Digital Commons Network^™

A Systemic Selective Modified Mrna Delivery Platform For Preventing Chemotherapy-Induced Cardiotoxicity, Jimeen Yoo, Mengcheng Shen, Et Al.

2020-Current year OA Pubs

Doxorubicin (Dox) is a widely employed chemotherapeutic agent, but its use is clinically limited by dose-accumulative cardiotoxicity. More specifically, Dox induces oxidative stress and causes pro-apoptotic ceramide accumulation in cardiomyocytes (CMs). Acid ceramidase (AC) modified mRNA (modRNA) has been shown to reduce ceramide levels and protect the heart following ischemic injury; however, therapeutic modRNA applications have been hindered by the need for invasive delivery. Here, we present a platform for minimally intrusive transmission of modRNA to the heart. This CM-selective modRNA translational system (cmSMRTs) is encapsulated in lipid nanoparticles for intravenous (IV) delivery to enable systemic administration with high cardiac …

Loss Of Beta-Cell Identity And Function As A Mechanism Of Secondary Failure Of Sulfonylurea Therapy In Diabetes, Sumit Patel, Zihan Yan, Maria S Remedi

2020-Current year OA Pubs

Sulfonylureas, commonly used to treat type 2 diabetes (T2D), often lose effectiveness over time when used as monotherapy; however, the underlying mechanisms remain unclear. To investigate the mechanisms of sulfonylurea failure, glibenclamide-releasing pellets were implanted in KK mice, a polygenic model that spontaneously develops T2D. KK mice receiving placebo pellets (KK-Placebo) developed hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance. Notably, KK mice implanted with glibenclamide (KK-Glib) showed improved blood glucose levels during the first 7 days, returning to KK-Placebo levels thereafter. KK-Glib mice exhibited reduced plasma insulin levels and insulin secretion in response to a glucose challenge compared with the …

Blood Dna Methylation-Predicted Plasma Protein Levels And Colorectal Cancer Survival, Alicia R Richards, Maria F Gomez, Bianca I Dowling, Esther Jean-Baptiste, Biljana Gigic, Jane C Figueiredo, Christopher I Li, David Shibata, Adetunji T Toriola, Doratha A Byrd, Cornelia M Ulrich, Paul A Stewart, Erin M Siegel, Jacob K Kresovich

2020-Current year OA Pubs

BACKGROUND: Protein EpiScores are a novel class of DNA methylation (DNAm)-based metrics proposed to measure peripheral immune system characteristics. Although Protein EpiScores have been associated with chronic disease risk, their relationship with colorectal cancer (CRC) survival has not been investigated.

METHODS: We generated new genome-wide DNAm data on pre-treatment whole blood samples from a case-control sample of 136 newly diagnosed CRC patients nested in the ColoCare Study and calculated 107 Protein EpiScores using the developer's algorithm. Over a median follow-up of 7.3 years (range: 0.3-13.8 years), 35 (26%) patients experienced disease recurrence, and 47 (35%) died. Protein EpiScore associations with …

Lightweight Open-Source Large Language Models Versus Ctakes For Information Extraction From Discharge Summaries: Tobacco Smoking Status Test Case, David M Dávila-García, Matthew J Schuelke, Adam B Wilcox

2020-Current year OA Pubs

OBJECTIVES: To compare lightweight open-source large language models (LLMs) with cTAKES, a state-of-the-art natural language processing (NLP) system, in an information extraction task from hospitalization discharge summaries.

MATERIALS AND METHODS: Two readers annotated 250 randomly sampled adult discharge summaries (BJC HealthCare, 2018-2023) for tobacco smoking status as "Smoker," "Never smoker," "Unknown." Six LLMs (Llama-3 [1B-70B], gpt-oss-20B, MedGemma-27B) and cTAKES extracted smoking status from summaries. Performance was benchmarked against consensus annotations using weighted F1-score, macro F1-score, and per-class F1-scores and a noninferiority test.

