Medical Specialties Commons^™

Circulating Immune Signatures In Chronic Pancreatitis With And Without Preceding Acute Pancreatitis: A Pilot Study, Rasmus Hagn-Meincke, Dhiraj Yadav, Dana K Andersen, Santhi Swaroop Vege, Evan L Fogel, Jose Serrano, Melena D Bellin, Mark D Topazian, Darwin L Conwell, Liang Li, Stephen K Van Den Eeden, Asbjørn M Drewes, Stephen J Pandol, Chris E Forsmark, William E Fisher, Phil A Hart, Søren S Olesen, Walter G Park, Consortium For The Study Of Chronic Pancreatitis, Diabetes, And Pancreatic Cancer (Cpdpc)

Faculty, Staff and Student Publications

Objective: To investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP).

Methods: We performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons …

Avoidant/Restrictive Food Intake Disorder Prevalence Is High In Children With Gastroparesis And Functional Dyspepsia, Isha Kaul, Helen Burton-Murray, Salma Musaad, Yiming Mirabile, Danita Czyzewski, Miranda A L Van Tilburg, Andrew C Sher, Bruno P Chumpitazi, Robert J Shulman

Children’s Nutrition Research Center Staff Publications

BACKGROUND: Avoidant/restrictive food intake disorder (ARFID) prevalence in children with gastroparesis (Gp) and/or functional dyspepsia (FD) is unknown. We aimed to identify ARFID prevalence and trajectory over 2 months in children with Gp, FD, and healthy children (HC) using two screening questionnaires. We also explored the frequency of a positive ARFID screen between those with/without delayed gastric emptying or abnormal fundic accommodation.

METHODS: In this prospective longitudinal study conducted at an urban tertiary care hospital, patients ages 10-17 years with Gp or FD and age- and gender-matched HC completed two validated ARFID screening tools at baseline and 2-month follow-up: the …

Genome-Wide Analysis In Over 1 Million Individuals Of European Ancestry Yields Improved Polygenic Risk Scores For Blood Pressure Traits, Jacob M Keaton, Zoha Kamali, Tian Xie, Ahmad Vaez, Ariel Williams, Slavina B Goleva, Alireza Ani, Evangelos Evangelou, Jacklyn N Hellwege, Loic Yengo, William J Young, Matthew Traylor, Ayush Giri, Zhili Zheng, Jian Zeng, Daniel I Chasman, Andrew P Morris, Mark J Caulfield, Shih-Jen Hwang, Jaspal S Kooner, David Conen, John R Attia, Alanna C Morrison, Ruth J F Loos, Kati Kristiansson, Reinhold Schmidt, Andrew A Hicks, Peter P Pramstaller, Christopher P Nelson, Nilesh J Samani, Lorenz Risch, Ulf Gyllensten, Olle Melander, Harriette Riese, James F Wilson, Harry Campbell, Stephen S Rich, Bruce M Psaty, Yingchang Lu, Jerome I Rotter, Xiuqing Guo, Kenneth M Rice, Peter Vollenweider, Johan Sundström, Claudia Langenberg, Martin D Tobin, Vilmantas Giedraitis, Jian'an Luan, Jaakko Tuomilehto, Zoltan Kutalik, Samuli Ripatti, Veikko Salomaa, Giorgia Girotto, Stella Trompet, J Wouter Jukema, Pim Van Der Harst, Paul M Ridker, Franco Giulianini, Veronique Vitart, Anuj Goel, Hugh Watkins, Sarah E Harris, Ian J Deary, Peter J Van Der Most, Albertine J Oldehinkel, Bernard D Keavney, Caroline Hayward, Archie Campbell, Michael Boehnke, Laura J Scott, Thibaud Boutin, Chrysovalanto Mamasoula, Marjo-Riitta Järvelin, Annette Peters, Christian Gieger, Edward G Lakatta, Francesco Cucca, Jennie Hui, Paul Knekt, Stefan Enroth, Martin H De Borst, Ozren Polašek, Maria Pina Concas, Eulalia Catamo, Massimiliano Cocca, Ruifang Li-Gao, Edith Hofer, Helena Schmidt, Beatrice Spedicati, Melanie Waldenberger, David P Strachan, Maris Laan, Alexander Teumer, Marcus Dörr, Vilmundur Gudnason, James P Cook, Daniela Ruggiero, Ivana Kolcic, Eric Boerwinkle, Michela Traglia, Terho Lehtimäki, Olli T Raitakari, Andrew D Johnson, Christopher Newton-Cheh, Morris J Brown, Anna F Dominiczak, Peter J Sever, Neil Poulter, John C Chambers, Roberto Elosua, David Siscovick, Tõnu Esko, Andres Metspalu, Rona J Strawbridge, Markku Laakso, Anders Hamsten, Jouke-Jan Hottenga, Eco De Geus, Andrew D Morris, Colin N A Palmer, Ilja M Nolte, Yuri Milaneschi, Jonathan Marten, Alan Wright, Eleftheria Zeggini, Joanna M M Howson, Christopher J O'Donnell, Tim Spector, Mike A Nalls, Eleanor M Simonsick, Yongmei Liu, Cornelia M Van Duijn, Adam S Butterworth, John N Danesh, Cristina Menni, Nicholas J Wareham, Kay-Tee Khaw, Yan V Sun, Peter W F Wilson, Kelly Cho, Peter M Visscher, Joshua C Denny, Million Veteran Program, Lifelines Cohort Study, Charge Consortium, Icbp Consortium, Daniel Levy, Todd L Edwards, Patricia B Munroe, Harold Snieder, Helen R Warren

