Medical Specialties Commons^™

Integrative Genomic Analysis Reveals Low T-Cell Infiltration As The Primary Feature Of Tobacco Use In Hpv-Positive Oropharyngeal Cancer, Benjamin M Wahle, Paul Zolkind, Ricardo J Ramirez, Zachary L Skidmore, Sydney R Anderson, Angela Mazul, D Neil Hayes, Vlad C Sandulache, Wade L Thorstad, Douglas Adkins, Obi L Griffith, Malachi Griffith, Jose P Zevallos

Faculty, Staff and Students Publications

Although tobacco use is an independent adverse prognostic feature in HPV(+) oropharyngeal squamous cell carcinoma (OPSCC), the biologic features associated with tobacco use have not been systematically investigated. We characterized genomic and immunologic features associated with tobacco use through whole exome sequencing, mRNA hybridization, and immunohistochemical staining in 47 HPV(+) OPSCC tumors. Low expression of transcripts in a T cell-inflamed gene expression profile (TGEP) was associated with tobacco use at diagnosis and lower overall and disease-free survival. Tobacco use was associated with an increased proportion of T > C substitutions and a lower proportion of expected mutational signatures, but not with …

Alterations Of The Gut Microbial Community Structure And Function With Aging In The Spontaneously Hypertensive Stroke Prone Rat, Huanan Shi, James W Nelson, Sharon Phillips, Joseph F Petrosino, Robert M Bryan, David J Durgan

Faculty, Staff and Students Publications

Gut dysbiosis, a pathological imbalance of bacteria, has been shown to contribute to the development of hypertension (HT), systemic- and neuro-inflammation, and blood-brain barrier (BBB) disruption in spontaneously hypertensive stroke prone rats (SHRSP). However, to date individual species that contribute to HT in the SHRSP model have not been identified. One potential reason, is that nearly all studies of the SHRSP gut microbiota have analyzed samples from rats with established HT. The goal of this study was to examine the SHRSP gut microbiota before, during, and after the onset of hypertension, and in normotensive WKY control rats over the same …

Rapid Molecular Diagnostics Of Tuberculosis Resistance By Targeted Stool Sequencing, Doctor B Sibandze, Alexander Kay, Viola Dreyer, Welile Sikhondze, Qiniso Dlamini, Andrew Dinardo, Godwin Mtetwa, Bhekumusa Lukhele, Debrah Vambe, Christoph Lange, Muyalo Glenn Dlamini, Tara Ness, Rojelio Mejia, Barbara Kalsdorf, Jan Heyckendorf, Martin Kuhns, Florian P Maurer, Sindisiwe Dlamini, Gugu Maphalala, Stefan Niemann, Anna Mandalakas

Faculty, Staff and Students Publications

BACKGROUND: Stool is an important diagnostic specimen for tuberculosis in populations who struggle to provide sputum, such as children or people living with HIV. However, the culture of Mycobacterium tuberculosis (M. tuberculosis) complex strains from stool perform poorly. This limits the opportunity for phenotypic drug resistance testing with this specimen. Therefore, reliable molecular methods are urgently needed for comprehensive drug resistance testing on stool specimens.

METHODS: We evaluated the performance of targeted next-generation sequencing (tNGS, Deeplex® Myc-TB) for the detection of mutations associated with M. tuberculosis complex drug resistance on DNA isolated from stool specimens provided by participants from a …

The Emotional Impact Of Urinary Tract Infections In Women: A Qualitative Analysis, Larissa Grigoryan, Aruni Mulgirigama, Marcy Powell, Guido Schmiemann

Faculty, Staff and Students Publications

BACKGROUND: While many studies address the clinical management of participants with uncomplicated urinary tract infection (uUTI), the emotional impact of uUTIs has been investigated less often. The aim of this qualitative study was to understand the emotional experience of women with uUTIs.