RESULTS: Inter-reader agreement was excellent (κ = 0.91). LLM size (2.3-47.3 GB) and inference time (2.5-14.5 s/note) varied. …

Effects Of Dual-Eligible Integrated Care Plans On Medicaid Enrollment And Retention: Evidence From The Implementation Of Medicare-Medicaid Plans, Eric T Roberts, Eliza Macneal, Kenton J Johnston, José F Figueroa

2020-Current year OA Pubs

Medicare and Medicaid are separate programs that together cover 13 million low-income older adults and people with disabilities, known as dual-eligible individuals. Concern about a lack of coordination across Medicare and Medicaid has prompted the development of Integrated Care Programs (ICPs). Although the primary goal of ICPs is to coordinate financing and care across Medicare and Medicaid, ICPs may also influence whether low-income individuals obtain or keep Medicaid. We evaluated whether the rollout of Medicare-Medicaid Plans (MMPs)-one of the largest ICPs-was associated with changes in Medicaid take-up and retention among Medicare beneficiaries residing in high-poverty zip codes. Using a stacked …

Seeg-Guided Responsive Neurostimulation To Treat Neocortical Epilepsy: A Multicenter Retrospective Study Of The Efficacy And Safety Of Depth Electrode-Mediated Neuromodulation, Sina Sadeghzadeh, Jon T Willie, Et Al.

2020-Current year OA Pubs

OBJECTIVES: Pivotal trials have established the effectiveness of the Responsive Neurostimulation System (RNS® System) in treating focal epilepsy. In clinical trials, depth leads were primarily used to treat mesial temporal seizure onsets while cortical strip leads were used to treat neocortical seizure onsets. Here, we systematically analyze the safety and efficacy of stereoelectroencephalography (sEEG)-guided depth leads to provide responsive stimulation to neocortical gray matter.

METHODS: Patients were stratified as strong responders (>median cohort seizure reduction %), weak responders (>0% and ≤median cohort seizure reduction %), and anti-responders (≤0%) based on percent seizure reduction at 1 year post-implant (1-Y). …

Neural Cells Are Susceptible To Historic And Recently Emerged Oropouche Virus Strains, Kaleigh A. Connors, Maris R. Pedlow, Zachary D. Frey, Marjorie Cornejo Pontelli, Sean P. J. Whelan, W. Paul Duprex, Leonardo D'Aiuto, Zachary P. Wills, Amy L. Hartman

2020-Current year OA Pubs

Oropouche fever is a re-emerging global viral threat caused by infection with Oropouche virus (OROV). While disease is generally self-limiting, historical and recent reports of neurologic involvement highlight the importance of understanding the neuropathogenesis of OROV. In this study, we characterize viral replication kinetics in neurons, microglia, and astrocytes derived from immortalized, primary, and induced pluripotent stem cell-derived cells, which are all permissive to infection with the prototypic OROV BeAn19991. We demonstrate cell-type dependent replication kinetics with both historic and recently emerged viral strains. Further, we show that ex vivo rat brain slice cultures can be infected by all OROV …

Serine/Threonine Protein Kinase Phosphorylation Of Dosr Alters Target Gene Transcription Mechanics And Regulates Mycobacterium Tuberculosis Response To Nitric Oxide Stress, Natalie R. Sontag, Ana Ruiz Manzano, Alwyn M. V. Ecker, Eric A. Galburt, Shumin Tan

2020-Current year OA Pubs

Successful host colonization by bacterial pathogens requires appropriate response and adaptation to environmental signals encountered during infection, with two-component systems (TCSs) and serine/threonine protein kinases (STPKs) being two important signal transduction mechanisms. Mycobacterium tuberculosis (Mtb) possesses similar numbers of STPKs (11) and TCSs (12), but if and how these two regulatory systems coordinate to enable Mtb adaptation in response to key environmental cues remains poorly understood. Here, we identify extensive interactions between STPKs and TCSs, with a subset of STPKs demonstrating interactions with multiple TCS response regulators. STPK phosphorylation of purified DosR, the response regulator of the key nitric oxide …

