Internal Medicine Commons^™

Cardio-Onco-Metabolism – Metabolic Vulnerabilities In Cancer And The Heart, Anja Karlstaedt, Heinrich Taegtmeyer

Faculty, Staff and Student Publications

Cancer and cardiovascular diseases (CVDs) are the leading cause of death worldwide. Metabolic remodeling is a hallmark of both cancer and the failing heart. Tumors reprogram metabolism to optimize nutrient utilization and meet increased demands for energy provision, biosynthetic pathways, and proliferation. Shared risk factors for cancer and CVDs suggest intersecting mechanisms for disease pathogenesis and progression. In this review, we aim to highlight the role of metabolic remodeling in cancer and its potential to impair cardiac function. Understanding these mechanisms will help us develop biomarkers, better therapies, and identify patients at risk of developing heart disease after surviving cancer.

First Steps: Primary Outcomes Of A Randomized, Stepped-Care Behavioral Clinical Trial For Parents Of Young Children With New-Onset Type 1 Diabetes, Marisa E Hilliard, Carrie Tully, Maureen Monaghan, Tom Hildebrandt, Christine H Wang, John R Barber, Lauren Clary, Katherine Gallagher, Wendy Levy, Fran Cogen, Celia Henderson, Lefkothea Karaviti, Randi Streisand

Faculty, Staff and Students Publications

OBJECTIVE: Despite the emotional challenges of parental adjustment to a child's type 1 diabetes diagnosis and the unique complexities of early childhood, there are few programs designed to meet the needs of parents of young children at new onset. This study evaluated First STEPS (Study of Type 1 in Early childhood and Parenting Support), a stepped-care behavioral intervention designed to support parents' psychosocial functioning and promote children's glycemic outcomes.

RESEARCH DESIGN AND METHODS: Using a two-site randomized clinical trial design, parents (n = 157) of children aged 1-6 years completed baseline data within 2 months of diabetes diagnosis and were …

The Association Of Baseline Plasma Sars-Cov-2 Nucleocapsid Antigen Level And Outcomes In Patients Hospitalized With Covid-19, Activ-3/Tico Study Group, Angela J Rogers, Deborah Wentworth, Andrew Phillips, Katy Shaw-Saliba, Robin L Dewar, Neil R Aggarwal, Abdel G Babiker, Weizhong Chang, Nila J Dharan, Victoria J Davey, Elizabeth S Higgs, Norman Gerry, Adit A Ginde, J W Awori Hayanga, Helene Highbarger, Jeroen L Highbarger, Mamta K Jain, Virginia Kan, Kami Kim, Perrine Lallemand, Bradley G Leshnower, Joseph K Lutaakome, Gail Matthews, Ahmad Mourad, Eleftherios Mylonakis, Ven Natarajan, Maria L Padilla, Lavannya M Pandit, Roger Paredes, Sarah Pett, Srikanth Ramachandruni, M Tauseef Rehman, Brad T Sherman, D Clark Files, Samuel M Brown, Michael A Matthay, B Taylor Thompson, James D Neaton, H Clifford Lane, Jens D Lundgren

Faculty, Staff and Students Publications

BACKGROUND: Levels of plasma SARS-CoV-2 nucleocapsid (N) antigen may be an important biomarker in patients with COVID-19 and enhance our understanding of the pathogenesis of COVID-19.

OBJECTIVE: To evaluate whether levels of plasma antigen can predict short-term clinical outcomes and identify clinical and viral factors associated with plasma antigen levels in hospitalized patients with SARS-CoV-2.

DESIGN: Cross-sectional study of baseline plasma antigen level from 2540 participants enrolled in the TICO (Therapeutics for Inpatients With COVID-19) platform trial from August 2020 to November 2021, with additional data on day 5 outcome and time to discharge.

SETTING: 114 centers in 10 countries. …

Prevalence And Predictors Of Urine Culture Contamination In Primary Care: A Cross-Sectional Study, Michael A Hansen, Marissa Valentine-King, Roger Zoorob, Matthew Schlueter, Jennifer L Matas, Samuel E Willis, Lisa C K Danek, Kenneth L Muldrew, Mohammad Zare, Forrest Hudson, Robert L Atmar, Andrew Chou, Barbara W Trautner, Larissa Grigoryan

Faculty, Staff and Students Publications

BACKGROUND: Antimicrobial resistance is a global health threat. To slow resistance and preserve antibiotics, stewardship interventions are increasingly promoted and mandated. Urine cultures are the most common microbiological test in the outpatient setting. Contamination most likely occurs during urine collection from surrounding vaginal, perineal, and epidermal flora. Sample contamination can lead to incorrect diagnosis, unnecessary or inappropriate treatment, poor patient outcomes, and higher costs. Therefore, ensuring proper collection of urinary samples serves as a prime diagnostic stewardship target, one that international nursing societies increasingly endorse as an opportunity for nurse involvement.