Faculty, Staff and Student Publications

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

Targeted Accurate Rna Consensus Sequencing (Tarc-Seq) Reveals Mechanisms Of Replication Error Affecting Sars-Cov-2 Divergence, Catherine C Bradley, Chen Wang, Alasdair J E Gordon, Alice X Wen, Pamela N Luna, Matthew B Cooke, Brendan F Kohrn, Scott R Kennedy, Vasanthi Avadhanula, Pedro A Piedra, Olivier Lichtarge, Chad A Shaw, Shannon E Ronca, Christophe Herman

Duncan NRI Faculty and Staff Publications

RNA viruses, like SARS-CoV-2, depend on their RNA-dependent RNA polymerases (RdRp) for replication, which is error-prone. Monitoring replication errors is crucial for understanding the virus’s evolution. Current methods lack the precision to detect rare de novo RNA mutations, particularly in low-input samples such as those from patients. Here, we introduce a new targeted Accurate RNA Consensus sequencing method (tARC-seq) to accurately determine the mutation frequency and types in SARS-CoV-2, both in cell culture and clinical samples. Our findings show an average of 2.68×10−5 new errors per cycle with a C>T bias that cannot be solely attributed to APOBEC …

Family Accommodation In Children And Adolescents With Misophonia, Eric A Storch, Andrew G Guzick, Johann D'Souza, Jane Clinger, Daphne Ayton, Minjee Kook, Conor Rork, Eleanor E Smith, Isabel A Draper, Nasim Khalfe, Catherine E Rast, Nicholas Murphy, Marijn Lijfijjt, Wayne K Goodman, Matti Cervin

Center for Medical Ethics and Health Policy Staff Publications

Family accommodation (e.g., reassurance, modifying routines, assisting avoidance) has not been explored among youth with misophonia but may have important clinical and intervention implications. We examined family accommodation in 102 children and adolescents with interview-confirmed misophonia and compared its frequency and content to family accommodation in 95 children and adolescents with anxiety disorders. Findings showed that family accommodation was ubiquitous in pediatric misophonia and may be even more frequent than in youth with anxiety disorders. Assisting the child, participating in misophonia-related behaviors, and modifying family routines were endorsed by more than 70% of parents of children with misophonia. Further, compared …

Parent-Led Cognitive Behavioral Teletherapy For Anxiety In Autistic Youth: A Randomized Trial Comparing Two Levels Of Therapist Support, Andrew G Guzick, Sophie C Schneider, Minjee Kook, Julia Rose Iacono, Saira A Weinzimmer, Troy Quast, Sean M Olsen, Killian Rainey Hughes, Emily Jellinek-Russo, Amanda Perozo Garcia, Abigail Candelari, Leandra N Berry, Robin P Goin-Kochel, Wayne K Goodman, Eric A Storch

