Digital Commons Network^™

Evaluation Of Methotrexate Pharmacogenomic Variation To Predict Acute Neurotoxicity In Children With Acute Lymphoblastic Leukemia, Rachel D Harris, Olga A Taylor, M Monica Gramatges, Amy E Hughes, Mark Zobeck, Sandi Pruitt, M Brooke Bernhardt, Ashley Chavana, Van Huynh, Kathleen Ludwig, Laura Klesse, Kenneth Heym, Timothy Griffin, Rodrigo Erana, Juan Carlos Bernini, Ashley Choi, Yuu Ohno, Melissa A Richard, Alanna C Morrison, Han Chen, Bing Yu, Philip J Lupo, Karen Rabin, Michael E Scheurer, Austin L Brown

Faculty, Staff and Students Publications

BACKGROUND: Methotrexate is an important component of curative therapy in childhood acute lymphoblastic leukemia (ALL), but the role of genetic variation influencing methotrexate clearance and transport in toxicity susceptibility in children with ALL is not well established. Therefore, we evaluated the association between suspected methotrexate pharmacogenomic variants and methotrexate-related neurotoxicity.

METHODS: This study included children (aged 2-20 years) diagnosed with ALL (2005-2019) at six treatment centers in the southwest United States. Clinical information was abstracted from medical records. Suspected neurotoxic events occurring within 21 days of intravenous and/or intrathecal methotrexate delivered between the end of induction and start of maintenance …

Head-To-Head Comparison Of Aptamer- And Antibody-Based Proteomic Platforms In Human Cerebrospinal Fluid Samples From A Real-World Memory Clinic Cohort, Raquel Puerta, Amanda Cano, Pablo García-González, Fernando García-Gutiérrez, Maria Capdevila, Itziar De Rojas, Clàudia Olivé, Josep Blázquez-Folch, Oscar Sotolongo-Grau, Andrea Miguel, Laura Montrreal, Pamela Martino-Adami, Asif Khan, Adelina Orellana, Yun Ju Sung, Ruth Frikke-Schmidt, Natalie Marchant, Jean Charles Lambert, Maitée Rosende-Roca, Montserrat Alegret, Maria Victoria Fernández, Marta Marquié, Sergi Valero, Lluís Tárraga, Carlos Cruchaga, Alfredo Ramírez, Mercè Boada, Bart Smets, Alfredo Cabrera-Socorro, Agustín Ruiz

Faculty, Staff and Student Publications

High-throughput proteomic platforms are crucial to identify novel Alzheimer’s disease (AD) biomarkers and pathways. In this study, we evaluated the reproducibility and reliability of aptamer-based (SomaScan® 7k) and antibody-based (Olink® Explore 3k) proteomic platforms in cerebrospinal fluid (CSF) samples from the Ace Alzheimer Center Barcelona real-world cohort. Intra- and inter-platform reproducibility were evaluated through correlations between two independent SomaScan® assays analyzing the same samples, and between SomaScan® and Olink® results. Association analyses were performed between proteomic measures, CSF biological traits, sample demographics, and AD endophenotypes. Our 12-category metric of reproducibility combining correlation analyses identified 2428 highly reproducible SomaScan CSF measures, …

Implications Of Myocardial Strain In Primary Mitral Regurgitation-A Cardiovascular Magnetic Resonance Study, Simone Romano, Danai Kitkungvan, Duc T Nguyen, Carlos El-Tallawi, Edward A Graviss, Afshin Farzaneh-Far, Dipan J Shah

Faculty, Staff and Student Publications

Aims: Chronic primary mitral regurgitation (MR) results in progressive left ventricular (LV) remodelling. Abnormal myocardial deformation (strain) can be present despite preserved ejection fraction (EF). Cardiovascular magnetic resonance (CMR) feature-tracking techniques allow assessment of global longitudinal strain (GLS) from routine cine images. The aim of this study is to evaluate the prognostic value of CMR feature tracking-derived GLS in patients with primary MR.

Methods and results: Consecutive patients undergoing CMR for chronic MR from January 2012 to June 2018 were enrolled. Patients with LVEF < 50% were excluded. The composite primary outcome aiming to detect decompensation related to MR comprised (i) referral for mitral surgery owing to symptoms or LV systolic dysfunction or (ii) cardiovascular death. The secondary outcome was all-cause death. A total of 422 patients were followed for a median of 2.7 years, and the primary endpoint was met in 93 patients (34 patients reported symptoms at baseline). At multivariable analysis, GLS≥ -16.6% was associated with primary outcome [hazard ratio (HR) 1.90, P = 0.01]. In moderate MR cohort, patients with GLS≥ -16.6% had worse event-free survival, whereas there was no significant difference in mild or severe MR groups. GLS≥ -16.0% remained associated with all-cause death after adjusting for other covariates including the MR severity (HR 2.24, P = 0.02).