OBJECTIVES: Determine the prevalence, predictors, and antibiotic prescribing associated …

Selective Iga Deficiency In Spontaneously Hypertensive Rats With Gut Dysbiosis, Piu Saha, Blair Mell, Rachel M Golonka, Venugopal R Bovilla, Ahmed A Abokor, Xue Mei, Beng San Yeoh, Peter A Doris, Andrew T Gewirtz, Bina Joe, Matam Vijay-Kumar

Faculty, Staff and Student Publications

BACKGROUND: The spontaneously hypertensive rat (SHR) is extensively used to study hypertension. Gut microbiota dysbiosis is a notable feature in SHR for reasons unknown. Immunoglobulin A (IgA) is a major host factor required for gut microbiota homeostasis. We hypothesized that inadequate IgA contributes to gut microbiota dysbiosis in SHR.

METHODS: IgA was measured in feces, cecum, serum, liver, gut-associated lymphoid tissue, and milk from SHR and Wistar Kyoto rats. IgA regulatory factors like IgM, IgG, and

RESULTS: Compared with Wistar Kyoto rats, SHR displayed remarkably near-deficient IgA levels accompanied by compensatory increases in serum IgM and IgG and gut-liver

CONCLUSIONS: …

Association Of Hypomagnesemia And Liver Injury, Role Of Gut-Barrier Dysfunction And Inflammation: Efficacy Of Abstinence, And 2-Week Medical Management In Alcohol Use Disorder Patients., Evan J. Winrich, Khushboo S. Gala, Abhas Rajhans, Christian D. Rios-Perez, Amor J. Royer, Zarlakhta Zamani, Ranganathan Parthasarathy, Luis S. Marsano-Obando, Ashutosh J. Barve, Melanie L. Schwandt, Vatsalya Vatsalya

Faculty and Staff Scholarship

(1) We investigated the involvement of serum magnesium level in early alcoholic liver disease (ALD), gut barrier dysfunction, and inflammation in alcohol use disorder (AUD) patients; and lastly, the efficacy of 2-week abstinence and medical management to alleviate hypomagnesemia. (2) Forty-eight heavy drinking AUD patients (34 males (M)/14 females (F)) participated in this study. Patients were grouped by serum alanine aminotransferase (ALT) level (a marker of liver injury) as group 1 (Group 1 (Gr.1); ALT ≤ 40 U/L, 7M/8F, without any indication of early-stage ALD) and group 2 (Group 2 (Gr.2); ALT > 40 U/L, 27M/6F or early-stage ALD). These patients …

Analysis Of The Efficacy Of Autologous Peripheral Blood Stem Cell Transplantation In High-Risk Neuroblastoma, Jin Yan, Li Jie, Yang Jiaxing, Cao Yanna, Li Zhanglin, Li Zhongyuan, Wang Daowei, Zhao Guangzong, Zhong Benfu, Yan Jie, Zhao Qiang

Faculty, Staff and Student Publications

Objective: This study aimed to analyze the efficacy of autologous peripheral blood stem cell transplantation for high-risk neuroblastoma in China.

Methods: The data of 90 high-risk neuroblastoma patients treated with the CCCG-NB 2015 regimen were reviewed. The baseline clinicopathological characteristics and prognosis were analyzed and compared. In addition, the prognoses of tandem autologous stem cell transplantation and single autologous stem cell transplantation groups were compared.

Results: The results of survival analysis showed that autologous peripheral blood stem cell transplantation based on this pretreatment regimen significantly improved the prognosis of children in the high-risk group. The 3-year event-free survival (EFS) and …

Veterans’ Ambulatory Care Experience During Covid-19: Veterans’ Access To And Satisfaction With Primary Care Early In The Pandemic, Brice Thomas, Aanchal Thadani, Patricia V Chen, Israel C Christie, Lisa M Kern, Mangala Rajan, Himabindu Kadiyala, Drew A Helmer

Faculty, Staff and Students Publications

BACKGROUND: The COVID-19 pandemic caused widespread changes to healthcare, but few studies focus on ambulatory care during the early phase of the pandemic. We characterize veterans' ambulatory care experience, specifically access and satisfaction, early in the pandemic.