Center for Medical Ethics and Health Policy Staff Publications

Parent-led cognitive behavioral therapy (CBT) is an efficient, promising form of therapy that may be well suited for autistic youth with anxiety disorders, though to date it has been minimally tested. In this study, 87 autistic youth (7 to 13 years old) with anxiety disorders and their parents were randomized to two forms of parent-led CBT in which parents led their child through a guided CBT workbook across 12 weeks: one with low therapist contact (four 30-minute telehealth calls), and one with standard therapist contact (ten 60-minute telehealth calls). Anxiety, functional impairment, and autism features significantly declined across therapy, without …

Use Of Topical Methylene Blue To Image Nuclear Morphometry With A Low-Cost Scanning Darkfield Microendoscope, Huayu Hou, Jennifer Carns, Richard A Schwarz, Ann M Gillenwater, Sharmila Anandasabapathy, Rebecca R Richards-Kortum

Faculty, Staff and Students Publications

SIGNIFICANCE: Fiber-optic microendoscopy is a promising approach to noninvasively visualize epithelial nuclear morphometry for early cancer and precancer detection. However, the broader clinical application of this approach is limited by a lack of topical contrast agents available for

AIM: The aim of this study was to evaluate the ability to image nuclear morphometry in vivo with a novel fiber-optic microendoscope used together with topical application of methylene blue (MB), a dye with FDA approval for use in chromoendoscopy in the gastrointestinal tract.

APPROACH: The low-cost, high-resolution microendoscope implements scanning darkfield imaging without complex optomechanical components by leveraging programmable illumination and …

Impact Of Obesity And Age On Mouse Corneal Innervation At The Epithelial-Stromal Interface, Justin A Courson, Rolando E Rumbaut, Alan R Burns

Faculty, Staff and Students Publications

PURPOSE: The corneal epithelium is the most highly innervated structure in the body. Previously, we reported a novel event whereby stromal axons fuse with basal epithelial cells, limiting nerve penetration into the epithelium. Although corneal-epithelial nerves undergo changes in sensitivity and distribution throughout life and in response to an obesogenic diet, it is unknown if neuronal-epithelial cell fusion is altered. Here, we sought to determine if neuronal-epithelial cell fusion frequency correlates with obesogenic diet consumption and age.

METHODS: Corneas were collected from C57BL/6 mice and evaluated for neuronal-epithelial cell fusion frequency using serial block-face scanning electron microscopy. To assess the …

Development Of A Weight-Band Dosing Approach For Vosoritide In Children With Achondroplasia Using A Population Pharmacokinetic Model, Yulan Qi, Ming Liang Chan, Diane R Mould, Kevin Larimore, Elena Fisheleva, Anu Cherukuri, Jonathan Day, Ravi Savarirayan, Melita Irving, Carlos A Bacino, Julie Hoover-Fong, Keiichi Ozono, Klaus Mohnike, William R Wilcox, Michael B Bober, Joshua Henshaw

Faculty, Staff and Students Publications

BACKGROUND AND OBJECTIVE: Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen.

METHODS: A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.95-15 years) who received daily per-kg doses of vosoritide. The model was used to simulate expected exposures in children with a refined weight-band dosing regimen. Simulated exposure was …

Age-Related Differences In The Mouse Corneal Epithelial Transcriptome And Their Impact On Corneal Wound Healing, Anmar Abu-Romman, Kaitlin K Scholand, Gowthaman Govindarajan, Zhiyuan Yu, Sonali Pal-Ghosh, Mary A Stepp, Cintia S De Paiva

Faculty, Staff and Students Publications

PURPOSE: Aging is a risk factor for dry eye. We sought to identify changes in the aged mouse corneal epithelial transcriptome and determine how age affects corneal sensitivity, re-epithelialization, and barrier reformation after corneal debridement.