The Death To Onchocerciasis And Lymphatic Filariasis (Dolf) Project: Accomplishments And Ongoing Research, Peter U. Fischer, Christopher L. King, Philip J. Budge, Gary J. Weil, Dolf Consortium

2020-Current year OA Pubs

The Death to Onchocerciasis and Lymphatic Filariasis (DOLF) project conducts clinical and translational research to accelerate the global elimination of lymphatic filariasis (LF) and onchocerciasis (river blindness). Research needs were identified during several meetings of experts and helped study design. Over the last 15 years the project has conducted mass drug administration (MDA) studies and clinical trials with outstanding research teams in 11 countries that have led to many important discoveries. For example, DOLF studies showed that annual MDA was as effective as semiannual MDA for LF elimination and that semiannual MDA with albendazole alone can eliminate LF in areas …

Long-Term Tofersen In Sod1 Amyotrophic Lateral Sclerosis, Timothy M Miller, Robert C Bucelli, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are attributable to a pathogenic variant in the superoxide dismutase 1 (SOD1) gene. Tofersen, an intrathecal antisense oligonucleotide designed to reduce SOD1 protein synthesis, is the first and only approved therapy for the treatment of ALS in adults who have a variant in the SOD1 gene.

OBJECTIVE: To evaluate the long-term effects of tofersen in adults with SOD1-ALS.

DESIGN, SETTING, AND PARTICIPANTS: The phase 3, randomized, double-blind, placebo-controlled VALOR trial (A Study to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Tofersen in SOD1-ALS; conducted from March 2019 to July 2021) …

Quantitative Echocardiography Markers To Denote Severity Of Tricuspid Regurgitation Compared To Cardiac Mri In Single Right Ventricle Variants, Tony Zunica, Daniel Forsha, Janelle Noel-Macdonnell, Anmol Goyal

Posters

Background: Single right ventricle and Hypoplastic Left Heart Syndrome (HLHS) are congenital heart diseases that require multiple palliative surgeries to create a single right ventricular system. 25-30% of these patients develop significant tricuspid regurgitation (TR), which is associated with worse outcomes among all stages of palliation. Echocardiography remains the cornerstone imaging modality for serial evaluation in these patients. However, estimating tricuspid regurgitation is highly subjective in the pediatric population, necessitating need for reliable and reproducible quantitative echocardiography markers. Currently, cardiac magnetic resonance (CMR) is considered the gold standard for quantification of tricuspid regurgitation with good accuracy and reproducibility. Objectives/Goal: Our …

Rare Heterozygous Missense Variants In Vsx2 Are Associated With Retinal Detachment, Daniel C Brock, Justin S Dhindsa, Yifan Chen, Vida Ravanmehr, Jonathan Mitchell, Fengyuan Hu, Xiaoyin Li, Likhita Nandigam, Quanli Wang, Kevin Wu, Jessica C Butts, Hardeep S Dhindsa, Benjamin J Frankfort, Nicholas M Tran, Slavé Petrovski, Ryan S Dhindsa

Duncan NRI Faculty and Staff Publications

Retinal detachment (RD) is a sight-threatening emergency requiring urgent intervention to prevent permanent vision loss. While both environmental and genetic risk factors contribute to RD, its complete genetic architecture remains unknown. Here, we performed the largest whole genome sequencing-based case-control study in RD to date, including data from 7,276 RD cases and 236,741 controls in the UK Biobank. Through variant- and gene-level association analyses, we identified VSX2 as a genetic determinant of RD risk while confirming established associations including FAT3, RDH5, and COL2A1. Gene-level collapsing analysis revealed that rare heterozygous missense variants in VSX2 confer a 2.8-fold …

