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Personalized Ctdna Micro-Panels Can Monitor And Predict Clinical Outcomes For Patients With Triple-Negative Breast Cancer, Erica K Barnell, Bryan Fisk, Zachary L Skidmore, Kelsy C Cotto, Anamika Basu, Aparna Anand, Megan M Richters, Jingqin Luo, Catrina Fronick, Meenakshi Anurag, Robert Fulton, Matthew J Ellis, Obi L Griffith, Malachi Griffith, Foluso O Ademuyiwa Oct 2022

Personalized Ctdna Micro-Panels Can Monitor And Predict Clinical Outcomes For Patients With Triple-Negative Breast Cancer, Erica K Barnell, Bryan Fisk, Zachary L Skidmore, Kelsy C Cotto, Anamika Basu, Aparna Anand, Megan M Richters, Jingqin Luo, Catrina Fronick, Meenakshi Anurag, Robert Fulton, Matthew J Ellis, Obi L Griffith, Malachi Griffith, Foluso O Ademuyiwa

2020-Current year OA Pubs

Circulating tumor DNA (ctDNA) in peripheral blood has been used to predict prognosis and therapeutic response for triple-negative breast cancer (TNBC) patients. However, previous approaches typically use large comprehensive panels of genes commonly mutated across all breast cancers. Given the reduction in sequencing costs and decreased turnaround times associated with panel generation, the objective of this study was to assess the use of custom micro-panels for tracking disease and predicting clinical outcomes for patients with TNBC. Paired tumor-normal samples from patients with TNBC were obtained at diagnosis (T0) and whole exome sequencing (WES) was performed to identify somatic variants associated …


A Randomized Feasibility Pilot-Study Of Intravenous And Subcutaneous Administration Of Ketamine To Prevent Postpartum Depression After Planned Cesarean Delivery Under Neuraxial Anesthesia, David Thomas Monks, Arvind Palanisamy, Danish Jaffer, Preet Mohinder Singh, Ebony Carter, Shannon Lenze Oct 2022

A Randomized Feasibility Pilot-Study Of Intravenous And Subcutaneous Administration Of Ketamine To Prevent Postpartum Depression After Planned Cesarean Delivery Under Neuraxial Anesthesia, David Thomas Monks, Arvind Palanisamy, Danish Jaffer, Preet Mohinder Singh, Ebony Carter, Shannon Lenze

2020-Current year OA Pubs

BACKGROUND: Evidence suggests ketamine may prevent postpartum depression (PPD) after cesarean delivery (CD) although intolerability and inconvenience of administration are problematic. We assessed the feasibility of studying ketamine (0.5 mg/kg, via subcutaneous injection or 40-min intravenous infusion) to prevent PPD after CD.

METHODS: Twenty-three women scheduled for cesarean delivery under neuraxial anesthesia were randomized to one of three groups: subcutaneous ketamine (SC Group, n = 8), intravenous ketamine (IV Group, n = 8) or placebo (n = 7). We measured depression (Edinburgh Postpartum Depression Scale [EPDS]) scores pre-operatively and at 1, 2, 21 and 42 days postoperatively. Anxiety, adverse effects, …


A Comparison Of Bioimpedance Analysis Vs. Dual X-Ray Absorptiometry For Body Composition Assessment In Postpartum Women And Non-Postpartum Controls, Valene Garr Barry, Samantha L Martin, Paula Chandler-Laney, Ebony B Carter, Camille S Worthington Oct 2022

A Comparison Of Bioimpedance Analysis Vs. Dual X-Ray Absorptiometry For Body Composition Assessment In Postpartum Women And Non-Postpartum Controls, Valene Garr Barry, Samantha L Martin, Paula Chandler-Laney, Ebony B Carter, Camille S Worthington

2020-Current year OA Pubs

Postpartum fat mass (FM) and fat-free mass (FFM) may be informative predictors of future disease risk among women; hence, there is growing use of bioelectrical impedance analysis (BIA) to quantify FFM and FM among postpartum women due to the quick, non-invasive, and inexpensive nature of BIA. Despite this, very few studies have examined BIA's performance, and it remains unclear as to whether specific BIA equations are needed for postpartum women. To explore these questions, we measured total body FFM and FM with a multi-frequency, segmental BIA, and dual-X-ray absorptiometry (DXA) in (1) women at one and four months postpartum (


Complete Genome Sequence Of The Uropathogenic Methicillin-Resistant Staphylococcus Aureus Strain Mrsa-1369, Hasan Tükenmez, Taylor M Nye, Mari Bonde, Michael G Caparon, Fredrik Almqvist, Scott J Hultgren, Jörgen Johansson Oct 2022

Complete Genome Sequence Of The Uropathogenic Methicillin-Resistant Staphylococcus Aureus Strain Mrsa-1369, Hasan Tükenmez, Taylor M Nye, Mari Bonde, Michael G Caparon, Fredrik Almqvist, Scott J Hultgren, Jörgen Johansson

2020-Current year OA Pubs

MRSA-1369 is a uropathogenic methicillin-resistant Staphylococcus aureus (MRSA) strain. Here, we present the complete genome sequence of MRSA-1369, which consists of one chromosome (2.87 Mb) and two plasmids (16.68 kb and 3.13 kb). This will serve as a reference genome for future Staphylococcus aureus pathogenesis and multiomic studies.


