Digital Commons Network^™

Hypoxia-Inducible Factor (Hif)-2Α Reprograms Liver Macrophages To Protect Against Acute Liver Injury Via The Production Of Interleukin-6, Yankai Wen, Cynthia Ju

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Acetaminophen (APAP) overdose represents the most frequent cause of acute liver failure, resulting in death or liver transplantation in more than one third of patients in the United States. The effectiveness of the only antidote, N-acetylcysteine, declines rapidly after APAP ingestion, long before patients are admitted to the clinic with symptoms of severe liver injury. The direct hepatotoxicity of APAP triggers a cascade of innate immune responses that may exacerbate or limit the progression of tissue damage. A better understanding of this complex mechanism will help uncover targets for therapeutic interventions.

APPROACH AND RESULTS: We observed that …

Role Of Micro-Rna For Pain After Surgery: Narrative Review Of Animal And Human Studies, Anil K Sood

Faculty, Staff and Student Publications

One of the most prevalent symptoms after major surgery is pain. When postoperative pain treatment is unsatisfactory, it can lead to poor surgical recovery, decreased quality of life, and increased health care costs. Current analgesics, single or in combination, have limited efficacy due to low potency, limited duration of action, toxicities, and risk of addiction. The lack of nonaddictive strong analgesics along with the over prescription of opioids has led to an opioid epidemic in the United States. Therefore, there is an urgent need for the development of newer analgesics. Microribonucleic acids (miRNAs) are small noncoding RNA molecules that modulate …

Wolff-Parkinson-White Syndrome: De Novo Variants And Evidence For Mutational Burden In Genes Associated With Atrial Fibrillation, Jaya Punetha, Bryan Cannon, Gladys Zapata, Patricia P Hernandez, Shalini Jhangiani, Harsha Doddapaneni, Jianhong Hu, Fatima Boricha, Donna M Muzny, Eric Boerwinkle, Yaping Yang, Richard A Gibbs, Jennifer E Posey, Xander H T Wehrens, John W Belmont, Jeffrey J Kim, Christina Y Miyake, James R Lupski, Seema R Lalani

Faculty, Staff and Student Publications

BACKGROUND: Wolff-Parkinson-White (WPW) syndrome is a relatively common arrhythmia affecting ~1-3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals. Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population.

METHODS: We applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, …

Decomposing Loss Aversion From Gaze Allocation And Pupil Dilation, Samuel Thelaus

Faculty, Staff and Student Publications

Loss-averse decisions, in which one avoids losses at the expense of gains, are highly prevalent. However, the underlying mechanisms remain controversial. The prevailing account highlights a valuation bias that overweighs losses relative to gains, but an alternative view stresses a response bias to avoid choices involving potential losses. Here we couple a computational process model with eye-tracking and pupillometry to develop a physiologically grounded framework for the decision process leading to accepting or rejecting gambles with equal odds of winning and losing money. Overall, loss-averse decisions were accompanied by preferential gaze toward losses and increased pupil dilation for accepting gambles. …

Vasopressor Treatment And Mortality Following Nontraumatic Subarachnoid Hemorrhage: A Nationwide Electronic Health Record Analysis, George Williams, Vahed Maroufy, Laila Rasmy, Derek Brown, Duo Yu, Yashar Talebi, Emy Thomas, Gen Zhu, Ashraf Yaseen, Hongyu Miao, Luis Leon Novelo, Degui Zhi, Stacia M Desantis, Hongjian Zhu, Jose-Miguel Yamal, David Aguilar, Hulin Wu

Faculty, Staff and Student Publications

OBJECTIVE: Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular condition, not only due to the effect of initial hemorrhage, but also due to the complication of delayed cerebral ischemia (DCI). While hypertension facilitated by vasopressors is often initiated to prevent DCI, which vasopressor is most effective in improving outcomes is not known. The objective of this study was to determine associations between initial vasopressor choice and mortality in patients with nontraumatic SAH.