METHODS: Corneal epithelium of female C57BL/6J (B6) mice of different ages (2, 12, 18, and 24 months) was collected, RNA extracted, and bulk RNA sequencing performed. Cornea sensitivity was measured with an esthesiometer in 2- to 3-month-old, 12- to 13-month-old, 18- to 19-month-old, and 22- to 25-month-old female and male mice. The 2-month-old and 18-month-old female and male mice underwent unilateral corneal debridement using a …

Patterns Of Multiple Organ Dysfunction And Renal Recovery In Critically Ill Children And Young Adults Receiving Continuous Renal Replacement Therapy, Sameer Thadani, Dana Fuhrman, Claire Hanson, Hyun Jung Park, Joseph Angelo, Poyyapakkam Srivaths, Katri Typpo, Michael J Bell, Katja M Gist, Joseph Carcillo, Ayse Akcan-Arikan

Faculty, Staff and Students Publications

OBJECTIVES: Acute kidney injury requiring dialysis (AKI-D) commonly occurs in the setting of multiple organ dysfunction syndrome (MODS). Continuous renal replacement therapy (CRRT) is the modality of choice for AKI-D. Mid-term outcomes of pediatric AKI-D supported with CRRT are unknown. We aimed to describe the pattern and impact of organ dysfunction on renal outcomes in critically ill children and young adults with AKI-D.

DESIGN: Retrospective cohort.

SETTING: Two large quarternary care pediatric hospitals.

PATIENTS: Patients 26 y old or younger who received CRRT from 2014 to 2020, excluding patients with chronic kidney disease.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: Organ …

Herbal And Dietary Supplement Induced Liver Injury Leading To Hepatitis-Associated Severe Aplastic Anemia: A Case Report, Rebecca Mercedes, Sanjiv Harpavat, Paula M Hertel, Ghadir Sasa, Susan Kirk, Kalyani Patel, Krupa R Mysore

Faculty, Staff and Students Publications

Herbal and dietary supplements (HDS) are a common etiology of drug induced liver injury and, specifically, Herbalife® supplements have been implicated. Hepatitis associated aplastic anemia (HAAA) is a rare and potentially fatal complication after acute hepatitis characterized by pancytopenia. While there have been rare cases of HDS leading to HAAA, no cases of Herbalife® induced liver injury leading to HAAA have been reported from this specific HDS. We report a unique case of severe aplastic anemia developing after sub-fulminant liver failure associated with chronic HDS use. This case illustrates the importance of warning the public about HDS as their use …

Gut Development Following Insulin-Like Growth Factor-1 Supplementation To Preterm Pigs, Martin Bo Rasmussen, Kristine Holgersen, Stanislava Pankratova, Ole Bæk, Douglas G Burrin, Thomas Thymann, Per Torp Sangild

Faculty, Staff and Students Publications

BACKGROUND: Reduced insulin-like growth factor-1 (IGF-1) levels may contribute to impaired organ development in preterm infants. Using preterm pigs as a model, we hypothesized that IGF-1 supplementation improves health and gut development during the first three weeks of life.

METHODS: First, clinical and organ endpoints were compared between artificially-reared, cesarean-delivered preterm pigs and vaginally-delivered, sow-reared term pigs at 5, 9 and 19 days. Next, preterm pigs were treated with recombinant human IGF-1 for 19 days (2.25 mg/kg/day, systemically).

RESULTS: Relative to term pigs, preterm pigs had lower body weight, fat, bone contents, relative weights of liver and spleen and a …

Sars-Cov-2 Viral Load In The Nasopharynx At Time Of First Infection Among Unvaccinated Individuals: A Secondary Cross-Protocol Analysis Of 4 Randomized Trials, Leigh H Fisher, Jia Jin Kee, Albert Liu, Claudia M Espinosa, April K Randhawa, James Ludwig, Craig A Magaret, Samuel T Robinson, Peter B Gilbert, Ollivier Hyrien, James G Kublin, Nadine Rouphael, Ann R Falsey, Magdalena E Sobieszczyk, Hana M El Sahly, Beatriz Grinsztejn, Glenda E Gray, Karen L Kotloff, Cynthia L Gay, Brett Leav, Ian Hirsch, Frank Struyf, Lisa M Dunkle, Kathleen M Neuzil, Lawrence Corey, Yunda Huang, Paul A Goepfert, Stephen R Walsh, Lindsey R Baden, Holly Janes, Covid-19 Prevention Network (Covpn)

Faculty, Staff and Students Publications

IMPORTANCE: SARS-CoV-2 viral load (VL) in the nasopharynx is difficult to quantify and standardize across settings, but it may inform transmission potential and disease severity.