Integrated Host-Microbe Plasma Metagenomics For Sepsis Diagnosis In A Prospective Cohort Of Critically Ill Adults, Katrina L Kalantar, Pratik Sinha, Et Al. Oct 2022

Integrated Host-Microbe Plasma Metagenomics For Sepsis Diagnosis In A Prospective Cohort Of Critically Ill Adults, Katrina L Kalantar, Pratik Sinha, Et Al.

2020-Current year OA Pubs

We carried out integrated host and pathogen metagenomic RNA and DNA next generation sequencing (mNGS) of whole blood (n = 221) and plasma (n = 138) from critically ill patients following hospital admission. We assigned patients into sepsis groups on the basis of clinical and microbiological criteria. From whole-blood gene expression data, we distinguished patients with sepsis from patients with non-infectious systemic inflammatory conditions using a trained bagged support vector machine (bSVM) classifier (area under the receiver operating characteristic curve (AUC) = 0.81 in the training set; AUC = 0.82 in a held-out validation set). Plasma RNA also yielded a …


Neoplastic Cell Enrichment Of Tumor Tissues Using Coring And Laser Microdissection For Proteomic And Genomic Analyses Of Pancreatic Ductal Adenocarcinoma, Qing Kay Li, Daniel Cui Zhou, Yize Li, Rita Jui-Hsien Lu, Li Ding, Et Al. Oct 2022

Neoplastic Cell Enrichment Of Tumor Tissues Using Coring And Laser Microdissection For Proteomic And Genomic Analyses Of Pancreatic Ductal Adenocarcinoma, Qing Kay Li, Daniel Cui Zhou, Yize Li, Rita Jui-Hsien Lu, Li Ding, Et Al.

2020-Current year OA Pubs

BACKGROUND: The identification of differentially expressed tumor-associated proteins and genomic alterations driving neoplasia is critical in the development of clinical assays to detect cancers and forms the foundation for understanding cancer biology. One of the challenges in the analysis of pancreatic ductal adenocarcinoma (PDAC) is the low neoplastic cellularity and heterogeneous composition of bulk tumors. To enrich neoplastic cells from bulk tumor tissue, coring, and laser microdissection (LMD) sampling techniques have been employed. In this study, we assessed the protein and KRAS mutation changes associated with samples obtained by these enrichment techniques and evaluated the fraction of neoplastic cells in …


Semi-Automated Assembly Of High-Quality Diploid Human Reference Genomes, Erich D Jarvis, Sarah Cody, Robert S Fulton, Lucinda L Fulton, Daofeng Li, Tina Lindsay, Nathan O Stitziel, Ting Wang, Et Al. Oct 2022

Semi-Automated Assembly Of High-Quality Diploid Human Reference Genomes, Erich D Jarvis, Sarah Cody, Robert S Fulton, Lucinda L Fulton, Daofeng Li, Tina Lindsay, Nathan O Stitziel, Ting Wang, Et Al.

2020-Current year OA Pubs

The current human reference genome, GRCh38, represents over 20 years of effort to generate a high-quality assembly, which has benefitted society1,2. However, it still has many gaps and errors, and does not represent a biological genome as it is a blend of multiple individuals3,4. Recently, a high-quality telomere-to-telomere reference, CHM13, was generated with the latest long-read technologies, but it was derived from a hydatidiform mole cell line with a nearly homozygous genome5. To address these limitations, the Human Pangenome Reference Consortium formed with the goal of creating high-quality, cost-effective, diploid genome assemblies for a …


Can The "Female Protective Effect" Liability Threshold Model Explain Sex Differences In Autism Spectrum Disorder?, Joseph D Dougherty, Natasha Marrus, Susan E Maloney, Benjamin Yip, Sven Sandin, Tychele N Turner, Din Selmanovic, Kristen L Kroll, David H Gutmann, John N Constantino, Lauren A Weiss Oct 2022

Can The "Female Protective Effect" Liability Threshold Model Explain Sex Differences In Autism Spectrum Disorder?, Joseph D Dougherty, Natasha Marrus, Susan E Maloney, Benjamin Yip, Sven Sandin, Tychele N Turner, Din Selmanovic, Kristen L Kroll, David H Gutmann, John N Constantino, Lauren A Weiss

