the disease caused by O. volvulus infection (onchocerciasis) began in 1974 and in recent years, following successful elimination of transmission in much of the Americas, the focus of efforts in Africa has moved from control to the more challenging goal of elimination of transmission in all endemic countries. Mass drug administration (MDA) with ivermectin has reached more than 150 million people and elimination of transmission has been confirmed in four South American countries, …
Tyvaso Dpi: Drug-Device Characteristics And Patient Clinical Considerations, Colleen Mcevoy, Rahul Argula, Sandeep Sahay, Shelley Shapiro, Christina Eagan, Anthony J Hickey, Chad Smutney, Chris Dillon, Thomas Winkler, Brittany N Davis, Meredith Broderick, Charles Burger
Tyvaso Dpi: Drug-Device Characteristics And Patient Clinical Considerations, Colleen Mcevoy, Rahul Argula, Sandeep Sahay, Shelley Shapiro, Christina Eagan, Anthony J Hickey, Chad Smutney, Chris Dillon, Thomas Winkler, Brittany N Davis, Meredith Broderick, Charles Burger
2020-Current year OA Pubs
Tyvaso DPI is a drug-device combination therapy comprised of a small, portable, reusable, breath-powered, dry powder inhaler (DPI) for the delivery of treprostinil. It is approved for the treatment of pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease. Tyvaso DPI utilizes single-use prefilled cartridges to ensure proper dosing. Unlike nebulizer devices, administration of Tyvaso DPI is passive and does not require coordination with the device. The low-flow rate design results in targeted delivery to the peripheral lungs due to minimal drug loss from impaction in the oropharynx. The inert fumaryl diketopiperazine (FDKP) excipient forms microparticles that carry …
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
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
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 …
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
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 …
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
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.
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
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, …
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.
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 …
Relationship Between The Covid-19 Pandemic And Structural Inequalities Within The Pediatric Trauma Population, Christina Georgeades, Martin S Keller, Et Al.
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 …
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.
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.
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
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 …
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.
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 …
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
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 …
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
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 …
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
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 …
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
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.
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
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 …
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
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 …
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.
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.
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
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
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 …
Association Between Microbiome And The Development Of Adverse Posttraumatic Neuropsychiatric Sequelae After Traumatic Stress Exposure, Abigail L Zeamer, Stacey L House, Et Al.
Association Between Microbiome And The Development Of Adverse Posttraumatic Neuropsychiatric Sequelae After Traumatic Stress Exposure, Abigail L Zeamer, Stacey L House, Et Al.
2020-Current year OA Pubs
Patients exposed to trauma often experience high rates of adverse post-traumatic neuropsychiatric sequelae (APNS). The biological mechanisms promoting APNS are currently unknown, but the microbiota-gut-brain axis offers an avenue to understanding mechanisms as well as possibilities for intervention. Microbiome composition after trauma exposure has been poorly examined regarding neuropsychiatric outcomes. We aimed to determine whether the gut microbiomes of trauma-exposed emergency department patients who develop APNS have dysfunctional gut microbiome profiles and discover potential associated mechanisms. We performed metagenomic analysis on stool samples (n = 51) from a subset of adults enrolled in the Advancing Understanding of RecOvery afteR traumA …
Effects Of Hepatic Mitochondrial Pyruvate Carrier Deficiency On De Novo Lipogenesis And Gluconeogenesis In Mice, Nicole K H Yiew, Stanislaw Deja, Daniel Ferguson, Kevin Cho, Chaowapong Jarasvaraparn, Miriam Jacome-Sosa, Andrew J Lutkewitte, Sandip Mukherjee, Xiaorong Fu, Jason M Singer, Gary J Patti, Shawn C Burgess, Brian N Finck
Effects Of Hepatic Mitochondrial Pyruvate Carrier Deficiency On De Novo Lipogenesis And Gluconeogenesis In Mice, Nicole K H Yiew, Stanislaw Deja, Daniel Ferguson, Kevin Cho, Chaowapong Jarasvaraparn, Miriam Jacome-Sosa, Andrew J Lutkewitte, Sandip Mukherjee, Xiaorong Fu, Jason M Singer, Gary J Patti, Shawn C Burgess, Brian N Finck
2020-Current year OA Pubs
The liver coordinates the systemic response to nutrient deprivation and availability by producing glucose from gluconeogenesis during fasting and synthesizing lipids via
Behavioral Mechanisms That Mediate Mental And Physical Health Improvements In People With Chronic Pain Who Receive A Digital Health Intervention: Prospective Cohort Pilot Study, Abby L Cheng, Mansi Agarwal, Melissa A Armbrecht, Joanna Abraham, Ryan P Calfee, Charles W Goss
Behavioral Mechanisms That Mediate Mental And Physical Health Improvements In People With Chronic Pain Who Receive A Digital Health Intervention: Prospective Cohort Pilot Study, Abby L Cheng, Mansi Agarwal, Melissa A Armbrecht, Joanna Abraham, Ryan P Calfee, Charles W Goss
2020-Current year OA Pubs
BACKGROUND: Preliminary evidence suggests that digital mental health intervention (Wysa for Chronic Pain) can improve mental and physical health in people with chronic musculoskeletal pain and coexisting symptoms of depression or anxiety. However, the behavioral mechanisms through which this intervention acts are not fully understood.
OBJECTIVE: The purpose of this study was to identify behavioral mechanisms that may mediate changes in mental and physical health associated with use of Wysa for Chronic Pain during orthopedic management of chronic musculoskeletal pain. We hypothesized that improved behavioral activation, pain acceptance, and sleep quality mediate improvements in self-reported mental and physical health.
METHODS: …
Sustainability Determinants Of An Intervention To Identify Clinical Deterioration And Improve Childhood Cancer Survival In Latin American Hospitals: The Inspire Study Protocol, Virginia Mckay, Bobbi Carothers, Dylan Graetz, Sara Malone, Maria Puerto-Torres, Kim Prewitt, Adolfo Cardenas, Yichen Chen, Meenakshi Devidas, Douglas A Luke, Asya Agulnik
Sustainability Determinants Of An Intervention To Identify Clinical Deterioration And Improve Childhood Cancer Survival In Latin American Hospitals: The Inspire Study Protocol, Virginia Mckay, Bobbi Carothers, Dylan Graetz, Sara Malone, Maria Puerto-Torres, Kim Prewitt, Adolfo Cardenas, Yichen Chen, Meenakshi Devidas, Douglas A Luke, Asya Agulnik
2020-Current year OA Pubs
BACKGROUND: More than 90% of children with cancer live in low-resourced settings, where survival is only 20%. Sustainable evidence-based (EB) interventions yielding ongoing beneficial patient outcomes are critical to improve childhood cancer survival. A better understanding of factors promoting intervention sustainability in these settings is urgently needed. The aim of this study is to provide an empirical understanding of how clinical capacity for sustainability, or the resources needed to sustain an intervention, impacts the sustainment of Pediatric Early Warning System (PEWS), an EB intervention that improves pediatric oncology outcomes in low-resource hospitals by detecting clinical deterioration and preventing the need …