Conclusion: In patients with primary MR with preserved systolic function, GLS was associated with our composite …

Acute Myocarditis Secondary To Human Metapneumovirus: A Case Series And Mini-Review, Hussam Al Hennawi, Aamna Khan, Alexander Shpilman, Jennifer A. Mazzoni

Abington Jefferson Health Papers

Among viral myocarditis, human metapneumovirus (hMPV) is a rare causative agent with associated cardiac complications. This report provides insight into the disease progression and sheds light on reported cases from the literature. We present the clinical courses of two patients, aged 68 and 58, who developed myocarditis secondary to hMPV infection. Despite the typical severity associated with viral myocarditis in older populations, both patients experienced significant improvement in their condition and ultimately survived. This report highlights the necessity of recognizing hMPV as a potential cause of myocarditis, particularly in older adults presenting with simultaneous respiratory and cardiac symptoms. The recovery …

Food For Thought: A Qualitative Assessment Of Medical Trainee And Faculty Perceptions Of Nutrition Education, Olivia Kunitsky, Mahdi Taye, Karla Feeley, Hugh Johnson, Abigail Glynn, Avery Stivale, Matthew Hamers, Alexis Notarianni, Sireesha Mamillapalli, Gabi Waite, Sonia Lobo

Department of Neurology Faculty Papers

BACKGROUND: The American Society of Clinical Nutrition recommends 37 to 44 h of undergraduate medical nutrition education. The Total Health Curriculum at Geisinger Commonwealth School of Medicine (GCSOM) contains 14 h of objective-based nutritional instruction. This study aimed to examine the perceptions of key stakeholders regarding the role of nutrition in medicine and to identify barriers, opportunities for improvement, and roles/responsibilities for innovative implementation of nutrition education.

METHODS: This exploratory, qualitative study employed a phenomenological approach and inductive coding process. Purposive sampling recruited medical students, undergraduate medical education (UME) faculty, physicians, and other healthcare professionals at GCSOM and affiliated clinical …

Age-Dependent Regulation Of Axoglial Interactions And Behavior By Oligodendrocyte Ankyring, Xiaoyun Ding, Yu Wu, Anna Vainshtein, Victoria Rodriguez, Emily Ricco, James T Okoh, Yanhong Liu, Daniel C Kraushaar, Elior Peles, Matthew N Rasband

Faculty, Staff and Students Publications

The bipolar disorder (BD) risk gene ANK3 encodes the scaffolding protein AnkyrinG (AnkG). In neurons, AnkG regulates polarity and ion channel clustering at axon initial segments and nodes of Ranvier. Disruption of neuronal AnkG causes BD-like phenotypes in mice. During development, AnkG is also expressed at comparable levels in oligodendrocytes and facilitates the efficient assembly of paranodal junctions. However, the physiological roles of glial AnkG in the mature nervous system, and its contributions to BD-like phenotypes, remain unexplored. Here, we show that oligodendroglia-specific AnkG conditional knockout results in destabilization of axoglial interactions in aged but not young adult mice. In …

Transition To Enteral Triazole Antifungal Therapy For Pediatric Invasive Candidiasis: Secondary Analysis Of A Multicenter Cohort Study Conducted By The Pediatric Fungal Network, Robert F T Bucayu, Craig L K Boge, Inci Yildirim, Martha Avilés-Robles, Surabhi B Vora, David M Berman, Tanvi S Sharma, Lillian Sung, Elio Castagnola, Debra L Palazzi, Lara Danziger-Isakov, Dwight E Yin, Emmanuel Roilides, Gabriela Maron, Alison C Tribble, Pere Soler-Palacin, Eduardo López-Medina, José Romero, Kiran Belani, Antonio C Arrieta, Fabianne Carlesse, Dawn Nolt, Natasha Halasa, Daniel Dulek, Sujatha Rajan, William J Muller, Monica I Ardura, Alice Pong, Blanca E Gonzalez, Christine M Salvatore, Anna R Huppler, Catherine Aftandilian, Mark J Abzug, Arunaloke Chakrabarti, Michael Green, Irja Lutsar, Elizabeth D Knackstedt, Sarah K Johnson, William J Steinbach, Brian T Fisher, Rachel L Wattier

Faculty, Staff and Students Publications

Of 319 children with invasive candidiasis, 67 (21%) transitioned from intravenous to enteral antifungal therapy. Eight (12%) transitioned back to intravenous antifungal therapy, one due to perceived treatment failure defined by clinical progression or worsening. Global treatment response at study completion was successful in 66 participants who transitioned to enteral therapy.

