Medical Specialties Commons^™

Seamless Phase Ii/Iii Design: A Useful Strategy To Reduce The Sample Size For Dose Optimization, Liyun Jiang, Ying Yuan

Faculty, Staff and Student Publications

Background: The traditional more-is-better dose selection paradigm, originally developed for cytotoxic chemotherapeutics, can be problematic when applied to the development of novel molecularly targeted agents. Recognizing this issue, the US Food and Drug Administration initiated Project Optimus to reform the dose optimization and selection paradigm in oncology drug development, emphasizing the need for greater attention to benefit-risk considerations.

Methods: We identify different types of phase II/III dose-optimization designs, classified according to trial objectives and endpoint types. Through computer simulations, we examine their operating characteristics and discuss the relevant statistical and design considerations for effective dose optimization.

Results: Phase II/III dose-optimization …

Evidence Of Neurovascular Water Exchange And Endothelial Vascular Dysfunction In Schizophrenia: An Exploratory Study, Eric L Goldwaser, Danny J J Wang, Bhim M Adhikari, Joshua Chiappelli, Xingfeng Shao, Jiaao Yu, Tong Lu, Shuo Chen, Wyatt Marshall, Alexa Yuen, Mark Kvarta, Yizhou Ma, Xiaoming Du, Si Gao, Osamah Saeedi, Heather Bruce, Patrick Donnelly, Hugh O'Neill, Alan R Shuldiner, Braxton D Mitchell, Peter Kochunov, L Elliot Hong

Faculty, Staff and Student Publications

BACKGROUND AND HYPOTHESIS: Mounting evidence supports cerebrovascular contributions to schizophrenia spectrum disorder (SSD) but with unknown mechanisms. The blood-brain barrier (BBB) is at the nexus of neural-vascular exchanges, tasked with regulating cerebral homeostasis. BBB abnormalities in SSD, if any, are likely more subtle compared to typical neurological insults and imaging measures that assess large molecule BBB leakage in major neurological events may not be sensitive enough to directly examine BBB abnormalities in SSD.

STUDY DESIGN: We tested the hypothesis that neurovascular water exchange (Kw) measured by non-invasive diffusion-prepared arterial spin label MRI (n = 27 healthy controls [HC], n = …

Clinically Conserved Genomic Subtypes Of Gastric Adenocarcinoma, Yun Seong Jeong, Young-Gyu Eun, Sung Hwan Lee, Sang-Hee Kang, Sun Young Yim, Eui Hyun Kim, Joo Kyung Noh, Bo Hwa Sohn, Seon Rang Woo, Moonkyoo Kong, Deok Hwa Nam, Hee-Jin Jang, Hyun-Sung Lee, Shumei Song, Sang Cheul Oh, Jeeyun Lee, Jaffer A Ajani, Ju-Seog Lee

Faculty, Staff and Student Publications

Gastric adenocarcinoma (GAC) is a lethal disease characterized by genomic and clinical heterogeneity. By integrating 8 previously established genomic signatures for GAC subtypes, we identified 6 clinically and molecularly distinct genomic consensus subtypes (CGSs). CGS1 have the poorest prognosis, very high stem cell characteristics, and high IGF1 expression, but low genomic alterations. CGS2 is enriched with canonical epithelial gene expression. CGS3 and CGS4 have high copy number alterations and low immune reactivity. However, CGS3 and CGS4 differ in that CGS3 has high HER2 activation, while CGS4 has high SALL4 and KRAS activation. CGS5 has the high mutation burden and moderately …

Stem-Like Cd4+T Cells In Perivascular Tertiary Lymphoid Structures Sustain Autoimmune Vasculitis, Yuki Sato, Abhinav Jain, Shozo Ohtsuki, Hirohisa Okuyama, Ines Sturmlechner, Yoshinori Takashima, Kevin-Phu C Le, Melanie C Bois, Gerald J Berry, Kenneth J Warrington, Jörg J Goronzy, Cornelia M Weyand