2020-Current year OA Pubs

Male sex is a strong risk factor for autism spectrum disorder (ASD). The leading theory for a "female protective effect" (FPE) envisions males and females have "differing thresholds" under a "liability threshold model" (DT-LTM). Specifically, this model posits that females require either a greater number or larger magnitude of risk factors (i.e., greater liability) to manifest ASD, which is supported by the finding that a greater proportion of females with ASD have highly penetrant genetic mutations. Herein, we derive testable hypotheses from the DT-LTM for ASD, investigating heritability, familial recurrence, correlation between ASD penetrance and sex ratio, population traits, clinical …


Prenatal Exposure To Maternal Social Disadvantage And Psychosocial Stress And Neonatal White Matter Connectivity At Birth, Rachel E Lean, Christopher D Smyser, Rebecca G Brady, Regina L Triplett, Sydney Kaplan, Jeanette K Kenley, Joshua S Shimony, Tara A Smyser, J Phillip Miller, Deanna M Barch, Joan L Luby, Barbara B Warner, Cynthia E Rogers Oct 2022

Prenatal Exposure To Maternal Social Disadvantage And Psychosocial Stress And Neonatal White Matter Connectivity At Birth, Rachel E Lean, Christopher D Smyser, Rebecca G Brady, Regina L Triplett, Sydney Kaplan, Jeanette K Kenley, Joshua S Shimony, Tara A Smyser, J Phillip Miller, Deanna M Barch, Joan L Luby, Barbara B Warner, Cynthia E Rogers

2020-Current year OA Pubs

Early life adversity (social disadvantage and psychosocial stressors) is associated with altered microstructure in fronto-limbic pathways important for socioemotional development. Understanding when these associations begin to emerge may inform the timing and design of preventative interventions. In this longitudinal study, 399 mothers were oversampled for low income and completed social background measures during pregnancy. Measures were analyzed with structural equation analysis resulting in two latent factors: social disadvantage (education, insurance status, income-to-needs ratio [INR], neighborhood deprivation, and nutrition) and psychosocial stress (depression, stress, life events, and racial discrimination). At birth, 289 healthy term-born neonates underwent a diffusion MRI (dMRI) scan. …


Activity-Dependent Translation Dynamically Alters The Proteome Of The Perisynaptic Astrocyte Process, Darshan Sapkota, Kristina Sakers, Kayla R Nygaard, Yating Liu, Sarah K Koester, Stuart B Fass, Allison M Lake, Rohan Khazanchi, Susan E Maloney, Joseph D Dougherty, Et Al. Oct 2022

Activity-Dependent Translation Dynamically Alters The Proteome Of The Perisynaptic Astrocyte Process, Darshan Sapkota, Kristina Sakers, Kayla R Nygaard, Yating Liu, Sarah K Koester, Stuart B Fass, Allison M Lake, Rohan Khazanchi, Susan E Maloney, Joseph D Dougherty, Et Al.

2020-Current year OA Pubs

Within eukaryotic cells, translation is regulated independent of transcription, enabling nuanced, localized, and rapid responses to stimuli. Neurons respond transcriptionally and translationally to synaptic activity. Although transcriptional responses are documented in astrocytes, here we test whether astrocytes have programmed translational responses. We show that seizure activity rapidly changes the transcripts on astrocyte ribosomes, some predicted to be downstream of BDNF signaling. In acute slices, we quantify the extent to which cues of neuronal activity activate translation in astrocytes and show that this translational response requires the presence of neurons, indicating that the response is non-cell autonomous. We also show that …


Cross-Species Efficacy Of Enzyme Replacement Therapy For Cln1 Disease In Mice And Sheep, Hemanth R. Nelvagal, Sophie H. Wang, Elizabeth M. Eultgen, Keigo Takashash, Steven Q. Le, Rachel Nesbitt, Joshua T. Dearborn, Patricia I. Dickson, Mark S. Sands, Jonathan D. Cooper, Et Al. Oct 2022

Cross-Species Efficacy Of Enzyme Replacement Therapy For Cln1 Disease In Mice And Sheep, Hemanth R. Nelvagal, Sophie H. Wang, Elizabeth M. Eultgen, Keigo Takashash, Steven Q. Le, Rachel Nesbitt, Joshua T. Dearborn, Patricia I. Dickson, Mark S. Sands, Jonathan D. Cooper, Et Al.