Three-Dimensional Displacement Of Upper Cervical Vertebrae In Severe Mandibular Deviation Caused By Condylar Hyperplasia: A Tomographic Segmentation Study, Claudia Milena Ramírez, Rodrigo Cárdenas-Perilla, Luis Eduardo Almeida, Diego Fernando López

School of Dentistry Faculty Research and Publications

Objective: To evaluate the three-dimensional (3D) angular displacement (Roll, Yaw, and Pitch) of the upper cervical vertebrae (C1, C2, and C3) in patients with severe mandibular deviation (MD) due to condylar hyperplasia (CH), utilizing a computed tomography (CT)-based segmentation approach. Methods: This retrospective cross-sectional study included 50 patients with MD ≥ 6 mm caused by hemimandibular elongation (HE) or a hybrid form (HF) of CH. The skull, mandible, and cervical vertebrae (C1–C3) were segmented using 3D Slicer software. Angular deviations (Pitch, Yaw, Roll) were measured relative to the Frankfurt plane. Patients were categorized by the side of CH (right or …

Cytotoxicity Of Ammonia- And Water-Based Silver Fluoride Treatments, Merve Uctasli, Roda Seseogullari-Dirihan, Mustafa Murat Mutluay, Arzu Tezvergil-Mutluay

School of Dentistry Faculty Research and Publications

This study aims to investigate the trans-dentinal and direct cell viability of ammonia- and water-based silver fluoride treatments. Deep dentin discs were prepared, balanced for permeability and autoclaved. Three-dimensional cultures of odontoblast-like cells were transferred to the pulpal aspect of the dentin slices inside perfusion split chambers designed for dentin-barrier cytotoxicity test, following ISO 7405. An experimental resin-based glass ionomer cement and a polyvinylsiloxane impression material served as positive and negative controls, respectively. The experimental treatments included: (i) ammonia-based silver fluoride = SDF, (ii) SDF + potassium iodide = KI, (iii) water-based silver fluoride = SF, and (iv) SF + …

Impacts Of Artificial Intelligence On Computed Tomography In Endodontics: An Integrative Review, Camila Da Silva Fagundes, Ana Ligya Monteiro Soares, Fabiofederal University Of Paraíba Luiz Cunha D'Assuncao, Elsbeth Kalenderian, Claudia Batista Melo

School of Dentistry Faculty Research and Publications

Background. Artificial Intelligence (AI), defined as systems capable of replicating human tasks aimed at performing complex tasks and supporting decision-making, is entering the field of Dentistry, standing out with its application in research and clinical practices, such as diagnosis using Cone Beam Computed Tomography. The objective of this study is to identify and organize scientific evidence related to the use of Artificial Intelligence in computed tomography as an advanced resource in Endodontics.

Materials and methods. This study is an integrative review, structured in well-defined steps, namely: formulation of the guiding question, selection of inclusion and exclusion criteria, identification of descriptors …

A Narrative Review On The Therapeutic Potential Of Stem Cells In Neurodegenerative Diseases: Advances, Insights, And Challenges, Tirath Patel, Fathimathul Henna, Iman Sharif, Inaya Javed, Fatima Mustafa, Hannan Sharif, Fatima Nasir, Mirat Javaid

School of Medicine Publications

Background: Neurodegenerative diseases (NDs) such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) are set apart by progressive neuronal loss and concomitant functional decline. Traditional therapies are equipped with only symptomatic relief, devoid of neurorestorative properties. Stem-cell-based therapies have the potential to revolutionize neurological care by replenishing lost cells, mitigating inflammation, and fostering a neuroprotective environment.

Objectives: This narrative review aims to appraise the treatment potential of various stem cell types in managing NDs, highlighting their functional pathways, delivery methods, and current experimental validation.