Double-Blind Randomised Trial Of Saline Solution For Gargling And Nasal Rinsing In Sars-Cov-2 Infection, Sebastian R Espinoza, Lexton Trauffler, Amir Shamshirsaz, Alireza Shamshirsaz, Andres Espinoza, Jimmy Espinoza, Alice O'Brien

Faculty, Staff and Student Publications

Background: Previous studies have shown that hypertonic saline nasal irrigation and gargling reduced the duration of symptoms in upper respiratory infections caused by coronavirus. This study aims to investigate the effects of two saline regimens on symptoms associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).

Methods: Between 2020 and 2022, individuals aged 18-65 years who tested positive for SARS-CoV-2 infection via polymerase chain reaction (PCR) were randomly assigned to either low- or high-saline regimens for 14 days. The low-saline solutions contained 2.13 g of salt dissolved in eight ounces of warm water, while the high-saline solution contained six grams of …

Potential Of Right Ventricular Function Assessment With Echocardiography In Transcatheter Aortic Valve Replacement, Yoshihisa Morita, Taro Kariya, Michael Dougherty, Andrew Peters, Nicholas Ruggiero

Division of Cardiology Faculty Papers

BACKGROUND: Right ventricular (RV) function assessment by echocardiography can be challenging due to its complex morphology. Also, increasing use of sedation rather than general anesthesia for transfemoral approach transcatheter aortic valve replacement (TAVR) reduces the need for intraoperative transesophageal echocardiography (TEE). Recent clinical studies have demonstrated the importance of 3-dimensional (3D) echocardiography and a longitudinal strain for RV function assessment. In this study, we compared RV function echocardiographic assessment methodologies in TAVR and investigated its clinical utility.

METHODS: This was a prospective, observational study of TAVR at a large academic hospital. Inclusion criteria were adult patients undergoing TAVR requiring intraoperative …

Aperiodic Spectral Slope Tracks The Effects Of Brain State On Saliency Responses In The Human Auditory Cortex, Madaline Mocchi, Eleonora Bartoli, John Magnotti, Jan Willem De Gee, Brian Metzger, Bailey Pascuzzi, Raissa Mathura, Suhruthaa Pulapaka, Wayne Goodman, Sameer Sheth, Matthew J Mcginley, Kelly Bijanki

Faculty, Staff and Students Publications

Alteration of responses to salient stimuli occurs in a wide range of brain disorders and may be rooted in pathophysiological brain state dynamics. Specifically, tonic and phasic modes of activity in the reticular activating system (RAS) influence, and are influenced by, salient stimuli, respectively. The RAS influences the spectral characteristics of activity in the neocortex, shifting the balance between low- and high-frequency fluctuations. Aperiodic '1/f slope' has emerged as a promising composite measure of these brain state dynamics. However, the relationship of 1/f slope to state-dependent processes, such as saliency, is less explored, particularly intracranially in humans. Here, we record …

Digital Cognitive Behavioral Therapy Vs Education For Pain In Adults With Sickle Cell Disease, Charles R. Jonassaint, Christina M. Lalama, C. Patrick Carroll, Sherif M. Badawy, Megan E. Hamm, Jennifer N. Stinson, Chitra Lalloo, Santosh L. Saraf, Victor R. Gordeuk, Robert M. Cronin, Nirmish Shah, Sophie M. Lanzkron, Darla Liles, Julia A. O'Brien, Cassandra Trimnell, Lakiea Bailey, Raymona H. Lawrence, Leshana Saint Jean, Michael Debaun, Laura M. De Castro, Tonya M. Palermo, Kaleab Z. Abebe

Department of Medicine Faculty Papers

Despite the burden of chronic pain in sickle cell disease (SCD), nonpharmacological approaches remain limited. This multisite, randomized trial compared digital cognitive behavioral therapy (CBT) with a digital pain/SCD education program ("Education") for managing pain and related symptoms. Participants were recruited virtually from seven SCD centers and community organizations in the United States. Adults (aged ≥18 years) with SCD-related chronic pain and/or daily opioid use were assigned to receive either CBT or Education for 12 weeks. Both groups used an app with interactive chatbot lessons and received personalized health coach support. The primary outcome was the change in pain interference …