METHODS: The authors conducted a retrospective cohort study using a large, national electronic medical record data set from 2000-2014 to identify patients with a new diagnosis of nontraumatic SAH …

Dietary Fat And Sugar Differentially Affect Β-Adrenergic Stimulation Of Cardiac Erk And Akt Pathways In C57bl/6 Male Mice Subjected To High-Calorie Feeding

Faculty, Staff and Student Publications

BACKGROUND: High dietary fat and sugar promote cardiac hypertrophy independently from an increase in blood pressure. The respective contribution that each macronutrient exerts on cardiac growth signaling pathways remains unclear.

OBJECTIVE: The goal of this study was to investigate the mechanisms by which high amounts of dietary fat and sugar affect cardiac growth regulatory pathways.

METHODS: Male C57BL/6 mice (9 wk old; n = 20/group) were fed a standard rodent diet (STD; kcal% protein-fat-carbohydrate, 29-17-54), a high-fat diet (HFD; 20-60-20), a high-fat and high-sugar Western diet (WD; 20-45-35), a high-sugar diet with mixed carbohydrates (HCD; 20-10-70), or a high-sucrose diet …

Dietary Fat And Sugar Differentially Affect Β-Adrenergic Stimulation Of Cardiac Erk And Akt Pathways In C57bl/6 Male Mice Subjected To High-Calorie Feeding

Faculty, Staff and Student Publications

BACKGROUND: High dietary fat and sugar promote cardiac hypertrophy independently from an increase in blood pressure. The respective contribution that each macronutrient exerts on cardiac growth signaling pathways remains unclear.

OBJECTIVE: The goal of this study was to investigate the mechanisms by which high amounts of dietary fat and sugar affect cardiac growth regulatory pathways.

METHODS: Male C57BL/6 mice (9 wk old; n = 20/group) were fed a standard rodent diet (STD; kcal% protein-fat-carbohydrate, 29-17-54), a high-fat diet (HFD; 20-60-20), a high-fat and high-sugar Western diet (WD; 20-45-35), a high-sugar diet with mixed carbohydrates (HCD; 20-10-70), or a high-sucrose diet …

Unique Case Of Anca-Negative Pauci-Immune Necrotizing Glomerulonephritis With Diffuse Alveolar Hemorrhage, Potentially Associated With Midostaurin, Jaya Kala

Faculty, Staff and Student Publications

We present a 61-year-old male with FLT3-mutated acute myeloid leukemia treated with midostaurin who developed acute kidney injury requiring hemodialysis and pulmonary renal syndrome. Antibodies to proteinase-3, myeloperoxidase, and glomerular basement membrane were negative. Renal biopsy confirmed acute pauci-immune focal necrotizing glomerulonephritis (GN) with fibrin crescents indicating rapidly progressing glomerulonephritis. He improved with pulse methylprednisolone, intravenous cyclophosphamide, and plasma exchange with resolution of hemoptysis. This case highlights the importance of prompt renal biopsy to guide early initiation of life-saving therapies. To our knowledge, this is the first reported case of ANCA-negative pauci-immune necrotizing GN likely secondary to midostaurin.

Surgical Management And Outcome Of Newly Diagnosed Glioblastoma Without Contrast Enhancement (Low-Grade Appearance): A Report Of The Rano Resect Group

Faculty, Staff and Student Publications

The palatomaxillary structure plays critical roles in both form and function of the midface. Surgical defects of the palate and maxilla can be associated with significant morbidity and deformity. Various defect classification systems have been used to assist in reconstruction and rehabilitation. Reconstructive options include prosthetic rehabilitation, local flaps, and free tissue transfer. Here, we review the functional and surgical anatomy of the palatomaxillary complex, defect classification systems, and provide an overview of reconstructive options.