2020-Current year OA Pubs

CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by administering monthly infusions of recombinant human PPT1 (rhPPT1) to PPT1-deficient …


Cellular Landscaping Of Covid-19 And Gynaecological Cancers: An Infrequent Correlation, Rahul Bhattacharjee, Debanjan Das, Radheka Bhadhuri, Srija Chakraborty, Tanima Dey, Rupam Buragohain, Asim Nath, Kartik Muduli, Pranjan Barman, Rohit Gundamaraju Oct 2022

Cellular Landscaping Of Covid-19 And Gynaecological Cancers: An Infrequent Correlation, Rahul Bhattacharjee, Debanjan Das, Radheka Bhadhuri, Srija Chakraborty, Tanima Dey, Rupam Buragohain, Asim Nath, Kartik Muduli, Pranjan Barman, Rohit Gundamaraju

2020-Current year OA Pubs

COVID-19 resulted in a mortality rate of 3-6% caused by SARS-CoV-2 and its variant leading to unprecedented consequences of acute respiratory distress septic shock and multiorgan failure. In such a situation, evaluation, diagnosis, treatment, and care for cancer patients are difficult tasks faced by medical staff. Moreover, patients with gynaecological cancer appear to be more prone to severe infection and mortality from COVID-19 due to immunosuppression by chemotherapy and coexisting medical disorders. To deal with such a circumtances oncologists have been obliged to reconsider the entire diagnostic, treatment, and management approach. This review will provide and discuss the molecular link …


Il-1Β-Dependent Extravasation Of Preexisting Lung-Restricted Autoantibodies During Lung Transplantation Activates Complement And Mediates Primary Graft Dysfunction, Wenbin Yang, Daniel Kreisel, Et Al. Oct 2022

Il-1Β-Dependent Extravasation Of Preexisting Lung-Restricted Autoantibodies During Lung Transplantation Activates Complement And Mediates Primary Graft Dysfunction, Wenbin Yang, Daniel Kreisel, Et Al.

2020-Current year OA Pubs

Preexisting lung-restricted autoantibodies (LRAs) are associated with a higher incidence of primary graft dysfunction (PGD), although it remains unclear whether LRAs can drive its pathogenesis. In syngeneic murine left lung transplant recipients, preexisting LRAs worsened graft dysfunction, which was evident by impaired gas exchange, increased pulmonary edema, and activation of damage-associated pathways in lung epithelial cells. LRA-mediated injury was distinct from ischemia-reperfusion injury since deletion of donor nonclassical monocytes and host neutrophils could not prevent graft dysfunction in LRA-pretreated recipients. Whole LRA IgG molecules were necessary for lung injury, which was mediated by the classical and alternative complement pathways and …


A Quantitative Metric Of Pioneer Activity Reveals That Hnf4a Has Stronger In Vivo Pioneer Activity Than Foxa1, Jeffrey L Hansen, Barak A Cohen Oct 2022

A Quantitative Metric Of Pioneer Activity Reveals That Hnf4a Has Stronger In Vivo Pioneer Activity Than Foxa1, Jeffrey L Hansen, Barak A Cohen

2020-Current year OA Pubs

BACKGROUND: We and others have suggested that pioneer activity - a transcription factor's (TF's) ability to bind and open inaccessible loci - is not a qualitative trait limited to a select class of pioneer TFs. We hypothesize that most TFs display pioneering activity that depends on the TF concentration and the motif content at their target loci.

RESULTS: Here, we present a quantitative in vivo measure of pioneer activity that captures the relative difference in a TF's ability to bind accessible versus inaccessible DNA. The metric is based on experiments that use CUT&Tag to measure the binding of doxycycline-inducible TFs. …


Hsf1 Is A Driver Of Leukemia Stem Cell Self-Renewal In Acute Myeloid Leukemia, Qianze Dong, Nick Borcherding, Et Al. Oct 2022

Hsf1 Is A Driver Of Leukemia Stem Cell Self-Renewal In Acute Myeloid Leukemia, Qianze Dong, Nick Borcherding, Et Al.

2020-Current year OA Pubs

Acute myeloid leukemia (AML) is maintained by self-renewing leukemic stem cells (LSCs). A fundamental problem in treating AML is that conventional therapy fails to eliminate LSCs, which can reinitiate leukemia. Heat shock transcription factor 1 (HSF1), a central regulator of the stress response, has emerged as an important target in cancer therapy. Using genetic Hsf1 deletion and a direct HSF1 small molecule inhibitor, we show that HSF1 is specifically required for the maintenance of AML, while sparing steady-state and stressed hematopoiesis. Mechanistically, deletion of Hsf1 dysregulates multifaceted genes involved in LSC stemness and suppresses mitochondrial oxidative phosphorylation through downregulation of …


Bold Cofluctuation 'Events' Are Predicted From Static Functional Connectivity, Zach Ladwig, Benjamin A. Seitzman, Ally Dworetsky, Yuhua Yu, Babatunde Adeyemo, Derek M. Smith, Steven E. Petersen, Caterina Gratton Oct 2022

Bold Cofluctuation 'Events' Are Predicted From Static Functional Connectivity, Zach Ladwig, Benjamin A. Seitzman, Ally Dworetsky, Yuhua Yu, Babatunde Adeyemo, Derek M. Smith, Steven E. Petersen, Caterina Gratton