Loss Of Chop Prevents Joint Degeneration And Pain In A Mouse Model Of Pseudoachondroplasia, Jacqueline T Hecht, Alka C Veerisetty, Mohammad G Hossain, Debabrata Patra, Michele Carrer, Frankie Chiu, Dorde Relic, Paymaan Jafar-Nejad, Karen L Posey

Faculty, Staff and Student Publications

Pseudoachondroplasia (PSACH), a severe dwarfing condition characterized by impaired skeletal growth and early joint degeneration, results from mutations in cartilage oligomeric matrix protein (COMP). These mutations disrupt normal protein folding, leading to the accumulation of misfolded COMP in chondrocytes. The MT-COMP mouse is a murine model of PSACH that expresses D469del human COMP in response to doxycycline and replicates the PSACH chondrocyte and clinical pathology. The basis for the mutant-COMP pathology involves endoplasmic reticulum (ER) stress signaling through the PERK/eIF2α/CHOP pathway. C/EBP homologous protein (CHOP), in conjunction with a TNFα inflammatory process, upregulates mTORC1, hindering autophagy clearance of mutant COMP …

Evaluating The Impact Of A Novel Program To Address Acute Food Insecurity Among Cancer Patients, Elliott M. Sina, Michael Rowe, Gina Mancuso, Gregory Garber, W. Kevin Kelly, Amy E. Leader

Kimmel Cancer Center Faculty Papers

INTRODUCTION: Acute food insecurity (FI) significantly impacts cancer patients' health, exacerbating physical and psychological burdens. While current interventions address chronic FI, acute cases remain undermanaged. Legacy of Hope, a Philadelphia-based non-profit, addresses this gap through its Emergency Patient Support Network (EPSN), offering free bi-weekly groceries to patients facing acute FI.

MATERIALS AND METHODS: The pilot study evaluated EPSN's impact utilizing the Legacy of Hope Acute Food Insecurity (LOHAFI) survey, which was performed at baseline and two weeks post-intervention. The survey combines the Functional Assessment of Cancer Therapy-General (FACT-G7) and questions on food and financial security. Mean scores and frequencies were …

Use Of Cigarettes And E-Cigarettes, Impulsivity, And Anxiety: Influences On Suicidal Ideation Among Youth And Young Adults In Texas, Anna V Wilkinson, Baojiang Chen, Alan C Swann, David P Graham, David A Nielsen, Thomas R Kosten, Alexandra Loukas, Dale S Mantey, Bara S Bataineh, Melissa B Harrell

Faculty, Staff and Students Publications

Introduction: Cigarette use and smoking intensity increase risk of suicidal ideation. Less is known about e-cigarette use. Here we examine direct influences of cigarette versus e-cigarette use on suicidal ideation among 16- to 23-year-olds in Texas.

Aims and methods: Since 2019, the Texas Adolescent Tobacco and Marketing Surveillance Study collected data on suicidal ideation every 6 months covering the previous 2 weeks. Youths answering that they had "thoughts that you would be better off dead, or of hurting yourself" on more than 2 of 14 days were categorized as having suicidal ideation. Generalized linear mixed-effects logistic regressions examined the influence …

Phenotypic And Genetic Heterogeneity Of A Pakistani Cohort Of 15 Consanguineous Families Segregating Variants In Leber Congenital Amaurosis-Associated Genes, Zainab Akhtar, Sumaira Altaf, Yumei Li, Sana Bibi, Jamal Shah, Kiran Afshan, Meng Wang, Hafiz Muhammad Jafar Hussain, Nadeem Qureshi, Rui Chen, Sabika Firasat

Faculty, Staff and Students Publications

Background: Leber congenital amaurosis (LCA) is a congenital onset severe form of inherited retinal dystrophy (IRD) and a common cause of pediatric blindness. Disease-causing variants in at least 14 genes are reported to predispose LCA phenotype. LCA is inherited as an autosomal recessive disease. It can be an isolated eye disorder or as part of a syndrome, such as Senior Loken or Joubert syndrome. Sequencing studies from consanguineous populations have proven useful for novel variants identification; thus, the present study aimed to explore the genetic heterogeneity of 15 consanguineous Pakistani families, each segregating a severe IRD phenotype using targeted next …

Survival Analysis Of Clear Cell Renal Cell Carcinoma Based On Radiomics And Deep Learning Features From Ct Images, Zhennan Lu, Sijia Wu, Dan Ni, Meng Zhou, Tao Wang, Xiaobo Zhou, Liyu Huang, Yu Yan

Faculty, Staff and Student Publications

Purpose: To create a nomogram for accurate prognosis of patients with clear cell renal cell carcinoma (ccRCC) based on computed tomography images.