Methods: A comprehensive literature search was carried out based on …

Overcoming Barriers To Hpv Vaccination In Pakistan: A Critical Need For A Proactive And Culturally-Sensitive Strategy, Syed Ahtisham Halim, Tirath Patel, Syeda Ramish Zehra Kazmi, Momina Khabir, Nikhilesh Anand

School of Medicine Publications

Cervical cancer continues to be one of the major causes of cancer-related mortalities among women worldwide, with a considerable share of this burden affecting developing countries like Pakistan. The addition of the HPV vaccine to the national immunization program of Pakistan had been a crucial leap toward the prevention of cervical cancer. Nevertheless, challenges that threaten the success of such a program are conspicuous. The most important ones are discussed in the letter, including the widespread dissemination of misinformation via social media on unfounded grounds, such as infertility resulting from the vaccine; deep-seated cultural taboos relating to sexual health; and …

Cleavage And Polyadenylation Specificity Factor Subunit 5 Regulates Pulmonary Artery Smooth Muscle Expansion And Hypoxic Response, Scott D Collum, Lisha Zhu, Tingting W Mills, Rene Girard, Jamie Tran, Tinne C J Mertens, Cory Wilson, Nancy Wareing, Erik E Suarez, Howard J Huang, Rahat Hussain, Bindu Akkanti, Wenjin J Zheng, Hari K Yalamanchili, Bela Patel, Eric J Wagner, Sandeep Agarwal, Harry Karmouty-Quintana

Faculty, Staff and Student Publications

Pulmonary hypertension (PH) is a fatal condition that affects individuals with systemic sclerosis (SSc), a multiorgan fibrotic disease with limited treatment options. A central feature of PH is vascular remodeling, defined by the narrowing of the arteriole lumen due to cell proliferation and extracellular matrix deposition. Herein, we identify a central mechanism that can regulate multiple transcripts important for vascular remodeling. The highlight of our study is the demonstration that reduced pulmonary artery smooth muscle (PASMC) Nudt21, which codes for the RNA binding protein Cleavage and Polyadenylation Specificity Factor Subunit 5 (CPSF5) The, known to regulate alternative polyadenylation, results …

Pair-Feeding Study Designs Can Create Biases And Inflate Type I Error Rates: A Simulation Study, Wasiuddin Najam, Daniel E Kpormegbey, Deependra K Thapa, Bret Rust, Lilian Golzarri-Arroyo, Lance H Baumgard, Louis Wai-Tong Fan, Joseph G Ibrahim, Edith J Mayorga, David B Allison

Children’s Nutrition Research Center Staff Publications

Objective: Pair-feeding is a study design element where one group's food intake is provided to another group to assess whether a treatment effect is independent of food intake. Investigators often assume equivalent food intake across experimental conditions and exclude it from the statistical analysis. However, the impact of this practice on type I error (T1Er) rates has not been quantified.

Methods: We conducted a Monte Carlo simulation in which animals were assigned baseline weights and food intakes, then randomized to non-pair-fed or pair-fed groups. Daily food intake for both groups was initially drawn from the baseline food intake distribution. For …

Life-Extending Interventions Do Not Necessarily Result In Compression Of Morbidity: A Case Example Offering A Robust Statistical Approach, Deependra K Thapa, Wasiuddin Najam, Erik S Parker, Xi Rita Wang, Daniel L Smith, Ufuk Beyaztas, James F Nelson, Steven N Austad, Gary A Churchill, David B Allison

Children’s Nutrition Research Center Staff Publications

Despite extensive research on life-extending interventions, rigorous statistical techniques to determine their impact on compression of morbidity (CoM) are rarely used. We present a case example of an analytical method for examining the effect of life-extending dietary interventions on CoM by comparing the rates of decline in vitality and survival toward the end of life. Using data from previous experimental studies in mice, we calculated the average rate of vitality decline by fitting exponential decay models to individual vitality trajectories and compared this rate with the rate of survival decline estimated from Cox proportional hazards model. The results showed that, …