OBJECTIVE: To characterize VL at COVID-19 diagnosis among previously uninfected and unvaccinated individuals by evaluating the association of demographic and clinical characteristics, viral variant, and trial with VL, as well as the ability of VL to predict severe disease.

DESIGN, SETTING, AND PARTICIPANTS: This secondary cross-protocol analysis used individual-level data from placebo recipients from 4 harmonized, phase 3 COVID-19 vaccine efficacy trials sponsored by Moderna, AstraZeneca, Janssen, and Novavax. Participants were SARS-CoV-2 negative at baseline …

A Biophysically Constrained Brain Connectivity Model Based On Stimulation-Evoked Potentials, William Schmid, Isabel A Danstrom, Maria Crespo Echevarria, Joshua Adkinson, Layth Mattar, Garrett P Banks, Sameer A Sheth, Andrew J Watrous, Sarah R Heilbronner, Kelly R Bijanki, Alessandro Alabastri, Eleonora Bartoli

Faculty, Staff and Students Publications

BACKGROUND: Single-pulse electrical stimulation (SPES) is an established technique used to map functional effective connectivity networks in treatment-refractory epilepsy patients undergoing intracranial-electroencephalography monitoring. While the connectivity path between stimulation and recording sites has been explored through the integration of structural connectivity, there are substantial gaps, such that new modeling approaches may advance our understanding of connectivity derived from SPES studies.

NEW METHOD: Using intracranial electrophysiology data recorded from a single patient undergoing stereo-electroencephalography (sEEG) evaluation, we employ an automated detection method to identify early response components, C1, from pulse-evoked potentials (PEPs) induced by SPES. C1 components were utilized for a …

A Phenome-Wide Association And Mendelian Randomisation Study Of Alcohol Use Variants In A Diverse Cohort Comprising Over 3 Million Individuals, Mariela V Jennings, José Jaime Martínez-Magaña, Natasia S Courchesne-Krak, Renata B Cupertino, Laura Vilar-Ribó, Sevim B Bianchi, Alexander S Hatoum, Elizabeth G Atkinson, Paola Giusti-Rodriguez, Janitza L Montalvo-Ortiz, Joel Gelernter, María Soler Artigas, Sarah L Elson, Howard J Edenberg, Pierre Fontanillas, Abraham A Palmer, Sandra Sanchez-Roige

Faculty, Staff and Students Publications

BACKGROUND: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes.

METHODS: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African …

Multimodal Neurologic Monitoring In Patients Undergoing Extracorporeal Membrane Oxygenation, Khwaja Siddiqui, Muhammad U Hafeez, Ali Ahmad, Syed O Kazmi, Subhasis Chatterjee, Eric Bershad, Mohammad Hirzallah, Chethan Rao, Rahul Damani

Faculty, Staff and Students Publications

Introduction Extracorporeal membrane oxygenation (ECMO) is associated with a high rate of neurologic complications. Multimodal neurologic monitoring (MNM) has the potential for early detection and intervention. We examined the safety and feasibility of noninvasive MNM during ECMO. We hypothesized that survivors and non-survivors would have meaningful differences in transcranial Doppler (TCD) sonography and electroencephalographic (EEG) characteristics, which we aimed to identify. We also investigated adverse neurologic events and attempted to identify differences in EEG and TCD characteristics among patients based on the type of ECMO and the occurrence of these events. Material and methods We performed an observational study on …

Performance Of A Stool-Based Quantitative Pcr Assay For The Diagnosis Of Tuberculosis In Adolescents And Adults: A Multinational, Prospective Diagnostic Accuracy Study, Alexander Kay, Anca Vasiliu, Lucia Carratala-Castro, Bariki Mtafya, Jose Euberto Mendez Reyes, Nontobeko Maphalala, Shilzia Munguambe, Durbbin Mulengwa, Tara Ness, Belen Saavedra, Jason Bacha, Gugu Maphalala, Rojelio Mejia, Godwin Mtetwa, Sozinho Acacio, Patricia Manjate, Edson Mambuque, Nosisa Shiba, Nokwanda Kota, Mangaliso Ziyane, Nyanda Elias Ntinginya, Christoph Lange, H Lester Kirchner, Andrew R Dinardo, Alberto L Garcia-Basteiro, Anna Maria Mandalakas, Stool4tb Global Partnership