Methods: Eight hundred twenty-two ccRCC patients with contrast-enhanced computed tomography images involved in this study were collected. A rectangular region of interest surrounding the tumor was used to extract quantitative radiomics and deep-learning features, which were filtered by Cox proportional hazard regression model and least absolute shrinkage and selection operator. Then the selected features formed a fusion signature, which was assessed by Cox proportional hazard regression model method, Kaplan-Meier analysis, receiver operating characteristic curves, and concordance index (C-index) …

Assessing Tolerability With The Functional Assessment Of Cancer Therapy Item Gp5: Psychometric Evidence From Libretto-531, A Phase 3 Trial Of Selpercatinib In Medullary Thyroid Cancer, Antoine Regnault, Laurine Bunod, Angely Loubert, Marcia S. Brose, Lisa M. Hess, Patricia Maeda, Yan Lin, Rebecca M. Speck, Adrienne M. Gilligan, Nalin Payakachat

Department of Medical Oncology Faculty Papers

BACKGROUND: This psychometric analysis generated evidence to support the use of the Functional Assessment of Cancer Therapy item GP5 (GP5) as a measure of tolerability and confirms the appropriateness of categorizing "high side-effect burden" using a rating of 3 or 4 (score ranges 0-4) in patients with advanced/metastatic RET-mutant medullary thyroid cancer (MTC).

METHODOLOGY: Blinded, pooled interim data from the safety population (n=290) enrolled in the phase 3 LIBRETTO-531 trial (NCT04211337) were used. Intraclass correlation coefficients (ICC) were calculated for test-retest reliability using data from cycles 1-2 post-baseline. Construct validity was evaluated by examining the correlations of GP5 ratings with …

Age-Related Tfeb Downregulation In Proximal Tubules Causes Systemic Metabolic Disorders And Occasional Apolipoprotein A4-Related Amyloidosis, Jun Nakamura, Takeshi Yamamoto, Yoshitsugu Takabatake, Tomoko Namba-Hamano, Atsushi Takahashi, Jun Matsuda, Satoshi Minami, Shinsuke Sakai, Hiroaki Yonishi, Shihomi Maeda, Sho Matsui, Hideaki Kawai, Isao Matsui, Tadashi Yamamuro, Ryuya Edahiro, Seiji Takashima, Akira Takasawa, Yukinori Okada, Tamotsu Yoshimori, Andrea Ballabio, Yoshitaka Isaka

Duncan NRI Faculty and Staff Publications

With the aging of society, the incidence of chronic kidney disease (CKD), a common cause of death, has been increasing. Transcription factor EB (TFEB), the master transcriptional regulator of the autophagy/lysosomal pathway, is regarded as a promising candidate for preventing various age-related diseases. However, whether TFEB in the proximal tubules plays a significant role in elderly patients with CKD remains unknown. First, we found that nuclear TFEB localization in proximal tubular epithelial cells (PTECs) declined with age in both mice and humans. Next, we generated PTEC-specific Tfeb-deficient mice and bred them for up to 24 months. We found that TFEB …

Deuterated Water Labeling In Ibrutinib-Treated Patients With Cll: Leukemia Cell Kinetics Correlate With Ighv, Zap-70, And Mrd, Ekaterina Kim, Shih-Shih Chen, Mariela Sivina, Hyunsoo Hwang, Xuelin Huang, Alessandra Ferrajoli, Nitin Jain, William G Wierda, Dominik Wodarz, Nicholas Chiorazzi, Jan A Burger

Faculty, Staff and Student Publications

Deuterated (“heavy”) water labeling in patients with chronic lymphocytic leukemia (CLL) demonstrates that IGHV unmutated and ZAP-70+ patients have higher blood and tissue CLL death rates on ibrutinib therapy, resulting in lower measurable residual disease levels with long-term ibrutinib treatment. This trial was registered at www.clinicaltrials.gov as #NCT01752426.