2020-Current year OA Pubs

Recent work identified single time points ("events") of high regional cofluctuation in functional Magnetic Resonance Imaging (fMRI) which contain more large-scale brain network information than other, low cofluctuation time points. This suggested that events might be a discrete, temporally sparse signal which drives functional connectivity (FC) over the timeseries. However, a different, not yet explored possibility is that network information differences between time points are driven by sampling variability on a constant, static, noisy signal. Using a combination of real and simulated data, we examined the relationship between cofluctuation and network structure and asked if this relationship was unique, or …


Impact Of The Covid-19 Pandemic On The Implementation Of Mobile Health To Improve The Uptake Of Hydroxyurea In Patients With Sickle Cell Disease: Mixed Methods Study, Sherif M Badawy, Lisa Dimartino, Donald Brambilla, Lisa Klesges, Ana Baumann, Ebony Burns, Terri Demartino, Sara Jacobs, Hamda Khan, Chinonyelum Nwosu, Nirmish Shah, Jane S Hankins, Sickle Cell Disease Implementation Consortium Oct 2022

Impact Of The Covid-19 Pandemic On The Implementation Of Mobile Health To Improve The Uptake Of Hydroxyurea In Patients With Sickle Cell Disease: Mixed Methods Study, Sherif M Badawy, Lisa Dimartino, Donald Brambilla, Lisa Klesges, Ana Baumann, Ebony Burns, Terri Demartino, Sara Jacobs, Hamda Khan, Chinonyelum Nwosu, Nirmish Shah, Jane S Hankins, Sickle Cell Disease Implementation Consortium

2020-Current year OA Pubs

BACKGROUND: Hydroxyurea therapy is effective for reducing complications related to sickle cell disease (SCD) and is recommended by National Health Lung and Blood Institute care guidelines. However, hydroxyurea is underutilized, and adherence is suboptimal. We wanted to test a multilevel mobile health (mHealth) intervention to increase hydroxyurea adherence among patients and improve prescribing among providers in a multicenter clinical trial. In the first 2 study sites, participants were exposed to the early phases of the COVID-19 pandemic, which included disruption to their regular SCD care.

OBJECTIVE: We aimed to describe the impact of the COVID-19 pandemic on the implementation of …


Trial Of Ultrasound Guided Carpal Tunnel Release Versus Traditional Open Release (Tutor), Kyle R. Eberlin, Christopher J. Dy, Mark D. Fischer, James L. Gluck, F. Thomas D. Kaplan, Thomas J. Mcdonald, Larry E. Miller, Alexander Palmer, Marc E. Walker, James F. Watt Oct 2022

Trial Of Ultrasound Guided Carpal Tunnel Release Versus Traditional Open Release (Tutor), Kyle R. Eberlin, Christopher J. Dy, Mark D. Fischer, James L. Gluck, F. Thomas D. Kaplan, Thomas J. Mcdonald, Larry E. Miller, Alexander Palmer, Marc E. Walker, James F. Watt

2020-Current year OA Pubs

BACKGROUND: Carpal tunnel release (CTR) is a surgical treatment option for patients with carpal tunnel syndrome (CTS) symptoms that are unresponsive to conservative treatment. Most patients experience symptomatic relief after CTR regardless of the surgical technique. However, direct comparisons of the safety and effectiveness between CTR surgical techniques are limited. The purpose of this randomized controlled trial is to compare the safety and effectiveness of CTR with ultrasound guidance (CTR-US) versus mini-open CTR (mOCTR) in subjects with symptomatic CTS.

DESIGN AND METHODS: TUTOR (Trial of Ultrasound guided CTR versus Traditional Open Release) is a randomized controlled trial in which 120 …


Predicting Postoperative Troponin In Patients Undergoing Elective Hip Or Knee Arthroplasty: A Comparison Of Five Cardiac Risk Prediction Tools, Merih T Tesfazghi, Anne R Bass, Noor Al-Hammadi, Scott C Woller, Scott M Stevens, Charles S Eby, Mitchell G Scott, Lindsey Snyder, Troy S Wildes, Brian F Gage Oct 2022

Predicting Postoperative Troponin In Patients Undergoing Elective Hip Or Knee Arthroplasty: A Comparison Of Five Cardiac Risk Prediction Tools, Merih T Tesfazghi, Anne R Bass, Noor Al-Hammadi, Scott C Woller, Scott M Stevens, Charles S Eby, Mitchell G Scott, Lindsey Snyder, Troy S Wildes, Brian F Gage

2020-Current year OA Pubs

BACKGROUND: Elderly patients undergoing hip or knee arthroplasty are at a risk for myocardial injury after noncardiac surgery (MINS). We evaluated the ability of five common cardiac risk scores, alone or combined with baseline high-sensitivity cardiac troponin I (hs-cTnI), in predicting MINS and postoperative day 2 (POD2) hs-cTnI levels in patients undergoing elective total hip or knee arthroplasty.