METHODS: This was a qualitative, exploratory, in-depth interview-based study conducted among women in the United States (US) and Germany. Women aged ≥ 18 years with at least one uUTI treated with antibiotics in the past year were recruited through a patient community panel and physician referrals. Participants were recruited using purposive sampling to include an equal split of …

Systematic Expression Profiling Of Dpr And Dip Genes Reveals Cell Surface Codes In Drosophila Larval Motor And Sensory Neurons, Yupu Wang, Meike Lobb-Rabe, James Ashley, Purujit Chatterjee, Veera Anand, Hugo J Bellen, Oguz Kanca, Robert A Carrillo

Faculty, Staff and Students Publications

In complex nervous systems, neurons must identify their correct partners to form synaptic connections. The prevailing model to ensure correct recognition posits that cell-surface proteins (CSPs) in individual neurons act as identification tags. Thus, knowing what cells express which CSPs would provide insights into neural development, synaptic connectivity, and nervous system evolution. Here, we investigated expression of Dpr and DIP genes, two CSP subfamilies belonging to the immunoglobulin superfamily, in Drosophila larval motor neurons (MNs), muscles, glia and sensory neurons (SNs) using a collection of GAL4 driver lines. We found that Dpr genes are more broadly expressed than DIP genes …

Global Community Of Practice: A Means For Capacity And Community Strengthening For Health Professionals In Low- And Middle-Income Countries, Allison Silverstein, Amy Benson, Catriona Gates, Diane Nguyen

Faculty, Staff and Students Publications

BACKGROUND: Low- and middle-income countries face distinct challenges in providing health care services and training. The community of practice (CoP) has been described as a method of facilitating much-needed connections and conversations on this topic and has been adapted over time to include virtual CoPs. We describe the development and evaluation of a global Clinical Lead Forum (CLF) using a CoP framework to structure informal continuing professional development (CPD) and enhance the capacity of health care professionals in low- and middle-income countries.

METHODS: Baylor College of Medicine International Pediatric AIDS Initiative (BIPAI) and its network of affiliated, independent non-governmental organizations …

Treatment For Mild Chronic Hypertension During Pregnancy, Alan T Tita, Jeff M Szychowski, Kim Boggess, Lorraine Dugoff, Baha Sibai, Kirsten Lawrence, Brenna L Hughes, Joseph Bell, Kjersti Aagaard, Rodney K Edwards, Kelly Gibson, David M Haas, Lauren Plante, Torri Metz, Brian Casey, Sean Esplin, Sherri Longo, Matthew Hoffman, George R Saade, Kara K Hoppe, Janelle Foroutan, Methodius Tuuli, Michelle Y Owens, Hyagriv N Simhan, Heather Frey, Todd Rosen, Anna Palatnik, Susan Baker, Phyllis August, Uma M Reddy, Wendy Kinzler, Emily Su, Iris Krishna, Nicki Nguyen, Mary E Norton, Daniel Skupski, Yasser Y El-Sayed, Dotum Ogunyemi, Zorina S Galis, Lorie Harper, Namasivayam Ambalavanan, Nancy L Geller, Suzanne Oparil, Gary R Cutter, William W Andrews

Faculty, Staff and Students Publications

BACKGROUND: The benefits and safety of the treatment of mild chronic hypertension (blood pressure, <160/100 mm Hg) during pregnancy are uncertain. Data are needed on whether a strategy of targeting a blood pressure of less than 140/90 mm Hg reduces the incidence of adverse pregnancy outcomes without compromising fetal growth.

METHODS: In this open-label, multicenter, randomized trial, we assigned pregnant women with mild chronic hypertension and singleton fetuses at a gestational age of less than 23 weeks to receive antihypertensive medications recommended for use in pregnancy (active-treatment group) or to receive no such treatment unless severe hypertension (systolic pressure, ≥160 mm Hg; or diastolic pressure, ≥105 mm Hg) developed (control group). The primary outcome was a composite of preeclampsia with severe features, medically indicated preterm birth at less than 35 weeks' gestation, placental abruption, or fetal …

Concerted Type I Interferon Signaling In Microglia And Neural Cells Promotes Memory Impairment Associated With Amyloid Β Plaques, Ethan R Roy, Gabriel Chiu, Sanming Li, Nicholas E Propson, Rupa Kanchi, Baiping Wang, Cristian Coarfa, Hui Zheng, Wei Cao