Faculty, Staff and Students Publications

BACKGROUND: Despite increasing availability of rapid molecular tests for the diagnosis of tuberculosis in high-burden settings, many people with tuberculosis are undiagnosed. Reliance on sputum as the primary specimen for tuberculosis diagnostics contributes to this diagnostic gap. We evaluated the diagnostic accuracy and additive yield of a novel stool quantitative PCR (qPCR) assay for the diagnosis of tuberculosis in three countries in Africa with high tuberculosis burdens.

METHODS: We undertook a prospective diagnostic accuracy study in Eswatini, Mozambique, and Tanzania from Sept 21, 2020, to Feb 2, 2023, to compare the diagnostic accuracy for tuberculosis of a novel stool qPCR …

Using Workplace-Based Assessments In Undergraduate Medical Education, Arindam Sarkar

Faculty, Staff and Students Publications

No abstract provided.

Cardiac Conduction Diseases: Understanding The Molecular Mechanisms To Uncover Targets For Future Treatments, Tingting Li, Qussay Marashly, Jitae A Kim, Na Li, Mihail G Chelu

Faculty, Staff and Students Publications

Introduction: The cardiac conduction system (CCS) is crucial for maintaining adequate cardiac frequency at rest and modulation during exercise. Furthermore, the atrioventricular node and His-Purkinje system are essential for maintaining atrioventricular and interventricular synchrony and consequently maintaining an adequate cardiac output.

Areas covered: In this review article, we examine the anatomy, physiology, and pathophysiology of the CCS. We then discuss in detail the most common genetic mutations and the molecular mechanisms of cardiac conduction disease (CCD) and provide our perspectives on future research and therapeutic opportunities in this field.

Expert opinion: Significant advancement has been made in understanding the molecular …

Atypical Diabetes: What Have We Learned And What Does The Future Hold?, Stephen I Stone, Ashok Balasubramanyam, Jennifer E Posey

Faculty, Staff and Students Publications

As our understanding of the pathophysiology of diabetes evolves, we increasingly recognize that many patients may have a form of diabetes that does not neatly fit with a diagnosis of either type 1 or type 2 diabetes. The discovery and description of these forms of "atypical diabetes" have led to major contributions to our collective understanding of the basic biology that drives insulin secretion, insulin resistance, and islet autoimmunity. These discoveries now pave the way to a better classification of diabetes based on distinct endotypes. In this review, we highlight the key biological and clinical insights that can be gained …

Selective Cdk7 Inhibition Suppresses Cell Cycle Progression And Myc Signaling While Enhancing Apoptosis In Therapy-Resistant Estrogen Receptor-Positive Breast Cancer, Cristina Guarducci, Agostina Nardone, Douglas Russo, Zsuzsanna Nagy, Capucine Heraud, Albert Grinshpun, Qi Zhang, Allegra Freelander, Mathew Joseph Leventhal, Avery Feit, Gabriella Cohen Feit, Ariel Feiglin, Weihan Liu, Francisco Hermida-Prado, Nikolas Kesten, Wen Ma, Carmine De Angelis, Antonio Morlando, Madison O'Donnell, Sergey Naumenko, Shixia Huang, Quang-Dé Nguyen, Ying Huang, Luca Malorni, Johann S Bergholz, Jean J Zhao, Ernest Fraenkel, Elgene Lim, Rachel Schiff, Geoffrey I Shapiro, Rinath Jeselsohn

Faculty, Staff and Students Publications

Purpose: Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER)-positive (ER+) breast cancer. Cyclin-dependent kinase 7 (CDK7) is a candidate target in endocrine-resistant ER+ breast cancer models and selective CDK7 inhibitors (CDK7i) are in clinical development for the treatment of ER+ breast cancer. Nonetheless, the precise mechanisms responsible for the activity of CDK7i in ER+ breast cancer remain elusive. Herein, we sought to unravel these mechanisms.