Transforming Growth Factor-Beta Is Increased In Sputum From Individuals With Rheumatoid Arthritis-Associated Pulmonary Fibrosis, Timothy M. Wilson, Matthew Bolt, Andrew Stahly, Joyce S. Lee, Tami J. Bang, Peter B. Sachs, Kevin D. Deane, Stephen M. Humphries, Joshua J. Solomon, M. Kristen Demoruelle

Division of Rheumatology Faculty Papers

BACKGROUND: Interstitial lung disease (ILD) develops in 5-10% of patients with RA and contributes significantly to morbidity and mortality, particularly in those with a fibrotic phenotype. Yet, biomarkers to reliably identify RA patients with underlying pulmonary fibrosis are inadequate. Herein, we used sputum to identify lung-based biomarkers that distinguish RA patients with underlying pulmonary fibrosis and may better inform underlying pathogenesis in RA-ILD.

METHODS: We included 37 RA patients with pulmonary fibrosis (RA-PF) and 30 RA patients without ILD (RA-no-ILD). Induced sputum and serum were tested for TGF-β levels by immunoassay. DNA was extracted to determine presence of the MUC5B …

High Ldl Particle And Apob Concentrations In Patients With Adrenal Cortical Adenomas, Rashi Sandooja, Jasmine Saini, Annop Kittithaworn, Raul Gregg-Garcia, Prerna Dogra, Elizabeth Atkinson, Kai Yu, Vanessa Fell, Vinaya Simha, Margery A Connelly, Robin P F Dullaart, Irina Bancos

Faculty, Staff and Students Publications

Context: Patients with nonfunctioning adenomas (NFAs), adenomas with mild autonomous cortisol secretion (MACS) and Cushing syndrome (CS) demonstrate an increased cardiovascular risk.

Objective: This work aimed to determine the extent of lipoprotein abnormalities in NFA, MACS, and CS.

Methods: We conducted a single-center, cross-sectional study of patients with NFA (n = 167), MACS (n = 213), CS (n = 142), and referent individuals (n = 202) between January 2015 and July 2022. Triglyceride-rich lipoprotein particles (TRLP), low-density lipoprotein particles (LDLP), high-density lipoprotein particles (HDLP), their subclasses and sizes were measured using nuclear magnetic resonance spectroscopy. Multivariable logistic analyses were adjusted …

Functional Properties Of Corticothalamic Circuits Targeting Paraventricular Thalamic Neurons, Guillermo Aquino-Miranda, Dounya Jalloul, Xu O Zhang, Sa Li, Gilbert J Kirouac, Michael Beierlein, Fabricio H Do Monte

Faculty, Staff and Student Publications

Corticothalamic projections to sensorimotor thalamic nuclei show modest firing rates and serve to modulate the activity of thalamic relay neurons. By contrast, here we find that high-order corticothalamic projections from the prelimbic (PL) cortex to the anterior paraventricular thalamic nucleus (aPVT) maintain high-frequency activity and evoke strong synaptic excitation of aPVT neurons in rats. In a significant fraction of aPVT cells, such high-frequency excitation of PL-aPVT projections leads to a rapid decay of action potential amplitudes, followed by a depolarization block (DB) that strongly limits aPVT maximum firing rates, thereby regulating both defensive and appetitive behaviors in a frequency-dependent manner. …

Centering Autonomy And Choice To Support Oral Prep Utilization Among People Who Inject Drugs: Qualitative Lessons From Hptn 094 Integra, Amaya Perez-Brumer, Rose Schmidt, Rebecca Kennedy, Jordan E Lake, Yolanda R Villarreal, Sydney Bornstein, Irene Kuo, Omar Nieto, Julie Franks, Cecile Denis, Nabila El-Bassel, Steve Shoptaw, Peter Davidson, Laramie R Smith

Faculty, Staff and Student Publications

Background: Oral Pre-exposure prophylaxis (PrEP) is effective in preventing HIV transmission. However, despite high rates of HIV risk behaviors among people who inject drugs (PWID), this population remains underserved by current HIV prevention efforts in the United States. To address this challenge, we conducted an in-depth exploration of perspectives on using oral PrEP among PWID engaged in the HIV Prevention Trials Network (HPTN) 094 INTEGRA Study.