Faculty, Staff and Students Publications

The principal signals that drive memory and cognitive impairment in Alzheimer's disease (AD) remain elusive. Here, we revealed brain-wide cellular reactions to type I interferon (IFN-I), an innate immune cytokine aberrantly elicited by amyloid β plaques, and examined their role in cognition and neuropathology relevant to AD in a murine amyloidosis model. Using a fate-mapping reporter system to track cellular responses to IFN-I, we detected robust, Aβ-pathology-dependent IFN-I activation in microglia and other cell types. Long-term blockade of IFN-I receptor (IFNAR) rescued both memory and synaptic deficits and resulted in reduced microgliosis, inflammation, and neuritic pathology. Microglia-specific Ifnar1 deletion attenuated …

Evaluation Of Heat Inactivation Of Human Norovirus In Freshwater Clams Using Human Intestinal Enteroids, Tsuyoshi Hayashi, Yoko Yamaoka, Atsushi Ito, Takashi Kamaishi, Ryuichi Sugiyama, Mary K Estes, Masamichi Muramatsu, Kosuke Murakami

Faculty, Staff and Students Publications

Foodborne disease attributed to the consumption of shellfish contaminated with human norovirus (HuNoV) is one of many global health concerns. Our study aimed to determine the conditions of the heat-inactivation of HuNoV in freshwater clams (Corbicula japonica) using a recently developed HuNoV cultivation system employing stem-cell derived human intestinal enteroids (HIEs). We first measured the internal temperature of the clam tissue in a water bath during boiling at 90 °C and found that approximately 2 min are required for the tissue to reach 90 °C. Next, GII.4 HuNoV was spiked into the center of the clam tissue, followed …

The Ep300/Tp53 Pathway, A Suppressor Of The Hippo And Canonical Wnt Pathways, Is Activated In Human Hearts With Arrhythmogenic Cardiomyopathy In The Absence Of Overt Heart Failure, Leila Rouhi, Siyang Fan, Sirisha M Cheedipudi, Aitana Braza-Boïls, Maria Sabater Molina, Yan Yao, Matthew J Robertson, Cristian Coarfa, Juan R Gimeno, Pilar Molina, Priyatansh Gurha, Esther Zorio, Ali J Marian

Faculty, Staff and Students Publications

AIMS: Arrhythmogenic cardiomyopathy (ACM) is a primary myocardial disease that typically manifests with cardiac arrhythmias, progressive heart failure, and sudden cardiac death (SCD). ACM is mainly caused by mutations in genes encoding desmosome proteins. Desmosomes are cell-cell adhesion structures and hubs for mechanosensing and mechanotransduction. The objective was to identify the dysregulated molecular and biological pathways in human ACM in the absence of overt heart failure.

METHODS AND RESULTS: Transcriptomes in the right ventricular endomyocardial biopsy samples from three independent individuals carrying truncating mutations in the DSP gene and five control samples were analysed by RNA-Seq (discovery group). These cases …

Burden Of Cardiovascular Risk Factors And Disease In Five Asian Groups In Catalonia: A Disaggregated, Population-Based Analysis Of 121 000 First-Generation Asian Immigrants, Priyanka Satish, Emili Vela, Usama Bilal, Montse Cleries, Alka M Kanaya, Namratha Kandula, Salim S Virani, Nadia Islam, Javier Valero-Elizondo, Tamer Yahya, Josep Comin-Colet, Khurram Nasir, Josepa Mauri, Miguel Cainzos-Achirica

Faculty, Staff and Students Publications

AIMS: To evaluate the burden of cardiovascular risk factors and disease (CVD) among five Asian groups living in Catalonia (Spain): Indian, Pakistani, Bangladeshi, Filipino, and Chinese.

METHODS AND RESULTS: Retrospective cohort study using the Catalan Health Surveillance System database including 42 488 Pakistanis, 40 745 Chinese, 21 705 Indians, 9544 Filipinos, and 6907 Bangladeshis; and 5.3 million native individuals ('locals'). We estimated the age-adjusted prevalence (as of 31 December 2019) and incidence (during 2019) of diabetes, hypertension, hyperlipidaemia, obesity, tobacco use, coronary heart disease (CHD), cerebrovascular disease, atrial fibrillation, and heart failure (HF). Bangladeshis had the highest prevalence of diabetes …

Intraovarian, Isoform-Specific Transcriptional Roles Of Progesterone Receptor In Ovulation, Kirsten M Smith, Doan T Dinh, Lisa K Akison, Matilda Nicholls, Kylie R Dunning, Atsushi Morimoto, John P Lydon, Darryl L Russell, Rebecca L Robker