Bispecific Human Il2-Ccr4 Immunotoxin Targets Human Cutaneous T-Cell Lymphoma, Ariel C Johnson, Christene A Huang, Zhirui Wang

Faculty, Staff and Student Publications

The majority of clinically diagnosed cutaneous T‐cell lymphomas (CTCL) highly express the cell‐surface markers CC chemokine receptor 4 (CCR4) and/or CD25. Recently, we have developed diphtheria toxin‐based recombinant Ontak®‐like human IL2 fusion toxin (IL2 fusion toxin) and anti‐human CCR4 immunotoxin (CCR4 IT). In this study, we first compared the efficacy of the CCR4 IT vs IL2 fusion toxin for targeting human CD25+CCR4+ CTCL. We demonstrated that CCR4 IT was more effective than IL2 fusion toxin. We further constructed an IL2‐CCR4 bispecific IT. The bispecific IT was significantly more effective than either IL2 fusion toxin or CCR4 IT alone. The bispecific …

A Validated Composite Organ And Hematologic Response Model For Early Assessment Of Treatment Outcomes In Light Chain Amyloidosis, Nidhi Tandon, Suzanne R Hayman, Francis K Buadi, Martha Q Lacy, Prashant Kapoor, Nelson Leung, S Vincent Rajkumar, Giampaolo Merlini, Giovanni Palladini, Shaji K Kumar

Faculty, Staff and Student Publications

Newly diagnosed AL amyloidosis patients were evaluated to develop a model for early assessment of treatment benefit at 6 months, integrating both hematologic (HR) and organ response (OR) assessment (testing cohort, Mayo: n = 473; validation cohort, Pavia: n = 575). Multiple OR were assessed as follows: All OR (AOR): response in all organs, mixed OR (MOR): response in some organs, no OR (NOR)]. AOR rates at 6 months improved with deepening HR; complete response (CR; 38%, 35%), very good partial response (VGPR; 30%, 26%), and partial response (PR; 16%, 21%), respectively. A composite HR/OR (CHOR) model was developed using …

On The Estimation Of The Incidence And Prevalence In Two-Phase Longitudinal Sampling Design

Faculty, Staff and Student Publications

Two-phase sampling design is a common practice in many medical studies. Generally, the first-phase classification is fallible but relatively cheap, while the accurate second phase state-of-the-art medical diagnosis is complex and rather expensive to perform. When constructed efficiently it offers great potential for higher true case detection as well as for higher precision at a limited cost. In this article, we consider epidemiological studies with two-phase sampling design. However, instead of a single two-phase study, we consider a scenario where a series of two-phase studies are done in a longitudinal fashion on a cohort of interest. Another major design issue …

Drug Deprescription-Withdrawal Risk, Prevention, And Treatment

Faculty, Staff and Student Publications

In most cases, a sudden interruption of most medications has no major consequences. There are well-recognized therapies that, when withheld, can either lead to the reappearance of the symptoms they were controlling or to signs or symptoms of withdrawal. In this article, we present a table including medications that when interrupted can produce withdrawal syndromes, the signs and symptoms of the withdrawal syndrome, the time to onset and resolution of the syndrome, information regarding alternative delivery options for the drug/s when the oral route is not possible, as well as prevention and therapy.

Pitfalls In Quantitative Myocardial Pet Perfusion I: Myocardial Partial Volume Correction, Amanda E Roby

Faculty, Staff and Student Publications

BACKGROUND: PET quantitative myocardial perfusion requires correction for partial volume loss due to one-dimensional LV wall thickness smaller than scanner resolution.

METHODS: We aimed to assess accuracy of risk stratification for death, MI, or revascularization after PET using partial volume corrections derived from two-dimensional ACR and three-dimensional NEMA phantoms for 3987 diagnostic rest-stress perfusion PETs and 187 MACE events. NEMA, ACR, and Tree phantoms were imaged with Rb-82 or F-18 for size-dependent partial volume loss. Perfusion and Coronary Flow Capacity were recalculated using different ACR- and NEMA-derived partial volume corrections compared by Kolmogorov-Smirnov statistics to standard perfusion metrics with established …