METHODS: We employed a semi-structured telephone interview to capture quantitative and qualitative data from patients scheduled with a primary care provider between March 1 - June 30, 2020. Forty veterans were randomly identified at a single large urban Veterans Health Administration (VHA) medical center. The interview guide utilized 56 closed and open-ended questions to characterize veterans' perceptions of access to and satisfaction with …

Association Between Abnormal Lipid Profile And Inflammation And Progression Of Myelodysplastic Syndrome To Acute Leukemia, Wei Qiao, Elliana Young, Chun Feng, Suyu Liu, Jeff Jin, Laila Noor, Cristhiam M Rojas Hernandez, Gautam Borthakur, Olga Gorlova, Vahid Afshar-Kharghan

Faculty, Staff and Student Publications

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with a small risk of developing hematologic malignancies and a higher risk of cardiovascular diseases (CVD). We asked whether the reverse correlation exists and cardiometabolic risk factors have an impact on the progression of myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). We investigated the association between abnormal lipid profiles and inflammation in MDS, which shares many genetic mutations with CHIP, and the risk of developing acute leukemia. We examined the medical records of 11071 MDS patients. Among them, 5422 had at least one lipid profile or C-reactive protein (CRP) measurement. In …

The Lawnmower And The Pediatric Lower Extremity: A Catastrophic Combination, Alvaro Tamayo-Gutierrez, Hassan N Ibrahim

Faculty, Staff and Student Publications

Heart failure can lead to renal impairment, an interaction now termed "cardiorenal syndrome." The prevalent physiological explanation for the renal impairment that accompanies heart failure centers around the forward failure hypothesis, which emphasizes the role of left ventricular dysfunction in causing edema, and the backward failure hypothesis, which singles out venous congestion as the dominant mechanism of edema and reduced glomerular filtration rate. In this review, we provide an appraisal on venous congestion, an extremely important contributor that has received little attention. We also summarize the pharmacology of loop diuretics, explain current understanding of diuretic resistance, and address controversies regarding …

Hypertension Management In Patients With Chronic Kidney Disease, Sean A Hebert, Hassan N Ibrahim

Faculty, Staff and Student Publications

Hypertension and chronic kidney disease are closely linked. Patients with chronic kidney disease have hypertension almost universally and uncontrolled hypertension accelerates the decline in kidney function. The pathophysiology of hypertension in chronic kidney disease is complex, but is largely related to reduced nephron mass, sympathetic nervous system overactivation, involvement of the renin-angiotensin-aldosterone system, and generalized endothelial dysfunction. Consensus guidelines for blood pressure targets have adopted a blood pressure <120/80 mm Hg in native chronic kidney disease and <130/80 mm Hg in kidney transplant recipients. Guidelines also strongly advocate for renin-angiotensin-aldosterone system blockade as the first-line therapy.

Comparative Analysis Of Co-Cultured Amniotic Cell-Conditioned Media With Cell-Free Amniotic Fluid Reveals Differential Effects On Epithelial-Mesenchymal Transition And Myofibroblast Activation, Naiyou Liu, Charles M Bowen, Mohammadali M Shoja, Karen Larissa Castro De Pereira, Laxmi Priya Dongur, Antonio Saad, William K Russell, Thomas Christopher Broderick, Jeffrey H Fair, William Samuel Fagg

Faculty, Staff and Student Publications

Myofibroblast activation is a cellular response elicited by a variety of physiological or pathological insults whereby cells initiate a coordinated response intended to eradicate the insult and then revert back to a basal state. However, an underlying theme in various disease states is persistent myofibroblast activation that fails to resolve. Based on multiple observations, we hypothesized that the secreted factors harvested from co-culturing amniotic stem cells might mimic the anti-inflammatory state that cell-free amniotic fluid (AF) elicits. We optimized an amnion epithelial and amniotic fluid cell co-culture system, and tested this hypothesis in the context of myofibroblast activation. However, we …

Preoperative Inflammatory Markers As Prognostic Predictors After Hepatocellular Carcinoma Resection: Data From A Western Referral Center, João Paulo Maciel Silva, Fabricio Ferreira Coelho, Alex Jones Flores Cassenote, Vagner Birk Jeismann, Gilton Marques Fonseca, Jaime Arthur Pirola Kruger, José Donizeti De Meira Júnior, Sérgio Carlos Nahas, Paulo Herman

Faculty, Staff and Student Publications

BACKGROUND: Recent studies from eastern centers have demonstrate an association between inflammatory response and long-term outcomes after hepatocellular carcinoma (HCC) resection. However, the prognostic impact of inflammatory markers in western patients, with distinct tumor and epidemiologic features, is still unknown.