Faculty, Staff and Students Publications

Progesterone receptor (PGR) activity is obligatory for mammalian ovulation; however, there is no established direct functional pathway explaining how progesterone receptor completely and specifically regulates oocyte release. This study examined the overarching cell- and isoform-specific effects of the PGR within each cellular compartment of the ovary, using mice null for the PGR (PRKO), as well as isoform-specific null mice. The PGR was expressed in ovarian granulosa and stromal cells and although PRKO ovaries showed no visible histological changes in preovulatory ovarian morphology, follicle rupture did not occur. Reciprocal ovarian transplant experiments established the necessity of ovarian PGR expression for ovulation. …

Novel Fold Of Rotavirus Glycan-Binding Domain Predicted By Alphafold2 And Determined By X-Ray Crystallography, Liya Hu, Wilhelm Salmen, Banumathi Sankaran, Yi Lasanajak, David F Smith, Sue E Crawford, Mary K Estes, B V Venkataram Prasad

Faculty, Staff and Students Publications

The VP8* domain of spike protein VP4 in group A and C rotaviruses, which cause epidemic gastroenteritis in children, exhibits a conserved galectin-like fold for recognizing glycans during cell entry. In group B rotavirus, which causes significant diarrheal outbreaks in adults, the VP8* domain (VP8*B) surprisingly lacks sequence similarity with VP8* of group A or group C rotavirus. Here, by using the recently developed AlphaFold2 for ab initio structure prediction and validating the predicted model by determining a 1.3-Å crystal structure, we show that VP8*B exhibits a novel fold distinct from the galectin fold. This fold with a β-sheet clasping …

Systems Biology Approach To Functionally Assess The Clostridioides Difficile Pangenome Reveals Genetic Diversity With Discriminatory Power, Charles J Norsigian, Heather A Danhof, Colleen K Brand, Firas S Midani, Jared T Broddrick, Tor C Savidge, Robert A Britton, Bernhard O Palsson, Jennifer K Spinler, Jonathan M Monk

Faculty, Staff and Students Publications

Combatting Clostridioides difficile infections, a dominant cause of hospital-associated infections with incidence and resulting deaths increasing worldwide, is complicated by the frequent emergence of new virulent strains. Here, we employ whole-genome sequencing, high-throughput phenotypic screenings, and genome-scale models of metabolism to evaluate the genetic diversity of 451 strains of C. difficile. Constructing the C. difficile pangenome based on this set revealed 9,924 distinct gene clusters, of which 2,899 (29%) are defined as core, 2,968 (30%) are defined as unique, and the remaining 4,057 (41%) are defined as accessory. We develop a strain typing method, sequence typing by accessory genome (STAG), …

Association Of Physical Activity, Sports, And Screen Time With Adolescent Behaviors In Youth Who Visit The Pediatric Emergency Department, Rohit P Shenoi, James G Linakis, Julie R Bromberg, T Charles Casper, Rachel Richards, Thomas H Chun, Victor M Gonzalez, Michael J Mello, Anthony Spirito

Faculty, Staff and Students Publications

Moderate to vigorous physical activity (MVPA), sports, and reduced screen time are associated with favorable youth risk profiles. We evaluated the association of MVPA, sports, and screen time with adolescent behaviors among pediatric emergency department youth. Adolescents were assessed for alcohol/drug use, risky behavior, conduct disorder, and depressive mood. MVPA was activity for ≥5 days/week and ≥60 minutes/day. Increased screen time was ≥3 hours/day computer/TV use for non-schoolwork. Multivariable regression studied association between MVPA, sports, and increased screen time and outcomes adjusting for demographics and academic achievement. Older age and lower academic achievement were significantly associated with risky behaviors, conduct …

Sirolimus (Rapamycin) Induced Mucosal Healing In Anti-Tumor Necrosis Factor Refractory Pediatric Ulcerative Colitis, Richard Kellermayer, Andrew Chang, Kalyani Patel

Faculty, Staff and Students Publications

Sirolimus (rapamycin) has been sparsely reported in the treatment of pediatric ulcerative colitis (PUC). Mucosal healing has not been examined in responders to the drug. We describe a case of infliximab refractory PUC where rapamycin induced sustained clinical remission along with mucosal healing. We conclude that rapamycin should be positioned into the expanding treatment repertoire of PUC.