Experimental design: We conducted multi-omic analyses in ER+ breast cancer models in vitro and in vivo, including models with different genetic backgrounds. We also performed genome-wide …

Deep Image Segmentation For Cardiomyocyte Proliferation, Md Abul Hassan Samee, James F Martin

Faculty, Staff and Students Publications

No abstract provided.

Contemporary American And European Guidelines For Heart Failure Management: Jacc: Heart Failure Guideline Comparison, John W Ostrominski, Ersilia M Defilippis, Kannu Bansal, Ralph J Riello, Biykem Bozkurt, Paul A Heidenreich, Muthiah Vaduganathan

Faculty, Staff and Students Publications

This review serves to compare contemporary clinical practice recommendations for the management of heart failure (HF), as codified in the 2021 European Society of Cardiology (ESC) guideline, the 2022 American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Failure Society of America (HFSA) guideline, and the 2023 focused update of the 2021 ESC document. Overall, these guidelines aim to solidify significant advances throughout the HF continuum since the publication of previous full guideline iterations (2013 and 2016 for the ACC/AHA and ESC, respectively). All guidelines provide new recommendations for an increasingly complex landscape of HF care, with focus on primary HF …

Predictors And Impact Of Prolonged Vasoplegia After Continuous-Flow Left Ventricular Assist Device Implantation, Harveen K Lamba, Mary Kim, Meng Li, Andrew B Civitello, Ajith P Nair, Leo Simpson, J Patrick Herlihy, O H Frazier, Joseph G Rogers, Gabriel Loor, Kenneth K Liao, Alexis E Shafii, Subhasis Chatterjee

Faculty, Staff and Students Publications

BACKGROUND: Vasoplegia after cardiac surgery is associated with adverse outcomes. However, the clinical effects of vasoplegia and the significance of its duration after continuous-flow left ventricular assist device (CF-LVAD) implantation are less known.

OBJECTIVES: This study aimed to identify predictors of and outcomes from transient vs prolonged vasoplegia after CF-LVAD implantation.

METHODS: The study was a retrospective review of consecutive patients who underwent CF-LVAD implantation between January 1, 2005, and December 31, 2017. Vasoplegia was defined as the presence of all of the following: mean arterial pressure ≤65 mm Hg, vasopressor (epinephrine, norepinephrine, vasopressin, or dopamine) use for >6 hours …

Chlorthalidone Vs Hydrochlorothiazide For Hypertension Treatment After Myocardial Infarction Or Stroke: A Secondary Analysis Of A Randomized Clinical Trial, Areef Ishani, Cynthia Hau, William C Cushman, Sarah M Leatherman, Robert A Lew, Peter A Glassman, Addison A Taylor, Ryan E Ferguson

Faculty, Staff and Students Publications

IMPORTANCE: Patients with prior myocardial infarction (MI) or stroke have a greater risk of recurrent cardiovascular (CV) events.

OBJECTIVE: To evaluate the association of chlorthalidone (CTD) vs hydrochlorothiazide (HCTZ) with CV outcomes and noncancer deaths in participants with and without prior MI or stroke.

DESIGN, SETTING, AND PARTICIPANTS: This was a prespecified secondary analysis of the Diuretic Comparison Project (DCP), a pragmatic randomized clinical trial conducted within 72 participating Veterans Affairs health care systems from June 2016 to June 2021, in which patients aged 65 years or older with hypertension taking HCTZ at baseline were randomized to continue HCTZ or …

Clofarabine Monotherapy In Aggressive, Relapsed And Refractory Langerhans Cell Histiocytosis, Deevyashali Parekh, Howard Lin, Akanksha Batajoo, Erin Peckham-Gregory, Vivekanudeep Karri, Whitney Stanton, Brooks Scull, Ryan Fleishmann, Nader El-Mallawany, Olive S Eckstein, Zachary D Prudowsky, Nitya Gulati, Jennifer E Agrusa, Asra Z Ahmed, Roland Chu, Matthew S Dietz, Stanton C Goldman, Michael D Hogarty, Hamayun Imran, Stefanos Intzes, Jenny M Kim, Lisa M Kopp, Carolyn Fein Levy, Philip Neff, Pallavi M Pillai, Bryan A Sisk, Deborah E Schiff, Angela D Trobaugh-Lotrario, Kelly Walkovich, Kenneth L Mcclain, Carl E Allen

Faculty, Staff and Students Publications

Over 50% of patients with systemic LCH are not cured with front-line therapies and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort including heavily pretreated patients with systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood correlated with positive clinical responses. Prospective multi-center trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.