AIM: To evaluate the prognostic impact of preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR), as well as their impact according to tumor size (< 5 cm, 5-10 cm, > 10 cm) in patients undergoing HCC resection with curative intent.

METHODS: Optimal cut-off values for NLR, PLR, and MLR were determined by plotting the receiver operator curves. Overall survival (OS) and disease-free …

Health Care Utilization And Costs Associated With Functional Status In Patients With Psoriatic Arthritis, Alexis Ogdie, Mark Hwang, Phani Veeranki, Alexandria Portelli, Steven Sison, Jason Shafrin, Sofia Pedro, Steven Hass, Peter Hur, Nina Kim, Esther Yi, Kaleb Michaud

Faculty, Staff and Student Publications

BACKGROUND: The Health Assessment Questionnaire Disability Index (HAQ-DI) has been validated and widely used in psoriatic arthritis (PsA) clinical trials for the assessment of patient functional status. Significant improvements in the HAQ-DI have been reported in response to therapeutic interventions; however, few US studies have evaluated the economic impact of functional disability in patients with PsA.

OBJECTIVE: To evaluate the association of functional status with health care resource utilization (HCRU) and total health care costs in US patients diagnosed with PsA.

METHODS: This retrospective study included adult patients with PsA enrolled in FORWARD between July 2009 and June 2019 who …

Fatal Case Of Ebv-Negative Posttransplant Lymphoproliferative Disorder With Hemophagocytic Lymphohistiocytosis In An Adult Kidney Transplant Recipient, Sergio Mazzola Poli De Figueiredo, John C Johnson, Kirill A Lyapichev, Heather L Stevenson, Alfred Lea, Syed Hussain, Rupak D Kulkarni, Jeffrey H Fair, Muhammad Mujtaba, Mike L Kueht

Faculty, Staff and Student Publications

Renal transplantation usually requires the administration of lifelong immunosuppressive therapy to minimize rejection.1 However, while these immunosuppressants are vital to graft protection, they increase the risk of infection and malignancy. Posttransplant lymphoproliferative disorder (PTLD), a troublesome combination of both, covers a wide range of lymphomas, most commonly B-cell type and has been described in pediatric and adult patients.2 Risk factors for PTLD include Epstein-Barr virus (EBV) infection and immunosuppression and the prevalence of adult kidney transplant PTLD is estimated to be 0.5% to 4%, with the highest incidences occurring within the first year of transplant.2-5 …

Distinguishing Intrathyroid Parathyroid Adenoma From Colloid Nodules And Papillary Thyroid Carcinomas Using Multiphasic Multidetector Computed Tomography, J Matthew Debnam, T Linda Chi, Michael Kwon, Jia Sun, Dawid Schellingerhout, Brandon T Golant, Salmaan Ahmed, Nancy D Perrier, Thinh Vu

Faculty, Staff and Student Publications

OBJECTIVE: The aim of the study is to determine whether multiphase multidetector computed tomography (4D-MDCT) can differentiate between intrathyroid parathyroid adenomas (ITPAs), colloid nodules, and papillary thyroid carcinoma (PTC).

METHODS: We studied 22 ITPAs, 22 colloid nodules, and 11 PTCs in 55 patients. Hounsfield unit (HU) values of the nodules were measured on 4D-MDCT in the precontrast, arterial, venous, and delayed phases. Raw HU values, phase with peak enhancement, and washout percentages between the phases were evaluated.

RESULTS: Regardless of size, all ITPAs (22/22) showed peak enhancement in the arterial phase, which was significantly greater than both colloid nodules (15/22) …

Hepatic Circadian And Differentiation Factors Control Liver Susceptibility For Fatty Liver Disease And Tumorigenesis, Baharan Fekry, Aleix Ribas-Latre, Rachel Van Drunen, Rafael Bravo Santos, Samay Shivshankar, Yulin Dai, Zhongming Zhao, Seung-Hee Yoo, Zheng Chen, Kai Sun, Frances M Sladek, Mamoun Younes, Kristin Eckel-Mahan

Faculty, Staff and Student Publications

Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, and the most common primary liver malignancy to present in the clinic. With the exception of liver transplant, treatment options for advanced HCC are limited, but improved tumor stratification could open the door to new treatment options. Previously, we demonstrated that the circadian regulator Aryl Hydrocarbon-Like Receptor Like 1 (ARNTL, or Bmal1) and the liver-enriched nuclear factor 4 alpha (HNF4α) are robustly co-expressed in healthy liver but incompatible in the context of HCC. Faulty circadian expression of HNF4α- either by isoform switching, or loss of expression- results in an increased …