Prevalence And Clinical Correlates Of Antinuclear Antibody In Patients With Gastroparesis, Henry P Parkman, Mark L Van Natta, Ashima Makol, Madhusudan Grover, Richard W Mccallum, Zubair Malik, Kenneth L Koch, Irene Sarosiek, Braden Kuo, Robert J Shulman, Gianrico Farrugia, Laura Miriel, James Tonascia, Frank Hamilton, Pankaj J Pasricha, Thomas L Abell, Niddk Gastroparesis Clinical Research Consortium

Faculty, Staff and Students Publications

BACKGROUND: Autoimmunity may play a role in the pathogenesis of gastroparesis in a subset of patients. Antinuclear antibody (ANA) testing is often used to screen for autoimmune disorders.

AIMS: 1) Determine prevalence of a positive ANA in patients with gastroparesis; 2) Describe characteristics of idiopathic gastroparesis patients with positive ANA.

METHODS: Patients were assessed with gastric emptying scintigraphy (GES), symptom assessment via Patient Assessment of Upper GI Symptoms [PAGI-SYM], and blood tests-ANA, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP).

RESULTS: Positive ANA was seen in 148 of 893 (17%) patients with gastroparesis, being similar in idiopathic (16% of 536 patients), …

Phgdh Heterogeneity Potentiates Cancer Cell Dissemination And Metastasis, Matteo Rossi, Patricia Altea-Manzano, Margherita Demicco, Ginevra Doglioni, Laura Bornes, Marina Fukano, Anke Vandekeere, Alejandro M Cuadros, Juan Fernández-García, Carla Riera-Domingo, Cristina Jauset, Mélanie Planque, H Furkan Alkan, David Nittner, Dongmei Zuo, Lindsay A Broadfield, Sweta Parik, Antonino Alejandro Pane, Francesca Rizzollo, Gianmarco Rinaldi, Tao Zhang, Shao Thing Teoh, Arin B Aurora, Panagiotis Karras, Ines Vermeire, Dorien Broekaert, Joke Van Elsen, Maximilian M L Knott, Martin F Orth, Sofie Demeyer, Guy Eelen, Lacey E Dobrolecki, Ayse Bassez, Thomas Van Brussel, Karl Sotlar, Michael T Lewis, Harald Bartsch, Manfred Wuhrer, Peter Van Veelen, Peter Carmeliet, Jan Cools, Sean J Morrison, Jean-Christophe Marine, Diether Lambrechts, Massimiliano Mazzone, Gregory J Hannon, Sophia Y Lunt, Thomas G P Grünewald, Morag Park, Jacco Van Rheenen, Sarah-Maria Fendt

Faculty, Staff and Students Publications

Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs1. Genetic, transcriptional and translational heterogeneity contributes to this dynamic process2,3. Metabolic heterogeneity has also been observed4, yet its role in cancer progression is less explored. Here, we discover that loss of phosphoglycerate dehydrogenase (PHGDH) potentiates metastatic dissemination. Specifically, we find that heterogeneous or low PHGDH expression in primary tumors of breast cancer patients is associated with decreased metastasis free survival time. In mice, circulating tumor cells and early metastatic lesions are enriched with PHGDH low cancer …

Primer For Development Of Guidelines For Helicobacter Pylori Therapy Using Antimicrobial Stewardship, David Y Graham, Jyh-Ming Liou

Faculty, Staff and Students Publications

We provide a primer to assist in the difficult transition of Helicobacter pylori therapy guidelines to those that adhere to the principles of antimicrobial stewardship. This transition will entail abandonment of many of the principles that heretofore formed the basis of treatment guidelines and recommendations. The goals of antimicrobial stewardship include optimization of the use of antibiotics while reducing antimicrobial resistance. The critical outcome measure is absolute cure rate which largely restricts comparative trials to those which reliably produce high cure rates (eg, ∼95%). Therapies that fail to achieve at least a 90% cure rate should be abandoned as unacceptable. …