Enteral And Intravenous Supplementation Of Arginine And Citrulline Fail To Prevent Necrotizing Enterocolitis In Preterm Neonatal Pigs, Caitlin Vonderohe, Julia Garcia Mancebo, Valeria Melendez Hebib, Barbara Stoll, Inka Didelija, Sarah Elefson, Mahmoud Mohammad, Brooklynn Earls, Greg Guthrie, Doug Burrin

Children’s Nutrition Research Center Staff Publications

Background: Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in preterm infants with a morality rate that approaches 50%. Arginine has been widely studied in the field of clinical nutrition as a supplement for patients experiencing critical illness because it can be metabolized into nitric oxide, an important agent for supporting immunity and microcirculation. Citrulline has received less attention but can be metabolized into arginine and has a much longer plasma half-life than arginine. We used the highly translational preterm pig model to determine the effect of intravenous and enteral supplementation of arginine and citrulline on NEC incidence in …

Circulating Metabolites, Genetics And Lifestyle Factors In Relation To Future Risk Of Type 2 Diabetes, Jun Li, Jie Hu, Huan Yun, Zhendong Mei, Xingyan Wang, Kai Luo, Marta Guasch-Ferré, Xikun Han, Buu Truong, Jordi Merino, Chengyong Jia, Miguel Ruiz-Canela, Casey M Rebholz, Eun Hye Moon, Taryn Alkis, Guning Liu, Jie Yao, Xiyuan Zhang, Bianca C Porneala, Jordi Salas-Salvadó, Thomas J Wang, Josée Dupuis, Elizabeth Selvin, Xiuqing Guo, Shilpa N Bhupathiraju, Jennifer A Brody, Yongmei Liu, Alexis C Wood, Kari E North, Su Yon Jung, Ching-Ti Liu, Nona Sotoodehnia, Simin Liu, Lesley F Tinker, A Heather Eliassen, Joann E Manson, Jose C Florez, Robert E Gerszten, Clary B Clish, Liming Liang, Rozenn N Lemaitre, Katherine L Tucker, Stephen S Rich, Jerome I Rotter, Miguel Angel Martínez-González, Kathryn M Rexrode, James B Meigs, Eric Boerwinkle, Robert C Kaplan, Frank B Hu, Bing Yu, Qibin Qi

Faculty, Staff and Student Publications

The human metabolome reflects complex metabolic states affected by genetic and environmental factors. However, metabolites associated with type 2 diabetes (T2D) risk and their determinants remain insufficiently characterized. Here we integrated blood metabolomic, genomic and lifestyle data from up to 23,634 initially T2D-free participants from ten cohorts. Of 469 metabolites examined, 235 were associated with incident T2D during up to 26 years of follow-up, including 67 associations not previously reported across bile acid, lipid, carnitine, urea cycle and arginine/proline, glycine and histidine pathways. Further genetic analyses linked these metabolites to signaling pathways and clinical traits central to T2D pathophysiology, including …

Aladdin: A Machine Learning Approach To Enhance The Prediction Of Significant Fibrosis Or Higher In Metabolic Dysfunction-Associated Steatotic Liver Disease, Naim Alkhouri, Terry Cheuk-Fung Yip, Laurent Castera, Marina Takawy, Leon A Adams, Nipun Verma, Juan Pablo Arab, Syed-Mohammed Jafri, Bihui Zhong, Julie Dubourg, Vincent L Chen, Ashwani K Singal, Luis Antonio Díaz, Nicholas Dunn, Rida Nadeem, Vincent Wai-Sun Wong, Manal F Abdelmalek, Zhengyi Wang, Ajay Duseja, Yousef Almahanna, Haya A Omeish, Junzhao Ye, Stephen A Harrison, Jessica Cristiu, Marco Arrese, Sage Robert, Grace Lai-Hung Wong, Amani Bajunayd, Congxiang Shao, Matthew Kubina, Winston Dunn

Faculty, Staff and Students Publications

Introduction: The recent US Food and Drug Administration approval of resmetirom for treating metabolic dysfunction-associated steatohepatitis in patients necessitates patient selection for significant fibrosis or higher (≥F2). No existing vibration-controlled transient elastography (VCTE) algorithm targets ≥F2.