Risk Of Variceal Hemorrhage And Pretransplant Mortality In Children With Biliary Atresia, Lee M Bass, Wen Ye, Kieran Hawthorne, Daniel H Leung, Karen F Murray, Jean P Molleston, Rene Romero, Saul Karpen, Philip Rosenthal, Kathleen M Loomes, Kasper S Wang, Robert H Squires, Alexander Miethke, Vicky L Ng, Simon Horslen, M Kyle Jensen, Ronald J Sokol, John C Magee, Benjamin L Shneider, Children

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: The natural history of gastroesophageal variceal hemorrhage (VH) in biliary atresia (BA) is not well characterized. We analyzed risk factors, incidence, and outcomes of VH in a longitudinal multicenter study.

APPROACH AND RESULTS: Participants enrolled in either an incident (Prospective Database of Infants with Cholestasis [PROBE]) or prevalent (Biliary Atresia Study of Infants and Children [BASIC]) cohort of BA were included. Variceal hemorrhage (VH) was defined based on gastrointestinal bleeding in the presence of varices accompanied by endoscopic or nontransplant surgical intervention. Cumulative incidence of VH and transplant-free survival was compared based on features of portal hypertension …

Extracellular Vesicles In Β Cell Biology: Role Of Lipids In Vesicle Biogenesis, Cargo, And Intercellular Signaling, Rebecca S Aguirre, Abhishek Kulkarni, Matthew W Becker, Xiaoyong Lei, Soumyadeep Sarkar, Sasanka Ramanadham, Edward A Phelps, Ernesto S Nakayasu, Emily K Sims, Raghavendra G Mirmira

Faculty, Staff and Students Publications

BACKGROUND: Type 1 diabetes (T1D) is a complex autoimmune disorder whose pathogenesis involves an intricate interplay between β cells of the pancreatic islet, other islet cells, and cells of the immune system. Direct intercellular communication within the islet occurs via cell surface proteins and indirect intercellular communication has traditionally been seen as occurring via secreted proteins (e.g., endocrine hormones and cytokines). However, recent literature suggests that extracellular vesicles (EVs) secreted by β cells constitute an additional and biologically important mechanism for transmitting signals to within the islet.

SCOPE OF REVIEW: This review summarizes the general mechanisms of EV formation, with …

Precision Diabetes: Lessons Learned From Maturity-Onset Diabetes Of The Young (Mody), Mustafa Tosur, Louis H Philipson

Faculty, Staff and Students Publications

Maturity-onset of diabetes of the young (MODY) are monogenic forms of diabetes characterized by early onset diabetes with autosomal dominant inheritance. Since its first description about six decades ago, there have been significant advancements in our understanding of MODY from clinical presentations to molecular diagnostics and therapeutic responses. The prevalence of MODY is estimated as at least 1.1-6.5% of the pediatric diabetes population with a high degree of geographic variability that might arise from several factors in the criteria used to ascertain cases. GCK-MODY, HNF1A-MODY, and HNF4A-MODY account for >90% of MODY cases. While some MODY forms do not require …

Efficacy And Safety Of Ensovibep For Adults Hospitalized With Covid-19 : A Randomized Controlled Trial, Christina Barkauskas, Eleftherios Mylonakis, Garyfallia Poulakou, Barnaby E Young, David M Vock, Lianne Siegel, Nicole Engen, Greg Grandits, Nilima R Mosaly, Andrew M Vekstein, Ralph Rogers, Fadi Shehadeh, Matthew Kaczynski, Evangelia K Mylona, Konstantinos N Syrigos, Vasiliki Rapti, David C Lye, Diong Shiau Hui, Lindsay Leither, Kirk U Knowlton, Mamta K Jain, Rubria Marines-Price, Alice Osuji, J Scott Overcash, Ioannis Kalomenidis, Zafeiria Barmparessou, Michael Waters, Karla Zepeda, Peter Chen, Sam Torbati, Francis Kiweewa, Nicholus Sebudde, Eyad Almasri, Alyssa Hughes, Sanjay R Bhagani, Alison Rodger, Uriel Sandkovsky, Robert L Gottlieb, Eriobu Nnakelu, Barbara Trautner, Vidya Menon, Joseph Lutaakome, Michael Matthay, Philip Robinson, Konstantinos Protopapas, Nikolaos Koulouris, Ivan Kimuli, Amiran Baduashvili, Dominique L Braun, Huldrych F Günthard, Srikanth Ramachandruni, Robert Kidega, Kami Kim, Timothy J Hatlen, Andrew N Phillips, Daniel D Murray, Tomas O Jensen, Maria L Padilla, Evan X Accardi, Katy Shaw-Saliba, Robin L Dewar, Marc Teitelbaum, Ven Natarajan, Sylvain Laverdure, Helene C Highbarger, M Tauseef Rehman, Susan Vogel, David Vallée, Page Crew, Negin Atri, Adam J Schechner, Sarah Pett, Fleur Hudson, Jonathan Badrock, Giota Touloumi, Samuel M Brown, Wesley H Self, Crystal M North, Adit A Ginde, Christina C Chang, Anthony Kelleher, Stephanie Nagy-Agren, Shikha Vasudeva, David Looney, Hien H Nguyen, Adriana Sánchez, Amy C Weintrob, Birgit Grund, Shweta Sharma, Cavan S Reilly, Roger Paredes, Agnieszka Bednarska, Norman P Gerry, Abdel G Babiker, Victoria J Davey, Annetine C Gelijns, Elizabeth S Higgs, Virginia Kan, Gail Matthews, B Taylor Thompson, Philippe Legenne, Richa Chandra, H Clifford Lane, James D Neaton, Jens D Lundgren