Faculty, Staff and Student Publications

Autoimmune vasculitis of the medium and large elastic arteries can cause blindness, stroke, aortic arch syndrome, and aortic aneurysm. The disease is often refractory to immunosuppressive therapy and progresses over decades as smoldering aortitis. How the granulomatous infiltrates in the vessel wall are maintained and how tissue-infiltrating T cells and macrophages are replenished are unknown. Single-cell and whole-tissue transcriptomic studies of immune cell populations in vasculitic arteries identified a CD4+ T cell population with stem cell-like features. CD4+ T cells supplying the tissue-infiltrating and tissue-damaging effector T cells survived in tertiary lymphoid structures around adventitial vasa vasora, expressed the transcription …

Hiv-1 Vpu Protein Forms Stable Oligomers In Aqueous Solution Via Its Transmembrane Domain Self-Association, Saman Majeed, Lan Dang, Md Majharul Islam, Olamide Ishola, Peter P Borbat, Steven J Ludtke, Elka R Georgieva

Faculty, Staff and Students Publications

We report our findings on the assembly of the HIV-1 protein Vpu into soluble oligomers. Vpu is a key HIV-1 protein. It has been considered exclusively a single-pass membrane protein. Previous observations show that this protein forms stable oligomers in aqueous solution, but details about these oligomers still remain obscure. This is an interesting and rather unique observation, as the number of proteins transitioning between soluble and membrane embedded states is limited. In this study we made use of protein engineering, size exclusion chromatography, cryoEM and electron paramagnetic resonance (EPR) spectroscopy to better elucidate the nature of the soluble oligomers. …

Integrating Participant Feedback And Concerns To Improve Community And Individual Level Chemical Exposure Assessment Reports, Samantha M Samon, Michael Barton, Kim Anderson, Abiodun Oluyomi, Melissa Bondy, Georgina Armstrong, Diana Rohlman

Faculty, Staff and Students Publications

BACKGROUND: As exposure assessment has shifted towards community-engaged research there has been an increasing trend towards reporting results to participants. Reports aim to increase environmental health literacy, but this can be challenging due to the many unknowns regarding chemical exposure and human health effects. This includes when reports encompass a wide-range of chemicals, limited reference or health standards exist for those chemicals, and/or incompatibility of data generated from exposure assessment tools with published reference values (e.g., comparing a wristband concentration to an oral reference dose).

METHODS: Houston Hurricane Harvey Health (Houston-3H) participants wore silicone wristbands that were analyzed for 1,530 …

Patient-Reported Outcomes Of Omission Of Breast Surgery Following Neoadjuvant Systemic Therapy: A Nonrandomized Clinical Trial, Helen M Johnson, Heather Lin, Yu Shen, Emilia J Diego, Savitri Krishnamurthy, Wei T Yang, Benjamin D Smith, Vicente Valero, Anthony Lucci, Susie X Sun, Simona F Shaitelman, Melissa P Mitchell, Judy C Boughey, Richard L White, Gaiane M Rauch, Henry M Kuerer

Faculty, Staff and Student Publications

IMPORTANCE: Patients should have an active role in decisions about pursuing or forgoing specific therapies in treatment de-escalation trials.

OBJECTIVE: To evaluate longitudinal patient-reported outcomes (PROs) encompassing decisional comfort and health-related quality of life (HRQOL) among patients who elected to enroll in a clinical trial evaluating radiotherapy alone, without breast surgery, for invasive breast cancers with exceptional response to neoadjuvant systemic therapy (NST).

DESIGN, SETTING, AND PARTICIPANTS: Prospective, single-group, phase 2 clinical trial at 7 US medical centers. Women aged 40 years or older with invasive cT1-2 N0-1 M0 triple-negative or human epidermal growth factor receptor 2 (ERBB2)-positive breast cancer …

Conditional Risks Of Biochemical Failure And Prostate Cancer-Specific Death In Patients Undergoing External Beam Radiotherapy: A Secondary Analysis Of 2 Randomized Clinical Trials, Gregory S. Alexander, Rebecca F Krc, James W Assif, Kai Sun, Jason K Molitoris, Phuoc Tran, Zaker Rana, Søren M Bentzen, Mark V Mishra

Department of Radiation Oncology Faculty Papers

IMPORTANCE: As patients achieve years of survival after treatment for prostate cancer, the risk of biochemical failure (BF) or prostate cancer-specific death (PCSD) may evolve over time, with clinical relevance to both patients and clinicians.