Curated Variation Benchmarks For Challenging Medically Relevant Autosomal Genes, Justin Wagner, Nathan D Olson, Lindsay Harris, Jennifer Mcdaniel, Haoyu Cheng, Arkarachai Fungtammasan, Yih-Chii Hwang, Richa Gupta, Aaron M Wenger, William J Rowell, Ziad M Khan, Jesse Farek, Yiming Zhu, Aishwarya Pisupati, Medhat Mahmoud, Chunlin Xiao, Byunggil Yoo, Sayed Mohammad Ebrahim Sahraeian, Danny E Miller, David Jáspez, José M Lorenzo-Salazar, Adrián Muñoz-Barrera, Luis A Rubio-Rodríguez, Carlos Flores, Giuseppe Narzisi, Uday Shanker Evani, Wayne E Clarke, Joyce Lee, Christopher E Mason, Stephen E Lincoln, Karen H Miga, Mark T W Ebbert, Alaina Shumate, Heng Li, Chen-Shan Chin, Justin M Zook, Fritz J Sedlazeck

Faculty, Staff and Students Publications

The repetitive nature and complexity of some medically relevant genes poses a challenge for their accurate analysis in a clinical setting. The Genome in a Bottle Consortium has provided variant benchmark sets, but these exclude nearly 400 medically relevant genes due to their repetitiveness or polymorphic complexity. Here, we characterize 273 of these 395 challenging autosomal genes using a haplotype-resolved whole-genome assembly. This curated benchmark reports over 17,000 single-nucleotide variations, 3,600 insertions and deletions and 200 structural variations each for human genome reference GRCh37 and GRCh38 across HG002. We show that false duplications in either GRCh37 or GRCh38 result in …

Developing And Optimizing A Computable Phenotype For Incident Venous Thromboembolism In A Longitudinal Cohort Of Patients With Cancer, Ang Li, Wilson L Da Costa, Danielle Guffey, Emily M Milner, Anthony K Allam, Karen M Kurian, Francisco J Novoa, Marguerite D Poche, Raka Bandyo, Carolina Granada, Courtney D Wallace, Neil A Zakai, Christopher I Amos

Faculty, Staff and Students Publications

BACKGROUND: Research on venous thromboembolism (VTE) that relies only on the International Classification of Diseases (ICD) can misclassify outcomes. Our study aims to discover and validate an improved VTE computable phenotype for people with cancer.

METHODS: We used a cancer registry electronic health record (EHR)-linked longitudinal database. We derived three algorithms that were ICD/medication based, natural language processing (NLP) based, or all combined. We then randomly sampled 400 patients from patients with VTE codes (n = 1111) and 400 from those without VTE codes (n = 7396). Weighted sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were …

Mitochondrial Sirtuin-3 (Sirt3) Prevents Doxorubicin-Induced Dilated Cardiomyopathy By Modulating Protein Acetylation And Oxidative Stress, Mateusz M Tomczyk, Kyle G Cheung, Bo Xiang, Nahid Tamanna, Ana L Fonseca Teixeira, Prasoon Agarwal, Stephanie M Kereliuk, Victor Spicer, Ligen Lin, Jason Treberg, Qiang Tong, Vernon W Dolinsky

Faculty, Staff and Students Publications

BACKGROUND: High doses of doxorubicin put cancer patients at risk for developing dilated cardiomyopathy. Previously, we showed that doxorubicin treatment decreases SIRT3 (sirtuin 3), the main mitochondrial deacetylase and increases protein acetylation in rat cardiomyocytes. Here, we hypothesize that SIRT3 expression can attenuate doxorubicin induced dilated cardiomyopathy in vivo by preventing the acetylation of mitochondrial proteins.

METHODS: Nontransgenic, M3-SIRT3 (truncated SIRT3; short isoform), and M1-SIRT3 (full-length SIRT3; mitochondrial localized) transgenic mice were treated with doxorubicin for 4 weeks (8 mg/kg body weight per week). Echocardiography was performed to assess cardiac structure and function and validated by immunohistochemistry and immunofluorescence (n=4-10). …

Contemporary Biomarker Strategies For Patients With Chest Pain, Stephen Boone, W Frank Peacock

Faculty, Staff and Students Publications

This review focuses on the strengths and limitations of conventional and high-sensitivity troponin in the evaluation of patients with suspected acute coronary syndromes. High-sensitivity troponin (hsTn) assays represent a significant innovation over prior generation troponin assays. Owing to superior analytical precision, hsTn permits more rapid "rule-in" and "rule-out" of myocardial infarction. Furthermore, hsTn assays, in properly implemented clinical pathways, permit a reduction in the portion of patients requiring extended observation and testing.