Faculty, Staff and Students Publications

BACKGROUND: Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection.

OBJECTIVE: To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone.

DESIGN: Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978).

SETTING: Multinational, multicenter trial.

PARTICIPANTS: Adults hospitalized with COVID-19.

INTERVENTION: Intravenous ensovibep, 600 mg, or placebo.

MEASUREMENTS: Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day …

Tertiary Syphilis Masquerading As Oropharyngeal Cancer, Caroline R Christmann, Wesley D Figg, Ritodhi Chatterjee, Philip F Lavere, Niraj Mehta

Faculty, Staff and Students Publications

Syphilis is re-emerging in the United States. Treponema pallidum, the spirochete bacterium responsible for syphilis, has immunoevasive properties that facilitate pathogenesis and widespread tissue involvement. Host immune status, particularly the presence of HIV/AIDS, can influence the presentation and severity of the disease. Patients co-infected with HIV and syphilis may develop atypical lesions, including those involving the oropharynx. Any immunocompromised patient with tongue lesions and lymphadenopathy is presumed to have a wide differential diagnosis, and tissue sampling with histopathologic analysis is indicated. We present a patient with gumma of the tongue as the initial manifestation of tertiary syphilis.

Lifestyle Intervention Strategy To Treat Diabetes In Older Adults: A Randomized Controlled Trial, Alessandra Celli, Yoann Barnouin, Bryan Jiang, Dean Blevins, Georgia Colleluori, Sanjay Mediwala, Reina Armamento-Villareal, Clifford Qualls, Dennis T Villareal

Faculty, Staff and Students Publications

OBJECTIVE: Lifestyle intervention is recommended as first-line treatment of diabetes at all ages; however, little is known about the efficacy of lifestyle intervention in older adults with diabetes. We aimed to determine whether lifestyle intervention would improve glycemic control and age-relevant outcomes in older adults with diabetes and comorbidities.

RESEARCH DESIGN AND METHODS: A total of 100 older adults with diabetes were randomly assigned to 1-year intensive lifestyle intervention (ILI) (diet and exercise at a facility transitioned into community-fitness centers and homes) or healthy lifestyle (HL) group. The primary outcome was change in HbA1c. Secondary outcomes included glucoregulation, body composition, …