OBJECTIVE: To determine conditional BF-free survival, PSCD, and overall survival estimates for patients with low- or intermediate-risk prostate cancer enrolled in the Radiation Therapy Oncology Group (RTOG) 0126 and RTOG 0415 clinical trials. A secondary objective was to determine whether prognostic factors at diagnosis remain relevant at later points in follow-up.

DESIGN, SETTING, AND PARTICIPANTS: A pooled secondary analysis of patients treated with external-beam radiotherapy …

Prognostic Evaluation Of Re-Resection For Recurrent Glioblastoma Using The Novel Rano Classification For Extent Of Resection: A Report Of The Rano Resect Group, Philipp Karschnia, Antonio Dono, Jacob S Young, Stephanie T Juenger, Nico Teske, Levin Häni, Tommaso Sciortino, Christine Y Mau, Francesco Bruno, Luis Nunez, Ramin A Morshed, Alexander F Haddad, Michael Weller, Martin Van Den Bent, Juergen Beck, Shawn Hervey-Jumper, Annette M Molinaro, Nitin Tandon, Roberta Rudà, Michael A Vogelbaum, Lorenzo Bello, Oliver Schnell, Stefan J Grau, Susan M Chang, Mitchel S Berger, Yoshua Esquenazi, Joerg-Christian Tonn

Faculty, Staff and Student Publications

BACKGROUND: The value of re-resection in recurrent glioblastoma remains controversial as a randomized trial that specifies intentional incomplete resection cannot be justified ethically. Here, we aimed to (1) explore the prognostic role of extent of re-resection using the previously proposed Response Assessment in Neuro-Oncology (RANO) classification (based upon residual contrast-enhancing (CE) and non-CE tumor), and to (2) define factors consolidating the surgical effects on outcome.

METHODS: The RANO resect group retrospectively compiled an 8-center cohort of patients with first recurrence from previously resected glioblastomas. The associations of re-resection and other clinical factors with outcome were analyzed. Propensity score-matched analyses were …

Genetic Susceptibility To Cognitive Decline Following Craniospinal Irradiation For Pediatric Central Nervous System Tumors, Austin L Brown, Pagna Sok, Kimberly P Raghubar, Philip J Lupo, Melissa A Richard, Alanna C Morrison, Jun J Yang, Clinton F Stewart, Mehmet Fatih Okcu, Murali M Chintagumpala, Amar Gajjar, Lisa S Kahalley, Heather Conklin, Michael E Scheurer

Faculty, Staff and Student Publications

BACKGROUND: Survivors of pediatric central nervous system (CNS) tumors treated with craniospinal irradiation (CSI) exhibit long-term cognitive difficulties. Goals of this study were to evaluate longitudinal effects of candidate and novel genetic variants on cognitive decline following CSI.

METHODS: Intelligence quotient (IQ), working memory (WM), and processing speed (PS) were longitudinally collected from patients treated with CSI (n = 241). Genotype-by-time interactions were evaluated using mixed-effects linear regression to identify common variants (minor allele frequency > 1%) associated with cognitive performance change. Novel variants associated with cognitive decline (P < 5 × 10-5) in individuals of European ancestry (n = 163) were considered replicated if they demonstrated consistent genotype-by-time interactions (P < .05) in individuals of non-European ancestries (n = 78) and achieved genome-wide statistical significance (P < 5 × 10-8) in a meta-analysis across ancestry groups.