Methods: Guided by the Practical, Robust, Implementation, and Sustainability Model (PRISM), our qualitative study drew on semi-structured interviews conducted as part of the embedded implementation science evaluation of HPTN 094 INTEGRA. Seventy-seven PWID participants …

Targeting Corticotropin-Releasing Hormone Receptor Type 1 (Crhr1) Neurons: Validating The Specificity Of A Novel Transgenic Crhr1-Flpo Mouse, Mason Hardy, Yuncai Chen, Tallie Z Baram, Nicholas J Justice

Faculty, Staff and Student Publications

Corticotropin-releasing hormone (CRH) signaling through its cognate receptors, CRHR1 and CRHR2, contributes to diverse stress-related functions in the mammalian brain. Whereas CRHR2 is predominantly expressed in choroid plexus and blood vessels, CRHR1 is abundantly expressed in neurons in discrete brain regions, including the neocortex, hippocampus and nucleus accumbens. Activation of CRHR1 influences motivated behaviors, emotional states, and learning and memory. However, it is unknown whether alterations in CRHR1 signaling contribute to aberrant motivated behaviors observed, for example, in stressful contexts. These questions require tools to manipulate CRHR1 selectively. Here we describe and validate a novel Crhr1-FlpO mouse. Using bacterial artificial …

Structural Variant Allelic Heterogeneity In Mecp2 Duplication Syndrome Provides Insight Into Clinical Severity And Variability Of Disease Expression, Davut Pehlivan, Jesse D Bengtsson, Sameer S Bajikar, Christopher M Grochowski, Ming Yin Lun, Mira Gandhi, Angad Jolly, Alexander J Trostle, Holly K Harris, Bernhard Suter, Sukru Aras, Melissa B Ramocki, Haowei Du, Michele G Mehaffey, Kyunghee Park, Ellen Wilkey, Cemal Karakas, Jesper J Eisfeldt, Maria Pettersson, Lynn Liu, Marwan S Shinawi, Virginia E Kimonis, Wojciech Wiszniewski, Kyle Mckenzie, Timo Roser, Angela M Vianna-Morgante, Alberto S Cornier, Ahmed Abdelmoity, James P Hwang, Shalini N Jhangiani, Donna M Muzny, Tadahiro Mitani, Kazuhiro Muramatsu, Shin Nabatame, Daniel G Glaze, Jawid M Fatih, Richard A Gibbs, Zhandong Liu, Anna Lindstrand, Fritz J Sedlazeck, James R Lupski, Huda Y Zoghbi, Claudia M B Carvalho

Faculty, Staff and Students Publications

BACKGROUND: MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXSL families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ copy number variant breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated.

METHODS: To study the role of the genomic rearrangement structures on an individual's clinical phenotypic variability, we employed a comprehensive …

Large-Scale Crispr/Cas9 Deletions Within The Wfdc Gene Cluster Uncover Gene Functionality And Critical Roles In Mammalian Reproduction, Katarzyna Kent, Kaori Nozawa, Rachel Parkes, Laura Dean, Frey Daniel, Mei Leng, Antrix Jain, Anna Malovannaya, Martin M Matzuk, Thomas X Garcia

Faculty, Staff and Students Publications

Despite 96 million years of evolution separating humans and rodents, 11 closely related reproductive tract-specific genes in humans—SPINT3, WFDC6, EPPIN, WFDC8, WFDC9, WFDC10A, WFDC11, WFDC10B, WFDC13, SPINT4, and WFDC3—and the 13 reproductive tract-specific orthologous genes in mice, form highly conserved syntenic gene clusters indicative of conserved, combined critical functions. Further, despite significant progress toward a nonhormonal male contraceptive targeting the protein encoded by one of these genes, epididymal peptidase inhibitor (EPPIN), and associations found between mutations in EPPIN and an increased risk of male infertility, neither EPPIN nor …

Whispers In The Wind: Face Mask Sampling For Mycobacterium Tuberculosis Detection In Children With Pulmonary Tuberculosis, Lennard Meiwes, Irina Kontsevaya, Dumitru Chesov, Stela Kulciţkaia, Viola Dreyer, Doris Hillemann, Qiniso Dlamini, Caroline Williams, Michael Barer, Folke Brinkmann, Renate Krüger, Stephanie Thee, Alexander Kay, Anna Maria Mandalakas, Christoph Lange

Faculty, Staff and Students Publications

Background: Recently, face mask sampling (FMS) confirmed detection of Mycobacterium tuberculosis DNA from exhaled breath in adults with tuberculosis. To date, no study has evaluated the use of FMS to detect pulmonary tuberculosis in children. We developed a method for FMS of M. tuberculosis-specific DNA in children and performed a clinical exploration to assess feasibility in children.