Neurochemical Characterization Of Brainstem Pro-Opiomelanocortin Cells, Oliver Marston, Giles S H Yeo, Justin J Rochford, Alastair S Garfield, Lora K Heisler

Faculty, Staff and Student Publications

Genetic research has revealed pro-opiomelanocortin (POMC) to be a fundamental regulator of energy balance and body weight in mammals. Within the brain, POMC is primarily expressed in the arcuate nucleus of the hypothalamus (ARC), while a smaller population exists in the brainstem nucleus of the solitary tract (POMCNTS). We performed a neurochemical characterization of this understudied population of POMC cells using transgenic mice expressing green fluorescent protein (eGFP) under the control of a POMC promoter/enhancer (PomceGFP). Expression of endogenous Pomc mRNA in the nucleus of the solitary tract (NTS) PomceGFP cells was confirmed using fluorescence-activating cell sorting (FACS) followed by …

Artificial Intelligence And Digital Microscopy Applications In Diagnostic Hematopathology

Faculty, Staff and Student Publications

Digital Pathology is the process of converting histology glass slides to digital images using sophisticated computerized technology to facilitate acquisition, evaluation, storage, and portability of histologic information. By its nature, digitization of analog histology data renders it amenable to analysis using deep learning/artificial intelligence (DL/AI) techniques. The application of DL/AI to digital pathology data holds promise, even if the scope of use cases and regulatory framework for deploying such applications in the clinical environment remains in the early stages. Recent studies using whole-slide images and DL/AI to detect histologic abnormalities in general and cancer in particular have shown encouraging results. …

Evidence For Gene-Smoking Interactions For Hearing Loss And Deafness In Japanese American Families, Trina M Norden-Krichmar, Karen L Edwards

Faculty, Staff and Student Publications

BACKGROUND: This study investigated the relationship between smoking and hearing loss and deafness (HLD) and whether the relationship is modified by genetic variation. Data for these analyses was from the subset of Japanese American families collected as part of the American Diabetes Association Genetics of Non-insulin Dependent Diabetes Mellitus study. Logistic regression with generalized estimating equations assessed the relationship between HLD and smoking. Nonparametric linkage analysis identified genetic regions harboring HLD susceptibility genes and ordered subset analysis was used to identify regions showing evidence for gene-smoking interactions. Genetic variants within these candidate regions were then each tested for interaction with …

Examining Measurement Reactivity In Daily Diary Data On Substance Use: Results From A Randomized Experiment, Rebecca M Cunningham

Faculty, Staff and Student Publications

The debate about whether measurement reactivity exists in daily diary research on substance use is still unsettled due to the issues of study design and statistical methodology. This study proposes a time-varying effect model (TVEM) that characterizes the trajectory of substance use behaviors with nonparametric functions determined by the data rather than imposes presumed parametric functions. It also allows researchers to investigate the effect of measurement reactivity on not only the likelihood of using substances but also the amount of substance use. The TVEM was applied to analyze diary data on alcohol and marijuana use collected from an experiment, which …

Deep Learning In Clinical Natural Language Processing: A Methodical Review, Zongcheng Ji, Yuqi Si, Sarvesh Soni, Qiong Wang, Qiang Wei, Yang Xiang, Bo Zhao, Hua Xu

Faculty, Staff and Student Publications

OBJECTIVE: This article methodically reviews the literature on deep learning (DL) for natural language processing (NLP) in the clinical domain, providing quantitative analysis to answer 3 research questions concerning methods, scope, and context of current research.

MATERIALS AND METHODS: We searched MEDLINE, EMBASE, Scopus, the Association for Computing Machinery Digital Library, and the Association for Computational Linguistics Anthology for articles using DL-based approaches to NLP problems in electronic health records. After screening 1,737 articles, we collected data on 25 variables across 212 papers.