RESULTS: Participants were mostly males (65%) diagnosed with embryonal tumors (98%) at …

Multiancestry Analysis Of The Hla Locus In Alzheimer’S And Parkinson’S Diseases Uncovers A Shared Adaptive Immune Response Mediated By Hla-Drb1*04 Subtypes, Yann Le Guen, Guo Luo, Aditya Ambati, Vincent Damotte, Iris Jansen, Eric Yu, Aude Nicolas, Itziar De Rojas, Thiago Peixoto Leal, Akinori Miyashita, Céline Bellenguez, Michelle Mulan Lian, Kayenat Parveen, Takashi Morizono, Hyeonseul Park, Benjamin Grenier-Boley, Tatsuhiko Naito, Fahri Küçükali, Seth D Talyansky, Selina Maria Yogeshwar, Vicente Sempere, Wataru Satake, Victoria Alvarez, Beatrice Arosio, Michael E Belloy, Luisa Benussi, Anne Boland, Barbara Borroni, María J Bullido, Paolo Caffarra, Jordi Clarimon, Antonio Daniele, Daniel Darling, Stéphanie Debette, Jean-François Deleuze, Martin Dichgans, Carole Dufouil, Emmanuel During, Emrah Düzel, Daniela Galimberti, Guillermo Garcia-Ribas, José María García-Alberca, Pablo García-González, Vilmantas Giedraitis, Oliver Goldhardt, Caroline Graff, Edna Grünblatt, Olivier Hanon, Lucrezia Hausner, Stefanie Heilmann-Heimbach, Henne Holstege, Jakub Hort, Yoo Jin Jung, Deckert Jürgen, Silke Kern, Teemu Kuulasmaa, Kun Ho Lee, Ling Lin, Carlo Masullo, Patrizia Mecocci, Shima Mehrabian, Alexandre De Mendonça, Mercè Boada, Pablo Mir, Susanne Moebus, Fermin Moreno, Benedetta Nacmias, Gael Nicolas, Shumpei Niida, Børge G Nordestgaard, Goran Papenberg, Janne Papma, Lucilla Parnetti, Florence Pasquier, Pau Pastor, Oliver Peters, Yolande A L Pijnenburg, Gerard Piñol-Ripoll, Julius Popp, Laura Molina Porcel, Raquel Puerta, Jordi Pérez-Tur, Innocenzo Rainero, Inez Ramakers, Luis M Real, Steffi Riedel-Heller, Eloy Rodriguez-Rodriguez, Owen A Ross, Luis Jose Royo, Dan Rujescu, Nikolaos Scarmeas, Philip Scheltens, Norbert Scherbaum, Anja Schneider, Davide Seripa, Ingmar Skoog, Vincenzo Solfrizzi, Gianfranco Spalletta, Alessio Squassina, John Van Swieten, Raquel Sánchez-Valle, Eng-King Tan, Thomas Tegos, Charlotte Teunissen, Jesper Qvist Thomassen, Lucio Tremolizzo, Martin Vyhnalek, Frans Verhey, Margda Waern, Jens Wiltfang, Jing Zhang, Eadb, Gr@Ace Study Group, Degesco Consortium, Demgene, Eadi, Gerad, Asian Parkinson’S Disease Genetics Consortium, Henrik Zetterberg, Kaj Blennow, Zihuai He, Julie Williams, Philippe Amouyel, Frank Jessen, Patrick G Kehoe, Ole A Andreassen, Cornelia Van Duin, Magda Tsolaki, Pascual Sánchez-Juan, Ruth Frikke-Schmidt, Kristel Sleegers, Tatsushi Toda, Anna Zettergren, Martin Ingelsson, Yukinori Okada, Giacomina Rossi, Mikko Hiltunen, Jungsoo Gim, Kouichi Ozaki, Rebecca Sims, Jia Nee Foo, Wiesje Van Der Flier, Takeshi Ikeuchi, Alfredo Ramirez, Ignacio Mata, Agustín Ruiz, Ziv Gan-Or, Jean-Charles Lambert, Michael D Greicius, Emmanuel Mignot

Faculty, Staff and Students Publications

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. …

Erythrophagocytosis In Autoimmune Immunoglobulin A-Mediated Hemolysis, Jahnavi Gollamudi, Swapan Kumar Dasgupta, Perumal Thiagarajan

Faculty, Staff and Students Publications

INTRODUCTION: Warm antibody-mediated autoimmune hemolysis (WAIHA) is most often due to immunoglobulin G (IgG) antibodies and is detected by direct antiglobulin test (DAT). However, about 10% cases of hemolytic anemia are DAT negative. Herein, we describe a patient with DAT-negative hemolytic anemia due to an anti-IgA antibody. We investigate if isolated IgA can promote erythrophagocytosis.