Clinical, Radiological And Molecular Responses To Combination Chemotherapy With Mapk Pathway Inhibition In Relapsed And Refractory Langerhans Cell Histiocytosis, Vivekanudeep Karri, Howard Lin, Jessica Velazquez, Akanksha Batajoo, Deevyashali Parekh, Whitney Stanton, Harshal Abhyankar, Nader K El-Mallawany, Jennifer Agrusa, Olive Eckstein, Nitya Gulati, Jeffrey Schwartz, Wendy Woods-Swafford, Jaime Boyd, Anikit Saha, Carl E Allen, Kenneth L Mcclain

Faculty, Staff and Students Publications

Optimal therapeutic approaches for advanced Langerhans cell histiocytosis (LCH) are not known. We assessed the safety and efficacy of combined chemotherapy with MAPK pathway inhibition in 10 patients with refractory systemic disease and/or LCH-associated neurodegeneration. Overall response rate was 9/10 (90%) for the entire cohort: 5/5 (100%) for patients with systemic disease and 6/7 (86%) for patients with central nervous system disease. BRAFV600E+ peripheral blood fraction decreased in 5/6 (83%). Toxicities included fever, skin rash, myalgias, neuropathy, cytopenias and hypocalcaemia. Prospective trials are required to optimize combination strategies, determine potential to achieve cure and compare outcomes to chemotherapy or MAPK …

Natural History Of Cancer-Associated Splanchnic Vein Thrombosis, Hanqing Shang, Jun Y Jiang, Danielle Guffey, Francisco Novoa, Raka Bandyo, Shengling Ma, Ang Li

Faculty, Staff and Students Publications

Background: There is uncertainty in the management of cancer-associated isolated splanchnic vein thrombosis (SpVT).

Objectives: To describe the natural history of SpVT by cancer type and thrombus composition and to review anticoagulation (AC) practices and associated rates of usual-site venous thromboembolism (VTE), major and clinically relevant nonmajor bleeding (MB/CRNMB), recanalization/progression, and mortality.

Methods: We performed a retrospective cohort study in patients with SpVT at 2 cancer care centers in Houston, Texas. We estimated the incidence of usual-site VTE and MB/CRNMB at 6 months using competing risk methods and examined venous patency in a subset of patients with repeat imaging. We …

Proteomic Biomarkers Of Quantitative Interstitial Abnormalities In Copdgene And Cardia Lung Study, Bina Choi, Gabrielle Y Liu, Quanhu Sheng, Kaushik Amancherla, Andrew Perry, Xiaoning Huang, Ruben San José Estépar, Samuel Y Ash, Weihua Guan, David R Jacobs, Fernando J Martinez, Ivan O Rosas, Russell P Bowler, Jonathan A Kropski, Nicholas E Banovich, Sadiya S Khan, Raúl San José Estépar, Ravi Shah, Bharat Thyagarajan, Ravi Kalhan, George R Washko

Faculty, Staff and Students Publications

Rationale: Quantitative interstitial abnormalities (QIAs) are early measures of lung injury automatically detected on chest computed tomography scans. QIAs are associated with impaired respiratory health and share features with advanced lung diseases, but their biological underpinnings are not well understood. Objectives: To identify novel protein biomarkers of QIAs using high-throughput plasma proteomic panels within two multicenter cohorts.

Methods: We measured the plasma proteomics of 4,383 participants in an older, ever-smoker cohort (COPDGene [Genetic Epidemiology of Chronic Obstructive Pulmonary Disease]) and 2,925 participants in a younger population cohort (CARDIA [Coronary Artery Disease Risk in Young Adults]) using the SomaLogic SomaScan assays. …