Methods: The mAchine Learning ADvanceD fibrosis and rIsk metabolic dysfunction-associated steatohepatitis Novel predictor (ALADDIN) study addressed this gap by introducing a machine-learning-based web calculator that estimates the likelihood of significant fibrosis using routine laboratory parameters with and without VCTE. Our study included a training set of 827 patients, a testing set of 504 patients with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease from 6 centers, …

Identification Of Affinity-Optimized Peptide Binders Of A Viral Protease For Chemical Genetic Applications, Fernando Banales-Mejia, Emily M Dieter, Kyler J Radmall, Glenna W Foight, Douglas M Fowler, Dustin J Maly

Faculty, Staff and Students Publications

Chemically-controlled genetic tools are useful for studying biological systems due to their ability to dose-dependently and temporally modulate intracellular function. Chemically-disrupted proximity (CDP) systems, which involve the pre-localization of two interacting protein components that can be disrupted with a small molecule, are complementary to more commonly used chemically-inducible dimerization (CID) systems. However, fewer CDP systems have been developed, and the genetically-encoded protein components have not been as optimized for intracellular applications. Here, we describe a transcriptional activation reporter assay for screening the intracellular interaction between the 21-amino acid peptide ANR and HCVp NS3a, which are the genetically-encoded components of a …

Icosapent Ethyl Reduces Cvd Risk In Cardiovascular-Kidney-Metabolic Syndrome: Reduce-It Ckm, Michael Miller, Deepak L Bhatt, Eliot A Brinton, Terry A Jacobson, Ph Gabriel Steg, Steven B Ketchum, Armando Lira Pineda, Jean-Claude Tardif, Christie M Ballantyne

Faculty, Staff and Students Publications

Background/introduction: Cardiovascular-kidney-metabolic (CKM) syndrome was recently identified as a cardiometabolic disorder that incorporates chronic kidney disease with the metabolic syndrome (MetS). REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) was an international, double-blind, placebo-controlled trial that randomized hypertriglyceridemic (TG, 150-499 mg/dL) statin-treated patients with established cardiovascular disease (CVD) or diabetes and multiple CVD risk factors to icosapent ethyl (IPE) or placebo (4 grams/day). It is unknown if renal insufficiency added to MetS confers incremental CVD risk in secondary prevention patients without diabetes and if IPE lowers that risk.

Methods: The current study evaluated the secondary prevention patient subgroup with …

Differential Longitudinal Effects Of Glucose-Lowering Medications On Glucagon And C-Peptide Responses In The Glycemia Reduction Approaches In Diabetes: A Comparative Effectiveness Study (Grade), Steven E Kahn, Mark Tripputi, John M Lachin, Ashok Balasubramanyam, Mary Ann Banerji, Joshua Barzilay, Robert M Cohen, W Timothy Garvey, Michaela R Gramzinski, Neda Rasouli, Mary Rhee, Jesse C Seegmiller, Vatsala Singh, William I Sivitz, Michael W Steffes, Kristina Utzschneider, Ralph A Defronzo

Faculty, Staff and Students Publications

Objective: To determine the longitudinal effects on α-cell function of four classes of glucose-lowering agents added to metformin in adults with type 2 diabetes.

Research design and methods: In a multicenter, randomized study, 5,047 participants ≥30 years of age with type 2 diabetes taking 1,000-2,000 mg metformin daily, HbA1c 6.8%-8.5%, were randomized to receive insulin glargine U100, glimepiride, liraglutide, or sitagliptin. In a subset of 724 participants, baseline and longitudinal measures of α-cell function were assessed as the fasting glucagon concentration and change in glucagon from fasting to 30 min following oral glucose (glucagon index [GGI]). Whether these measures and …

Hyperglycemia, Receptor For Advanced Glycation End Products, And Small Airways Dysfunction In Asthma, Paula Sierra Salas, Dennis T Villareal, Vickram Tejwani, Amrit Koirala, Cristian Coarfa, Meredith C Mccormack, Nicola A Hanania, Tianshi David Wu

Faculty, Staff and Students Publications

Background: Diabetes and insulin resistance are associated with higher risk of asthma exacerbation and preserved ratio impaired spirometry (PRISm), but the pathophysiology is unclear. These conditions may cause small airways dysfunction (SAD), which is an under-recognized cause of PRISm.