METHODS: This study is ancillary to the Genetics-InFormatics Trial (GIFT) of Warfarin Therapy to Prevent Deep Venous Thrombosis, which enrolled patients 65 years and older undergoing elective total hip or knee arthroplasty. The five cardiac risk scores evaluated were the atherosclerotic cardiovascular …


Clinical And Molecular Response To Tebentafusp In Previously Treated Patients With Metastatic Uveal Melanoma: A Phase 2 Trial, Richard D Carvajal, Leonel Hernandez-Aya, Et Al. Oct 2022

Clinical And Molecular Response To Tebentafusp In Previously Treated Patients With Metastatic Uveal Melanoma: A Phase 2 Trial, Richard D Carvajal, Leonel Hernandez-Aya, Et Al.

2020-Current year OA Pubs

In patients with previously treated metastatic uveal melanoma, the historical 1 year overall survival rate is 37% with a median overall survival of 7.8 months. We conducted a multicenter, single-arm, open-label phase 2 study of tebentafusp, a soluble T cell receptor bispecific (gp100×CD3), in 127 patients with treatment-refractory metastatic uveal melanoma (NCT02570308). The primary endpoint was the estimation of objective response rate based on RECIST (Response Evaluation Criteria in Solid Tumours) v1.1. Secondary objectives included safety, overall survival, progression-free survival and disease control rate. All patients had at least one treatment-related adverse event, with rash (87%), pyrexia (80%) and pruritus …


Personalized Structural Biology Reveals The Molecular Mechanisms Underlying Heterogeneous Epileptic Phenotypes Caused By De Novo Kcnc2 Variants, Souhrid Mukherjee, Jonathan H Sheehan, Et Al. Oct 2022

Personalized Structural Biology Reveals The Molecular Mechanisms Underlying Heterogeneous Epileptic Phenotypes Caused By De Novo Kcnc2 Variants, Souhrid Mukherjee, Jonathan H Sheehan, Et Al.

2020-Current year OA Pubs

Whole-exome sequencing (WES) in the clinic has identified several rare monogenic developmental and epileptic encephalopathies (DEE) caused by ion channel variants. However, WES often fails to provide actionable insight for rare diseases, such as DEEs, due to the challenges of interpreting variants of unknown significance (VUS). Here, we describe a "personalized structural biology" (PSB) approach that leverages recent innovations in the analysis of protein 3D structures to address this challenge. We illustrate this approach in an Undiagnosed Diseases Network (UDN) individual with DEE symptoms and a


Ho'ouna Pono Implementation: Applying Concept Mapping To A Culturally Grounded Substance Use Prevention Curriculum In Rural Hawai'i Schools, Kelsie H Okamura, Scott K Okamoto, Sarah Momilani Marshall, Steven Keone Chin, Pamela M Garcia, Byron J Powell, Kelly A Stern, Sara J Becker, David S Mandell Oct 2022

Ho'ouna Pono Implementation: Applying Concept Mapping To A Culturally Grounded Substance Use Prevention Curriculum In Rural Hawai'i Schools, Kelsie H Okamura, Scott K Okamoto, Sarah Momilani Marshall, Steven Keone Chin, Pamela M Garcia, Byron J Powell, Kelly A Stern, Sara J Becker, David S Mandell

2020-Current year OA Pubs

BACKGROUND: Despite their potential to ameliorate health disparities and address youth substance use, prevention programs have been poorly disseminated and implemented across Hawai'i, which begs the question: Why are effective prevention programs not being used in communities most in need of them? Implementing and sustaining culturally grounded prevention programs is critical to address equitable healthcare and minimize health disparities in communities. The field of implementation science provides frameworks, theories, and methods to examine factors associated with community adoption of these programs.

METHOD: Our project applies concept mapping methods to a culturally grounded youth drug prevention program with state level educational …


Collaborative Quality Improvement Strategy In Secondary Prevention Of Cardiovascular Disease In India: Findings From A Multi-Stakeholder, Qualitative Study Using Consolidated Framework For Implementation Research (Cfir), Kavita Singh, Mark D. Huffman, Leslie C M Johnson, Nikhil Tandon, Dorairaj Prabhakaran, Emily Mendenhall Oct 2022

Collaborative Quality Improvement Strategy In Secondary Prevention Of Cardiovascular Disease In India: Findings From A Multi-Stakeholder, Qualitative Study Using Consolidated Framework For Implementation Research (Cfir), Kavita Singh, Mark D. Huffman, Leslie C M Johnson, Nikhil Tandon, Dorairaj Prabhakaran, Emily Mendenhall

2020-Current year OA Pubs

BACKGROUND: Cardiovascular disease (CVD) is highly prevalent in India, and little is known about the perception of patients and providers about a package of collaborative quality improvement (C-QIP) strategies consisting of provider-focused electronic health records-decision support system (EHR-DSS), non-physician health workers (NPHW), and patient-facing text messages to enhance the CVD care.