METHODS: We isolated patient and control IgA on Jacalin agarose. Isolated IgA was used to sensitize healthy ABO/Rh-matched donor red blood cells (RBC). Antibody binding was examined by flowcytometry. The effect of IgA on erythrophagocytosis was evaluated using Macrophage colony stimulating factor 1 (M-CSF)-differentiated autologous …

A Two-Step Transcriptome Analysis Of The Human Heart Reveals Broad And Disease-Responsive Expression Of Ectopic Olfactory Receptors, Sadia Ashraf, O Howard Frazier, Sylvia Carranza, David D Mcpherson, Heinrich Taegtmeyer, Romain Harmancey

Faculty, Staff and Student Publications

G-protein-coupled receptors (GPCRs) are critical regulators of cardiac physiology and a key therapeutic target for the treatment of heart disease. Ectopic olfactory receptors (ORs) are GPCRs expressed in extra-nasal tissues which have recently emerged as new mediators in the metabolic control of cardiac function. The goals of this study were to profile OR gene expression in the human heart, to identify ORs dysregulated by heart failure caused by ischemic cardiomyopathy, and to provide evidence suggestive of a role for those altered ORs in the pathogenesis of heart failure. Left ventricular tissue from heart failure patients (

Surgical Management Of Congenital Malrotation Presenting In Adulthood., Jacob Holzemer, Krishna Patel, Oscar Ruiz, Jodi Oostra

Surgery Articles

Intestinal malrotation is characterised by positional and congenital fixation abnormalities resulting from a failure in embryonic development in the normal 270° rotation around the axis of the superior mesenteric artery. Intestinal malrotation is primarily thought to affect neonates with an incidence of 1 in 500, however, only 1 in 6000 live births are symptomatic, and these usually present within the first month of life in 40% of cases and within the first year in over 5% of cases as an obstructive pathology or volvulus. In adults, however, the incidence has been documented at 0.2%. These patients usually present with postprandial …

Low-Grade Serous Ovarian Cancer: Expert Consensus Report On The State Of The Science, Rachel N Grisham, Brian M Slomovitz, Nicole Andrews, Susana Banerjee, Jubilee Brown, Mark S Carey, Herman Chui, Robert L Coleman, Amanda N Fader, Stephanie Gaillard, Charlie Gourley, Anil K Sood, Bradley J Monk, Kathleen N Moore, Isabelle Ray-Coquard, Ie-Ming Shih, Shannon N Westin, Kwong-Kwok Wong, David M Gershenson

Faculty, Staff and Student Publications

Compared with high-grade serous carcinoma, low-grade serous carcinoma of the ovary or peritoneum is a less frequent epithelial ovarian cancer type that is poorly sensitive to chemotherapy and affects younger women, many of whom endure years of ineffective treatments and poor quality of life. The pathogenesis of this disease and its management remain incompletely understood. However, recent advances in the molecular characterization of the disease and identification of novel targeted therapies with activity in low-grade serous carcinoma offer the promise of improved outcomes. To update clinicians regarding recent scientific and clinical trial advancements and discuss unanswered questions related to low-grade …

The Characterization And Evaluation Of The Soluble Triggering Receptor Expressed On Myeloid Cells-Like Transcript-1 In Stable Coronary Artery Disease, Zaida Bayrón-Marrero, Siobhan Branfield, Javier Menéndez-Pérez, Benjamín Nieves-López, Laura Ospina, Yadira Cantres-Rosario, Loyda M Melendez, Robert Hunter, Angelia Gibson, Gerónimo Maldonado-Martínez, A Valance Washington