Objective: To determine whether insulin resistance and poor glucose control associate with SAD and to explore whether proteins prognostic of diabetes end-organ complications predict lung function abnormalities.

Methods: We recruited a prospective cohort of adults with physician-diagnosed asthma. Fasting insulin, glucose, hemoglobin A1c, and concentrations of 13 proteins prognostic of diabetes end-organ complications were measured. Static insulin resistance was calculated by …

Cressent: A Bioinformatics Toolkit To Explore And Improve Ssdna Virus Annotation, Ricardo R Pavan, Matthew B Sullivan, Michael J Tisza

Faculty, Staff and Students Publications

ssDNA viruses are important components of diverse ecosystems; however, it remains challenging to systematically identify and classify them. This is partly due to their broad host range and resulting genomic diversity, structure and rapid evolutionary rates. In addition, distinguishing genuine ssDNA genomes from contaminating sequences in metagenomic datasets (e.g. from commercial kits) has been an unresolved issue for years. Here, we present CRESSENT (CRESS-DNA Extended aNnotation Toolkit), a comprehensive and modular bioinformatic pipeline focused on ssDNA virus 'genome-to-analysis' and annotation. The pipeline integrates multiple functionalities organized into several modules: sequence dereplication, decontamination, phylogenetic analysis, …

A Scalable Organoid Model Of Urothelial Aging For Metabolic Interrogation, Infection Modeling, And Reversal Of Age-Associated Changes, Adwaita R Parab, Arnold M Salazar, Steven J Bark, Margarita Divenko, Vasanta Putluri, D'Feau J Lieu, Aadya S Singh, Nagireddy Putluri, Indira U Mysorekar

Faculty, Staff and Students Publications

Aging leads to a progressive decline in overall bladder function resulting in lower urinary tract symptoms and increased susceptibility to infections. However, tissue-specific mechanisms of aging, specifically the contributions of the urothelium, remain elusive. Here, we introduce mouse bladder epithelium-derived organoids (mBEDOs) as a scalable platform to model urothelial aging. mBEDOs from aged mice recapitulate key features of age-associated cellular reprogramming, including oxidative stress, senescence, and DNA damage. We demonstrate the utility of mBEDOs for modeling Uropathogenic Escherichia coli (UPEC) infection, generating assembloids between mBEDOs and macrophages to model epithelial-immune interactions, and genetic perturbation. Using the mBEDO platform, we also …

Analysis Of Failure To Rescue In Adult Patients Who Undergo Open, Proximal Aortic Repair, Kyle W Blackburn, Joseph S Coselli, Armin Farazdaghi, Lynna Nguyen, Susan Y Green, Anna Xue, Vicente Orozco-Sevilla, Scott M Leikin, Marc R Moon, Subhasis Chatterjee

Faculty, Staff and Students Publications

Objective: Failure to rescue (FTR) is a metric of postoperative care, measuring a center's ability to prevent operative death after a surgical complication. We evaluated trends in and contributors to FTR after proximal aortic surgery at a high-volume institution.

Methods: Of 4180 patients in our single practice who underwent open proximal aortic repair from 1990 to 2024, 1304 (31.2%) had at least 1 of 4 FTR-related complications identified by the Society of Thoracic Surgeons (STS). Operative death was defined as death within 30 days of surgery or before hospital discharge or transfer. We analyzed FTR rate by specific complication, including …