Methods: Face masks were spiked, analyzed on GeneXpert-Ultra, quantitative polymerase chain reaction, and targeted next-generation sequencing. Children with pulmonary tuberculosis were asked to wear 3 modified FFP2 masks for 30 minutes as part of an exploratory clinical study.

Results: Experiments with H37Ra M. …

Correlation Of Genogroup I, Genotype 1 (Gi.1) Norovirus Neutralizing Antibody Levels With Gi.1 Histo-Blood Group Antigen-Blocking Antibody Levels, Robert L Atmar, Khalil Ettayebi, Frederick H Neill, Ralph P Braun, James Sherwood, Sasirekha Ramani, Mary K Estes

Faculty, Staff and Students Publications

Background: The in vitro cultivation of human noroviruses allows a comparison of antibody levels measured in neutralization and histo-blood group antigen (HBGA)-blocking assays.

Methods: Serum samples collected during the evaluation of an investigational norovirus vaccine (HIL-214 [formerly TAK-214]) were assayed for neutralizing antibody levels against the vaccine's prototype Norwalk virus/genogroup I, genotype 1 (GI.1) (P1) virus strain. Results were compared with those previously determined using HBGA-blocking assays.

Results: Neutralizing antibody seroresponses were observed in 83% of 24 vaccinated adults, and antibody levels were highly correlated (r = 0.81; P < .001) with those measured by HBGA blocking.

Conclusions: Genogroup I, genotype 1 (GI.1)-specific HBGA-blocking antibodies are a surrogate …

Development, Progression, And Mortality Of Suspected Interstitial Lung Disease In Copdgene, Jonathan A Rose, Ann-Marcia C Tukpah, Claire Cutting, Noriaki Wada, Mizuki Nishino, Matthew Moll, Sean Kalra, Bina Choi, David A Lynch, Benjamin A Raby, Ivan O Rosas, Raúl San José Estépar, George R Washko, Edwin K Silverman, Michael H Cho, Hiroto Hatabu, Rachel K Putman, Gary M Hunninghake

Faculty, Staff and Students Publications

Rationale: Some with interstitial lung abnormalities (ILA) are suspected to have interstitial lung disease (ILD), a subgroup with adverse outcomes. Rates of development and progression of suspected ILD and their effect on mortality are unknown. Objectives: To determine rates of development, progression, and mortality in those with suspected ILD and assess effects of individual ILD and progression criteria.

Methods: Participants from COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) with ILA characterization and FVC at enrollment and 5-year follow-up were included. ILD was defined as ILA and fibrosis and/or FVC < 80% predicted. Prevalent ILD was assessed at enrollment and incident ILD and progression were assessed at 5-year follow-up. Computed tomography (CT) progression was assessed visually and FVC decline as relative change. Multivariable Cox regression tested associations between mortality and prevalent ILD, incident ILD, and progression groups.

Measurements and Main Results: Of 9,588 participants at enrollment, 268 …

Global Impact Of Aging On The Hemodynamic Response Function In The Gray Matter Of Human Cerebral Cortex, Nooshin J Fesharaki, Amanda Taylor, Keisjon Mosby, Ruosha Li, Jung Hwan Kim, David Ress

Faculty, Staff and Students Publications

In functional magnetic resonance imaging, the hemodynamic response function (HRF) is a stereotypical response to local changes in cerebral hemodynamics and oxygen metabolism due to briefly (< 4 s) evoked neural activity. Accordingly, the HRF is often used as an impulse response with the assumption of linearity in data analysis. In cognitive aging studies, it has been very common to interpret differences in brain activation as age-related changes in neural activity. Contrary to this assumption, however, evidence has accrued that normal aging may also significantly affect the vasculature, thereby affecting cerebral hemodynamics and metabolism, confounding interpretation of fMRI cognitive aging studies. In this study, use was made of a multisensory task to evoke the HRF in ~87% of cerebral cortex in cognitively intact adults with ages ranging from 22 to 75 years. This widespread activation enabled us to investigate age trends in the spatial distributions of HRF characteristics within the majority of cortical gray matter, which we termed as global age trends. The task evoked both positive and negative HRFs, which were characterized using model-free parameters in native-space coordinates. We found significant global age trends in the distributions of HRF parameters in terms of both amplitudes (e.g., peak amplitude and contrast-to-noise ratio) and temporal dynamics (e.g., full-width-at-half-maximum). Our findings offer insight into how age-dependent changes affect neurovascular coupling and show promise for use of HRF parameters as non-invasive indicators for age-related pathology.