RESULTS: DL in clinical NLP publications more than doubled each year, through 2018. Recurrent neural networks (60.8%) …

Coaction Between Physical Activity And Fruit And Vegetable Intake In Racially Diverse, Obese Adults, Harold W Kohl

Faculty, Staff and Student Publications

PURPOSE: There is minimal understanding of the potential for coaction, defined as action on one behavior increasing the likelihood of taking action on another behavior, between physical activity (PA) and fruit and vegetable (FV) intake. The purpose of this study was to assess the bidirectional coaction between FV intake and PA, as well as self-efficacy for these behaviors, in a racially diverse sample of obese adults.

DESIGN: This is a secondary analysis using data collected from the Path to Health study, a randomized controlled trial. ClinicalTrials.gov Identifier: NCT03674229.

SAMPLE: Obese adults who completed baseline and 6-month follow-up assessments.

MEASURES: For …

Fibrin Clots Maintain The Viability And Proliferative Capacity Of Human Mesenchymal Stem Cells: An In Vitro Study, Walter R Lowe

Faculty, Staff and Student Publications

BACKGROUND: Augmentation of soft-tissue repairs with an autologous fibrin clot has been used clinically for nearly four decades; however, fibrin clots tend to produce an abundance of scar tissue, which is known to inhibit soft-tissue regeneration. Mesenchymal stem cells (MSCs) embedded in fibrin clots before repair could reduce scar tissue deposition and facilitate soft-tissue regeneration. To our knowledge, no published studies have directly evaluated the viability or bioactivity of MSCs in fresh human fibrin clots over time. The purpose of this study was to evaluate the viability and bioactivity of human MSCs inside human fibrin clots over time in nutritive …

Characterization Of Urinary Concentrations Of Heavy Metals Among Socioeconomically Disadvantaged Black Pregnant Women, Pamela D Berens

Faculty, Staff and Student Publications

The objective of this study was to characterize exposures to metals using biological samples collected on socioeconomically disadvantaged black pregnant women. We obtained 131 anonymous urine samples provided by black pregnant women visiting a Medicaid-serving prenatal clinic in Houston, TX, from March 27, 2017 to April 11, 2017. We analyzed urine samples for 15 metals including cadmium (Cd), arsenic (As), lead (Pb), and nickel (Ni) and for creatinine and cotinine. We found that median concentrations of zinc (Zn), selenium (Se), and aluminum (Al) among black pregnant women in this study were 1.5 to 3 times higher than levels reported among …

Pesticides Decrease Bacterial Diversity And Abundance Of Irrigated Rice Fields, Paul J Van Den Brink

Faculty, Staff and Student Publications

Bacteria play an important role in soil ecosystems and their activities are crucial in nutrient composition and recycling. Pesticides are extensively used in agriculture to control pests and improve yield. However, increased use of pesticides on agricultural lands results in soil contamination, which could have adverse effect on its bacterial communities. Here, we investigated the effect of pesticides commonly used on irrigated rice fields on bacterial abundance and diversity. Irrigated soil samples collected from unexposed, pesticide-exposed, and residual exposure areas were cultured under aerobic and anaerobic conditions. DNA was extracted and analysed by 16S rRNA sequencing. The results showed overall …

De Novo Mutations Across 1,465 Diverse Genomes Reveal Mutational Insights And Reductions In The Amish Founder Population, Daniel Taliun, Michelle Daya, John Ziniti, Soma Datta, Juan C Celedón, Manuel E Soto-Quiros, Lydiana Avila, Scott T Weiss, Kathleen Barnes, Susan S Redline, Ramachandran S Vasan, Andrew D Johnson, Rasika A Mathias, Ryan Hernandez, James G Wilson, Deborah A Nickerson, Goncalo Abecasis, Sharon R Browning, Jeffrey R O'Connell, Braxton D Mitchell, Timothy D O'Connor

Faculty, Staff and Student Publications

De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a …

Patients' Perspectives Of Tuberculosis Treatment Challenges And Barriers To Treatment Adherence In Ukraine: A Qualitative Study, Mariya Bachmaha, Anne E Becker, Megan B Murray

Faculty, Staff and Student Publications

OBJECTIVES: To understand the challenges faced by patients with tuberculosis (TB) and factors that influence TB treatment adherence in Ukraine.