Faculty, Staff and Student Publications

Platelets play crucial roles in the development and progression of coronary artery disease (CAD). The triggering receptor expressed in myeloid cells-like transcript-1 (TLT-1) is stored in platelet α granules, and activated platelets release a soluble fragment (sTLT-1). We set out to better characterize the constituent amino acids of sTLT-1 and to evaluate sTLT-1 for use as a biomarker in patients with stable CAD. We evaluated sTLT-1 release using immunoprecipitation and mass spectrometry and employed statistical methods to retrospectively correlate sTLT-1 concentrations, utilizing ELISA in plasma samples from 1510 patients with documented stable CAD. We identified TLT-1 residues to 133 in …

Trends And Associated Factors Of Hiv, Hcv And Syphilis Infection Among Different Drug Users In The China-Vietnam Border Area: An 11-Year Cross-Sectional Study (2010-2020), Tong Luo, Zhaosen Lin, Zhenxian Wu, Ping Cen, Aidan Nong, Rongye Huang, Jianhua Che, Fengfeng Liang, Yuan Yang, Jie Liu, Li Huang, Jie Cai, Yanyun Ou, Li Ye, Lijuan Bao, Bingyu Liang, Hao Liang

Faculty, Staff and Student Publications

BACKGROUND: Data on recent human immunodeficiency virus (HIV), hepatitis C virus (HCV) and syphilis prevalence among drug users in the Southwest China are sparse despite the high burden of drug use. This study aims at assessing the prevalence trends and related factors of HIV, HCV and syphilis infection among different drug users in the China-Vietnam border area.

METHODS: A continuous cross-sectional survey was conducted among drug users from 2010 to 2020 in the China-Vietnam border area. Chi-square trend tests were used to assess the trend of HIV, HCV and syphilis prevalence and the proportion for drug type used by drug …

Uptake Of Hiv Testing And Its Correlates Among Sexually Experienced College Students In Southwestern, China: A Web-Based Online Cross-Sectional Study, Jinfeng He, Ping Cen, Jiao Qin, Weiao Qin, Xiudong Xu, Yuanhong Yang, Jinglan Wu, Mu Li, Rongjing Zhang, Tong Luo, Zhifeng Lin, Xinju Huang, Chuanyi Ning, Hao Liang, Li Ye, Bin Xu, Bingyu Liang

Faculty, Staff and Student Publications

BACKGROUND: The prevalence of human immunodeficiency virus (HIV) is becoming more common among college students in China. However, latest data on the prevalence and correlates of HIV testing among sexually experienced college students is rarely.

METHODS: An online survey was conducted among college students aged 18 years or older using multistage stratified cluster sampling from 16 colleges. Data on socio-demographic, HIV testing, HIV-related awareness, attitudes, sexual education and behaviors were collected. Propensity score matching (PSM) and logistic regression model were used to identify factors associated with HIV testing.

RESULT: A total of 108,987 students participated the survey, of which 13,201 …

Autoantibodies Neutralizing Type I Ifns Underlie West Nile Virus Encephalitis In ∼40% Of Patients, Adrian Gervais, Francesca Rovida, Maria Antonietta Avanzini, Stefania Croce, Astrid Marchal, Shih-Ching Lin, Alessandro Ferrari, Christian W Thorball, Orianne Constant, Tom Le Voyer, Quentin Philippot, Jérémie Rosain, Micol Angelini, Malena Pérez Lorenzo, Lucy Bizien, Cristian Achille, Francesca Trespidi, Elisa Burdino, Irene Cassaniti, Daniele Lilleri, Chiara Fornara, José Camilla Sammartino, Danilo Cereda, Chiara Marrocu, Antonio Piralla, Chiara Valsecchi, Stefano Ricagno, Paola Cogo, Olaf Neth, Inés Marín-Cruz, Monia Pacenti, Alessandro Sinigaglia, Marta Trevisan, Andrea Volpe, Antonio Marzollo, Francesca Conti, Tiziana Lazzarotto, Andrea Pession, Pierluigi Viale, Jacques Fellay, Stefano Ghirardello, Mélodie Aubart, Valeria Ghisetti, Alessandro Aiuti, Emmanuelle Jouanguy, Paul Bastard, Elena Percivalle, Fausto Baldanti, Anne Puel, Margaret R Macdonald, Charles M Rice, Giada Rossini, Kristy O Murray, Yannick Simonin, Anna Nagy, Luisa Barzon, Laurent Abel, Michael S Diamond, Aurélie Cobat, Shen-Ying Zhang, Jean-Laurent Casanova, Alessandro Borghesi