Genetic Loci And Prioritization Of Genes For Kidney Function Decline Derived From A Meta-Analysis Of 62 Longitudinal Genome-Wide Association Studies, Mathias Gorski, Humaira Rasheed, Alexander Teumer, Laurent F Thomas, Sarah E Graham, Gardar Sveinbjornsson, Thomas W Winkler, Felix Günther, Klaus J Stark, Jin-Fang Chai, Bamidele O Tayo, Matthias Wuttke, Yong Li, Adrienne Tin, Tarunveer S Ahluwalia, Johan Ärnlöv, Bjørn Olav Åsvold, Stephan J L Bakker, Bernhard Banas, Nisha Bansal, Mary L Biggs, Ginevra Biino, Michael Böhnke, Eric Boerwinkle, Erwin P Bottinger, Hermann Brenner, Ben Brumpton, Robert J Carroll, Layal Chaker, John Chalmers, Miao-Li Chee, Miao-Ling Chee, Ching-Yu Cheng, Audrey Y Chu, Marina Ciullo, Massimiliano Cocca, James P Cook, Josef Coresh, Daniele Cusi, Martin H De Borst, Frauke Degenhardt, Kai-Uwe Eckardt, Karlhans Endlich, Michele K Evans, Mary F Feitosa, Andre Franke, Sandra Freitag-Wolf, Christian Fuchsberger, Piyush Gampawar, Ron T Gansevoort, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Christian Gieger, Daniel F Gudbjartsson, Stein Hallan, Pavel Hamet, Asahi Hishida, Kevin Ho, Edith Hofer, Bernd Holleczek, Hilma Holm, Anselm Hoppmann, Katrin Horn, Nina Hutri-Kähönen, Kristian Hveem, Shih-Jen Hwang, M Arfan Ikram, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Irma Karabegović, Chiea-Chuen Khor, Wolfgang Koenig, Holly Kramer, Bernhard K Krämer, Brigitte Kühnel, Johanna Kuusisto, Markku Laakso, Leslie A Lange, Terho Lehtimäki, Man Li, Wolfgang Lieb, Lifelines Cohort Study, Lars Lind, Cecilia M Lindgren, Ruth J F Loos, Mary Ann Lukas, Leo-Pekka Lyytikäinen, Anubha Mahajan, Pamela R Matias-Garcia, Christa Meisinger, Thomas Meitinger, Olle Melander, Yuri Milaneschi, Pashupati P Mishra, Nina Mononen, Andrew P Morris, Josyf C Mychaleckyj, Girish N Nadkarni, Mariko Naito, Masahiro Nakatochi, Mike A Nalls, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja M Nolte, Teresa Nutile, Michelle L O'Donoghue, Jeffrey O'Connell, Isleifur Olafsson, Marju Orho-Melander, Afshin Parsa, Sarah A Pendergrass, Brenda W J H Penninx, Mario Pirastu, Michael H Preuss, Bruce M Psaty, Laura M Raffield, Olli T Raitakari, Myriam Rheinberger, Kenneth M Rice, Federica Rizzi, Alexander R Rosenkranz, Peter Rossing, Jerome I Rotter, Daniela Ruggiero, Kathleen A Ryan, Charumathi Sabanayagam, Erika Salvi, Helena Schmidt, Reinhold Schmidt, Markus Scholz, Ben Schöttker, Christina-Alexandra Schulz, Sanaz Sedaghat, Christian M Shaffer, Karsten B Sieber, Xueling Sim, Mario Sims, Harold Snieder, Kira J Stanzick, Unnur Thorsteinsdottir, Hannah Stocker, Konstantin Strauch, Heather M Stringham, Patrick Sulem, Silke Szymczak, Kent D Taylor, Chris H L Thio, Johanne Tremblay, Simona Vaccargiu, Pim Van Der Harst, Peter J Van Der Most, Niek Verweij, Uwe Völker, Kenji Wakai, Melanie Waldenberger, Lars Wallentin, Stefan Wallner, Judy Wang, Dawn M Waterworth, Harvey D White, Cristen J Willer, Tien-Yin Wong, Mark Woodward, Qiong Yang, Laura M Yerges-Armstrong, Martina Zimmermann, Alan B Zonderman, Tobias Bergler, Kari Stefansson, Carsten A Böger, Cristian Pattaro, Anna Köttgen, Florian Kronenberg, Iris M Heid

Faculty, Staff and Student Publications

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine …

Phenotypic And Genetic Spectrum Of Atp6v1a Encephalopathy: A Disorder Of Lysosomal Homeostasis, Renzo Guerrini, Davide Mei, Katalin Kerti-Szigeti, Sara Pepe, Mary Kay Koenig, Gretchen Von Allmen, Megan T Cho, Kimberly Mcdonald, Janice Baker, Vikas Bhambhani, Zöe Powis, Lance Rodan, Rima Nabbout, Giulia Barcia, Jill A Rosenfeld, Carlos A Bacino, Cyril Mignot, Lillian H Power, Catharine J Harris, Dragan Marjanovic, Rikke S Møller, Trine B Hammer, Riikka Keski Filppula, Päivi Vieira, Clara Hildebrandt, Stephanie Sacharow, Luca Maragliano, Fabio Benfenati, Katherine Lachlan, Andreas Benneche, Florence Petit, Jean Madeleine De Sainte Agathe, Barbara Hallinan, Yue Si, Ingrid M Wentzensen, Fanggeng Zou, Vinodh Narayanan, Naomichi Matsumoto, Alessandra Boncristiano, Giancarlo La Marca, Mitsuhiro Kato, Kristin Anderson, Carmen Barba, Luisa Sturiale, Domenico Garozzo, Roberto Bei, Laura Masuelli, Valerio Conti, Gaia Novarino, Anna Fassio