DESIGN: Qualitative study.

SETTING: TB treatment facilities in Kyiv Oblast, Ukraine.

PARTICIPANTS: Sixty adults who had undergone treatment for drug-sensitive TB between June 2012 and August 2015.

METHODS: We conducted semistructured, in-depth, individual interviews among a purposively selected clinical sample of patients previously treated for drug-sensitive TB. Interview content encompassed WHO's framework for barriers to adherence to long-term therapies and included questions about patient preferences and motivators concerning treatment adherence. We examined treatment experience across strata defined by previously identified …

Periodontal Inflammation: Integrating Genes And Dysbiosis

Faculty, Staff and Student Publications

Biofilm bacteria co-evolve and reach a symbiosis with the host on the gingival surface. The disruption of the homeostatic relationship between plaque bacteria and the host can initiate and promote periodontal disease progression. Recent advances in sequencing technologies allow researchers to profile disease-associated microbial communities and quantify microbial metabolic activities and host transcriptional responses. In addition to confirming the findings from previous studies, new putative pathogens and novel genes that have not previously been associated with periodontitis, emerge. For example, multiple studies have reported that Synergistetes bacteria are associated with periodontitis. Genes involved in epithelial barrier defense were downregulated in …

Role Of Dendritic Cell-Mediated Immune Response In Oral Homeostasis: A New Mechanism Of Osteonecrosis Of The Jaw, Carlos Isales, Mohammed E Elsalanty

Faculty, Staff and Student Publications

Dendritic cells are an important link between innate and adaptive immune response. The role of dendritic cells in bone homeostasis, however, is not understood. Osteoporosis medications that inhibit osteoclasts have been associated with osteonecrosis, a condition limited to the jawbone, thus called medication-related osteonecrosis of the jaw. We propose that disruption of the local immune response renders the oral microenvironment conducive to osteonecrosis. We tested whether zoledronate (Zol) treatment impaired dendritic cell (DC) functions and increased bacterial load in alveolar bone in vivo and whether DC inhibition alone predisposed the animals to osteonecrosis. We also analyzed the role of Zol …

Everolimus-Induced Pneumonitis: A Diagnostic Challenge

Faculty, Staff and Student Publications

No abstract provided.

Ablation Of Refractory Papillary Muscle Ventricular Tachycardia Warranting Multiple Adjunctive Ablation Techniques: A Combined Approach For Success, Nilesh Mathuria

Faculty, Staff and Student Publications

A 27-year-old male presented to our institution with recurrent unifocal premature ventricular contraction/nonsustained ventricular tachycardia (VT) with associated cardiomyopathy. The patient had undergone three prior ablation procedures with continued arrhythmia. Mapping led to identification of the VT arising from the basal aspect of the left ventricular anterolateral papillary muscle. Conventional ablation techniques were unsuccessful. We incorporated adjunctive ablation techniques in this case that ultimately led to a successful outcome. The present discussion covers the roles of intracardiac echocardiography, induced apnea, and low-ionic irrigation.

Diagnostic Criteria For Detection Of Retinal Nerve Fibre Layer Thickness And Neuroretinal Rim Width Abnormalities In Glaucoma

Faculty, Staff and Student Publications

BACKGROUND/AIMS: Although measurements of the Bruch's membrane opening minimum rim width (BMO-MRW) and retinal nerve fibre layer thickness (RNFLT) with optical coherence tomography (OCT) have been widely adopted in the diagnostic evaluation of glaucoma, there is no consensus on the diagnostic criteria to define BMO-MRW and RNFLT abnormalities. This study investigated the sensitivities and specificities of different diagnostic criteria based on the OCT classification reports for detection of glaucoma.

METHODS: 340 eyes of 137 patients with glaucoma and 87 healthy individuals, all with axial length ≤26mm, had global and sectoral BMO-MRW and RNFLT measured with Spectralis OCT (Heidelberg Engineering). Six …