The Disordered N-Terminal Domain Of Dnmt3a Recognizes H2ak119ub And Is Required For Postnatal Development, Tianpeng Gu, Dapeng Hao, Junsung Woo, Teng-Wei Huang, Lei Guo, Xueqiu Lin, Anna G Guzman, Ayala Tovy, Carina Rosas, Mira Jeong, Yubin Zhou, Benjamin Deneen, Yun Huang, Wei Li, Margaret A Goodell

Faculty, Staff and Students Publications

DNA methyltransferase 3a (DNMT3A) plays a crucial role during mammalian development. Two isoforms of DNMT3A are differentially expressed from stem cells to somatic tissues, but their individual functions remain largely uncharacterized. Here we report that the long isoform DNMT3A1, but not the short DNMT3A2, is essential for mouse postnatal development. DNMT3A1 binds to and regulates bivalent neurodevelopmental genes in the brain. Strikingly, Dnmt3a1 knockout perinatal lethality could be partially rescued by DNMT3A1 restoration in the nervous system. We further show that the intrinsically disordered N terminus of DNMT3A1 is required for normal development and DNA methylation at DNMT3A1-enriched regions. Mechanistically, …

Risk Factors For Early Symptomatic Femoroacetabular Impingement Following In Situ Fixation Of Slipped Capital Femoral Epiphysis, Melissa M Allen, Ramesh B Ghanta, Matthew Lahey, Scott B Rosenfeld

Faculty, Staff and Students Publications

In situ fixation of slipped capital femoral epiphysis (SCFE) results in residual deformity that can cause femoroacetabular impingement (FAI). It is unknown what factors could help differentiate patients who are more likely to become symptomatic. We performed a retrospective review of 55 hips treated with in situ pinning for SCFE and subsequent secondary deformity correction procedure for symptomatic FAI and compared them to 39 asymptomatic hips with SCFE deformity using multivariable analysis. Case patients were slightly older than controls (12.6 vs 11.3 years, p = 0.0002) but had similar BMI. The mean epiphyseal-diaphyseal angle was 56° in cases versus 44° …

Tocilizumab In Patients Hospitalised With Covid-19 Pneumonia: Efficacy, Safety, Viral Clearance, And Antibody Response From A Randomised Controlled Trial (Covacta), Ivan O Rosas, Norbert Bräu, Michael Waters, Ronaldo C Go, Atul Malhotra, Bradley D Hunter, Sanjay Bhagani, Daniel Skiest, Sinisa Savic, Ivor S Douglas, Julia Garcia-Diaz, Mariam S Aziz, Nichola Cooper, Taryn Youngstein, Lorenzo Del Sorbo, David J De La Zerda, Andrew Ustianowski, Antonio Cubillo Gracian, Kevin G Blyth, Jordi Carratalà, Bruno François, Thomas Benfield, Derrick Haslem, Paolo Bonfanti, Cor H Van Der Leest, Nidhi Rohatgi, Lothar Wiese, Charles Edouard Luyt, Rebecca N Bauer, Fang Cai, Ivan T Lee, Balpreet Matharu, Louis Metcalf, Steffen Wildum, Emily Graham, Larry Tsai, Min Bao

Faculty, Staff and Students Publications

BACKGROUND: In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated.

METHODS: Adults in Europe and North America hospitalised with COVID-19 (

FINDINGS: By day 60, 24·5% (72/294) of patients in the tocilizumab arm and 25·0% (36/144) in the placebo arm died (weighted …

Berberine Remodels Adipose Tissue To Attenuate Metabolic Disorders By Activating Sirtuin 3, Dan Li, Chao Yang, Jian-Zhong Zhu, Eduardo Lopez, Tian Zhang, Qiang Tong, Cheng Peng, Li-Gen Lin