OBJECTIVE: To explore the barriers and enablers of the C-QIP strategy from the perspective of providers, health administrators, patients, and care givers in India.

METHODS: We conducted a qualitative study using the consolidated framework for implementation research (CFIR) to understand the challenges and facilitators of implementing C-QIP strategy to …


Amyloid Β, Lipid Metabolism, Basal Cholinergic System, And Therapeutics In Alzheimer's Disease, Victoria Campos-Peña, Pavel Pichardo-Rojas, Talía Sánchez-Barbosa, Emma Ortíz-Islas, Citlali Ekaterina Rodríguez-Pérez, Pedro Montes, Gerardo Ramos-Palacios, Daniela Silva-Adaya, Rafael Valencia-Quintana, Jorge Francisco Cerna-Cortes, Danira Toral-Rios Oct 2022

Amyloid Β, Lipid Metabolism, Basal Cholinergic System, And Therapeutics In Alzheimer's Disease, Victoria Campos-Peña, Pavel Pichardo-Rojas, Talía Sánchez-Barbosa, Emma Ortíz-Islas, Citlali Ekaterina Rodríguez-Pérez, Pedro Montes, Gerardo Ramos-Palacios, Daniela Silva-Adaya, Rafael Valencia-Quintana, Jorge Francisco Cerna-Cortes, Danira Toral-Rios

2020-Current year OA Pubs

The presence of insoluble aggregates of amyloid β (Aβ) in the form of neuritic plaques (NPs) is one of the main features that define Alzheimer's disease. Studies have suggested that the accumulation of these peptides in the brain significantly contributes to extensive neuronal loss. Furthermore, the content and distribution of cholesterol in the membrane have been shown to have an important effect on the production and subsequent accumulation of Aβ peptides in the plasma membrane, contributing to dysfunction and neuronal death. The monomeric forms of these membrane-bound peptides undergo several conformational changes, ranging from oligomeric forms to beta-sheet structures, each …


Mesoscale Structure-Function Relationships In Mitochondrial Transcriptional Condensates, Marina Feric, Azadeh Sarfallah, Furqan Dar, Dmitry Temiakov, Rohit V Pappu, Tom Misteli Oct 2022

Mesoscale Structure-Function Relationships In Mitochondrial Transcriptional Condensates, Marina Feric, Azadeh Sarfallah, Furqan Dar, Dmitry Temiakov, Rohit V Pappu, Tom Misteli

2020-Current year OA Pubs

In live cells, phase separation is thought to organize macromolecules into membraneless structures known as biomolecular condensates. Here, we reconstituted transcription in condensates from purified mitochondrial components using optimized in vitro reaction conditions to probe the structure-function relationships of biomolecular condensates. We find that the core components of the mt-transcription machinery form multiphasic, viscoelastic condensates in vitro. Strikingly, the rates of condensate-mediated transcription are substantially lower than in solution. The condensate-mediated decrease in transcriptional rates is associated with the formation of vesicle-like structures that are driven by the production and accumulation of RNA during transcription. The generation of RNA alters …


Whole Genome Sequence Analysis Of Blood Lipid Levels In >66,000 Individuals, Margaret Sunitha Selvaraj, Lisa De Las Fuentes, Susan K. Dutcher, Et Al. Oct 2022

Whole Genome Sequence Analysis Of Blood Lipid Levels In >66,000 Individuals, Margaret Sunitha Selvaraj, Lisa De Las Fuentes, Susan K. Dutcher, Et Al.

2020-Current year OA Pubs

No abstract provided.


Association Of Α-Klotho With Subclinical Carotid Atherosclerosis In Subjects With Type 1 Diabetes Mellitus, Esmeralda Castelblanco, Marta Hernández, Nuria Alonso, Aina Ribes-Betriu, Jordi Real, Minerva Granado-Casas, Joana Rossell, Marina Idalia Rojo-López, Adriana Silvia Dusso, Josep Julve, Didac Mauricio Oct 2022

Association Of Α-Klotho With Subclinical Carotid Atherosclerosis In Subjects With Type 1 Diabetes Mellitus, Esmeralda Castelblanco, Marta Hernández, Nuria Alonso, Aina Ribes-Betriu, Jordi Real, Minerva Granado-Casas, Joana Rossell, Marina Idalia Rojo-López, Adriana Silvia Dusso, Josep Julve, Didac Mauricio

2020-Current year OA Pubs

BACKGROUND: Compelling evidence suggests that the fibroblast growth factor 23 (FGF23) / α-klotho axis is impaired in subjects with diabetes mellitus. We examined the relationship between parameters related to calcium/phosphate homeostasis, including FGF23 and α-klotho, and subclinical carotid atherosclerosis burden in type 1 diabetes mellitus (T1D) subjects.