Faculty, Staff and Student Publications

Vacuolar-type H+-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease. Here we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/β family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased …

Immunotherapy For Type 1 Diabetes Mellitus By Adjuvant-Free Schistosoma Japonicum-Egg Tip-Loaded Asymmetric Microneedle Patch (Stamp), Haoming Huang, Dian Hu, Zhuo Chen, Jiarong Xu, Rengui Xu, Yusheng Gong, Zhengming Fang, Ting Wang, Wei Chen

Faculty, Staff and Student Publications

BACKGROUND: Type 1 diabetes mellitus (T1DM) is an autoimmune disease mediated by autoreactive T cells and dominated by Th1 response polarization. Insulin replacement therapy faces great challenges to this autoimmune disease, requiring highly frequent daily administration. Intriguingly, the progression of T1DM has proven to be prevented or attenuated by helminth infection or worm antigens for a relatively long term. However, the inevitable problems of low safety and poor compliance arise from infection with live worms or direct injection of antigens. Microneedles would be a promising candidate for local delivery of intact antigens, thus providing an opportunity for the clinical immunotherapy …

Understanding Diagnostic Pathways In Systemic Sclerosis And Systemic Sclerosis-Associated Interstitial Lung Disease: A Retrospective Cohort Study, Shervin Assassi, Nan Shao, Ziwei Yin, Elizabeth R Volkmann, Donald F Zoz, Thomas B Leonard

Faculty, Staff and Student Publications

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is usually detected in a patient known to have SSc but may be diagnosed prior to SSc. We probed an insurance database to investigate documentation of ILD prior to SSc. Using Optum's Clinformatics® Data Mart Database, we identified patients with an SSc index date between January 1, 2010, and September 30, 2015, based on International Classification of Diseases (ICD)-9-Clinical Modification (CM) codes, ≥2 medical claims associated with SSc on different dates within 1 year, and ≥3 years of continuous enrollment prior to SSc index date (ICD-9-CM cohort). We identified an ICD-10-CM cohort comprising patients …

Structural Plasticity Can Produce Metaplasticity, Wenli Zhao, Shuo Han, Na Qiu, Wenbo Feng, Mengjie Lu, Wenru Zhang, Mu Wang, Qingtong Zhou, Shutian Chen, Wei Xu, Juan Du, Xiaojing Chu, Cuiying Yi, Antao Dai, Liaoyuan Hu, Michelle Y Shen, Yaping Sun, Qing Zhang, Yingli Ma, Wenge Zhong, Dehua Yang, Ming-Wei Wang, Beili Wu, Qiang Zhao

Faculty, Staff and Student Publications

Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of Gi1-bound SSTR2 in the presence of the …

Placental Pathology In Spontaneous And Iatrogenic Preterm Birth: Different Entities With Unique Pathologic Features, Lucy T Brink, Drucilla J Roberts, Colleen A Wright, Daan G Nel, Pawel T Schubert, Theonia K Boyd, David R Hall, Hein Odendaal

Faculty, Staff and Student Publications

INTRODUCTION: Placental pathology is an important contributor to the understanding of preterm birth and reveals major differences between spontaneous preterm birth (SPTB) and iatrogenic preterm birth (IPTB). The aim of this study was to investigate these relationships.

METHODS: Research midwives collected placentas from 1101 women with singleton pregnancies who were enrolled in the Safe Passage Study. Trained pathology technologists prepared and processed placenta specimens for macroscopic and microscopic examination by designated pathologists. Statistical analyses were done with STATISTICA version 13.

RESULTS: In SPTB we found more cases of accelerated villous maturation; however, the other features of maternal vascular malperfusion (MVM) …

Influenza-Induced Thrombotic Microangiopathy In A Patient With Cancer On Proteasome Inhibitor: A Diagnostic Dilemma, Christopher D Hamad, Zachary C Hoelscher, Amanda Tchakarov, Jaya Kala

Faculty, Staff and Student Publications

Thrombotic microangiopathy (TMA) in a cancer patient is a common complication of either cancer itself or anticancer therapy. Incidence of TMA from anticancer therapy was found to be > 15%, since the introduction of anti-angiogenic drugs like anti-vascular endothelial growth factor agents. It is, however, important to not ignore other causes of TMA such as bacteria, viruses, antiplatelet drugs, hereditary complement mutations, and autoimmune disorders. We present such a diagnostic dilemma in our patient who was admitted with influenza and was found to have TMA on renal biopsy, while on proteasome inhibitor (PI) therapy. With this case, we would like to …