Faculty, Staff and Students Publications

Adipose tissue remodelling is considered a critical pathophysiological hallmark of obesity and related metabolic diseases. Berberine (BBR), a natural isoquinoline alkaloid, has potent anti-hyperlipidaemic and anti-hyperglycaemic effects. This study aimed to explore the role of BBR in modulating adipose tissue remodelling and the underlying mechanisms. BBR protected high fat diet (HFD)-fed mice against adiposity, insulin resistance and hyperlipidemia. BBR alleviated adipose tissue inflammation and fibrosis by inhibiting macrophage infiltration, pro-inflammatory macrophage polarization and the abnormal deposition of extracellular matrix, and the effect was mediated by BBR directly binding and activating the deacetylase Sirtuin 3 (SIRT3) and suppressing the activation of …

A D2 To D1 Shift In Dopaminergic Inputs To Midbrain 5-Ht Neurons Causes Anorexia In Mice, Xing Cai, Hailan Liu, Bing Feng, Meng Yu, Yang He, Hesong Liu, Chen Liang, Yongjie Yang, Longlong Tu, Nan Zhang, Lina Wang, Na Yin, Junying Han, Zili Yan, Chunmei Wang, Pingwen Xu, Qi Wu, Qingchun Tong, Yanlin He, Yong Xu

Faculty, Staff and Students Publications

Midbrain dopamine (DA) and serotonin (5-HT) neurons regulate motivated behaviors, including feeding, but less is known about how these circuits may interact. In this study, we found that DA neurons in the mouse ventral tegmental area bidirectionally regulate the activity of 5-HT neurons in the dorsal raphe nucleus (DRN), with weaker stimulation causing DRD2-dependent inhibition and overeating, while stronger stimulation causing DRD1-dependent activation and anorexia. Furthermore, in the activity-based anorexia (ABA) paradigm, which is a mouse model mimicking some clinical features of human anorexia nervosa (AN), we observed a DRD2 to DRD1 shift of DA neurotransmission on 5-HT

Health-Related Quality Of Life In Pediatric Acute Recurrent Or Chronic Pancreatitis: Association With Biopsychosocial Risk Factors, See Wan Tham, Fuchenchu Wang, Cheryl E Gariepy, Gretchen A Cress, Maisam A Abu-El-Haija, Melena D Bellin, Kate M Ellery, Douglas S Fishman, Tanja Gonska, Melvin B Heyman, Tom K Lin, Asim Maqbool, Brian A Mcferron, Veronique D Morinville, Jaimie D Nathan, Chee Y Ooi, Emily R Perito, Sarah Jane Schwarzenberg, Zachary M Sellers, Uzma Shah, David M Troendle, Michael Wilschanski, Yuhua Zheng, Ying Yuan, Mark E Lowe, Aliye Uc, Tonya M Palermo, International Study Group Of Pediatric Pancreatitis: In Search For A Cure (Insppire) And Consortium For The Study Of Chronic Pancreatitis, Diabetes And Pancreatic Cancer (Cpdpc)

Faculty, Staff and Students Publications

OBJECTIVES: Abdominal pain, emergency department visits, and hospitalizations impact lives of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). Data on health-related quality of life (HRQOL) in this population, however, remains limited. We aimed to evaluate HRQOL in children with ARP or CP; and test biopsychosocial risk factors associated with low HRQOL.

METHODS: Data were acquired from the INternational Study Group of Pediatric Pancreatitis: In search for a cuRE registry. Baseline demographic and clinical questionnaires, the Child Health Questionnaire (measures HRQOL) and Child Behavior Checklist (measures emotional and behavioral functioning) were completed at enrollment.

RESULTS: The sample included …

A Retrospective Study Of Canine Transmissible Venereal Tumour In Grenada, West Indies, Sara J Schectman, Afroza Khanam, Mellisa N D Walters, Elliot Kirwan, Wayne R Sylvester, Firdous A Khan

Faculty, Staff and Students Publications

BACKGROUND: Canine transmissible venereal tumour (CTVT) is a naturally occurring neoplasia affecting dogs worldwide. Previous CTVT studies in Grenada were limited to case records of dogs with neoplastic conditions at a veterinary diagnostic laboratory.

OBJECTIVES: The present retrospective study aimed to determine the occurrence and risk factors of CTVT in a wider population of owned dogs presented to a university-affiliated veterinary hospital between 2008 and 2018.

METHODS: Data on the age, breed, gender, and gonadectomy status were retrieved from an electronic database and analyzed using logistic regression.

RESULTS: Of the 7180 dogs presented during the period, 102 dogs (1.4%) were …