METHODS: This cross-sectional study involved 226 subjects with T1D and 147 age-, sex- and plaque-matched, non-diabetic (non-T1D) subjects, both with normal renal function. Carotid ultrasound was performed to determine the presence and burden of atheromatous plaques. Concentrations of the intact form of FGF23 and α-klotho were assessed by ELISA. Calcium, phosphate, parathyroid hormone, …


Blood Culture Utilization Practices Among Febrile And/Or Hypothermic Inpatients, Kap Sum Foong, Satish Munigala, Stephanie Kern-Allely, David K Warren Oct 2022

Blood Culture Utilization Practices Among Febrile And/Or Hypothermic Inpatients, Kap Sum Foong, Satish Munigala, Stephanie Kern-Allely, David K Warren

2020-Current year OA Pubs

BACKGROUND: Predictors associated with the decision of blood culture ordering among hospitalized patients with abnormal body temperature are still underexplored, particularly non-clinical factors. In this study, we evaluated the factors affecting blood culture ordering in febrile and hypothermic inpatients.

METHODS: We performed a retrospective study of 15,788 adult inpatients with fever (≥ 38.3℃) or hypothermia (< 36.0℃) from January 2016 to December 2017. We evaluated the proportion of febrile and hypothermic episodes with an associated blood culture performed within 24h. Generalized Estimating Equations were used to determine independent predictors associated with blood culture ordering among febrile and hypothermic inpatients.

RESULTS: We identified 21,383 abnormal body temperature episodes among 15,788 inpatients (13,093 febrile and 8,290 hypothermic episodes). Blood cultures were performed in 36.7% (7,850/ 21,383) of these episodes. Predictors for blood culture ordering among inpatients with abnormal body temperature included fever ≥ 39℃ (adjusted …


Occupational Characteristics Associated With Sars-Cov-2 Infection In The Uk Biobank During August-November 2020: A Cohort Study, Elizabeth L Yanik, Bradley A Evanoff, Ann Marie Dale, Yinjiao Ma, Karen E Walker-Bone Oct 2022

Occupational Characteristics Associated With Sars-Cov-2 Infection In The Uk Biobank During August-November 2020: A Cohort Study, Elizabeth L Yanik, Bradley A Evanoff, Ann Marie Dale, Yinjiao Ma, Karen E Walker-Bone

2020-Current year OA Pubs

BACKGROUND: Occupational exposures may play a key role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection risk. We used a job-exposure matrix linked to the UK Biobank to measure occupational characteristics and estimate associations with a positive SARS-CoV-2 test.

METHODS: People reporting job titles at their baseline interview in England who were < 65 years of age in 2020 were included. Healthcare workers were excluded because of differential access to testing. Jobs were linked to the US Occupational Information Network (O*NET) job exposure matrix. O*NET-based scores were examined for occupational physical proximity, exposure to diseases/infection, working outdoors exposed to weather, and working outdoors under cover (score range = 1-5). Jobs were classified as remote work using two algorithms. SARS-CoV-2 test results were evaluated between August 5th-November 10th, 2020, when the UK was released from lockdown. Cox regression was used to calculate adjusted hazard ratios (aHRs), accounting for age, sex, race, education, neighborhood deprivation, assessment center, household size, and income.

RESULTS: We included 115,451 people with job titles, of whom 1746 tested positive for SARS-CoV-2. A one-point increase in physical proximity score was associated with 1.14 times higher risk of SARS-CoV-2 (95%CI = 1.05-1.24). A one-point increase in the exposure to diseases/infections score was associated with 1.09 …


Global Variation In Isolated Posterior Cruciate Ligament Reconstruction, Derrick M Knapik, Varun Gopinatth, Garrett R Jackson, Jorge Chahla, Matthew V Smith, Matthew J Matava, Robert H Brophy Oct 2022

Global Variation In Isolated Posterior Cruciate Ligament Reconstruction, Derrick M Knapik, Varun Gopinatth, Garrett R Jackson, Jorge Chahla, Matthew V Smith, Matthew J Matava, Robert H Brophy

2020-Current year OA Pubs

PURPOSE: In the setting of persistent instability or failed non-operative management, surgical reconstruction is commonly recommended for isolated posterior cruciate ligament (PCL) tears. The purpose of this study was to systematically review published studies to evaluate regional variation in the epidemiology of and surgical approaches to primary, isolated PCL reconstruction.

METHODS: A systematic review was performed in June 2022 to identify studies examining operative techniques during primary, isolated PCL reconstruction. Collected variables consisted of reconstruction technique, graft type, graft source, tibial reconstruction technique, femoral and tibial drilling and fixation methods, and whether the remnant PCL was preserved or debrided. Studies …