Faculty, Staff and Students Publications

Mosquito-borne West Nile virus (WNV) infection is benign in most individuals but can cause encephalitis in <1% of infected individuals. We show that ∼35% of patients hospitalized for WNV disease (WNVD) in six independent cohorts from the EU and USA carry auto-Abs neutralizing IFN-α and/or -ω. The prevalence of these antibodies is highest in patients with encephalitis (∼40%), and that in individuals with silent WNV infection is as low as that in the general population. The odds ratios for WNVD in individuals with these auto-Abs relative to those without them in the general population range from 19.0 (95% CI 15.0–24.0, P value <10–15) for auto-Abs neutralizing only 100 pg/ml IFN-α and/or IFN-ω to 127.4 (CI 87.1–186.4, P value <10–15) for auto-Abs neutralizing both IFN-α and IFN-ω at a concentration of 10 ng/ml. These antibodies block the protective effect of IFN-α in Vero cells infected with WNV in vitro. Auto-Abs neutralizing IFN-α and/or IFN-ω underlie ∼40% of cases of WNV encephalitis.

Taz2 Truncation Confers Overactivation Of P300 And Cellular Vulnerability To Hdac Inhibition, Longxia Xu, Hongwen Xuan, Wei He, Liang Zhang, Mengying Huang, Kuai Li, Hong Wen, Han Xu, Xiaobing Shi

Faculty, Staff and Student Publications

The histone acetyltransferase p300/CBP is composed of several conserved domains, among which, the TAZ2 domain is known as a protein-protein interaction domain that binds to E1A and various transcription factors. Here we show that TAZ2 has a HAT autoinhibitory function. Truncating p300/CBP at TAZ2 leads to hyperactive HAT and elevated histone H3K27 and H3K18 acetylation in cells. Mechanistically, TAZ2 cooperates with other HAT neighboring domains to maintain the HAT active site in a 'closed' state. Truncating TAZ2 or binding of transcription factors to TAZ2 induces a conformational change that 'opens' the active site for substrate acetylation. Importantly, genetic mutations that …

Aenmd: Annotating Escape From Nonsense-Mediated Decay For Transcripts With Protein-Truncating Variants, Jonathan Klonowski, Qianqian Liang, Zeynep Coban-Akdemir, Cecilia Lo, Dennis Kostka

Faculty, Staff and Student Publications

DNA changes that cause premature termination codons (PTCs) represent a large fraction of clinically relevant pathogenic genomic variation. Typically, PTCs induce transcript degradation by nonsense-mediated mRNA decay (NMD) and render such changes loss-of-function alleles. However, certain PTC-containing transcripts escape NMD and can exert dominant-negative or gain-of-function (DN/GOF) effects. Therefore, systematic identification of human PTC-causing variants and their susceptibility to NMD contributes to the investigation of the role of DN/GOF alleles in human disease. Here we present aenmd, a software for annotating PTC-containing transcript-variant pairs for predicted escape from NMD. aenmd is user-friendly and self-contained. It offers functionality not currently available …

Endoscopic Ultrasound-Guided Transluminal Gallbladder Drainage In Patients With Acute Cholecystitis: A Prospective Multicenter Trial., Shayan S Irani, Neil R. Sharma Md, Andrew C Storm, Raj J Shah, Prabhleen Chahal, Field F Willingham, Lee Swanstrom, Todd H Baron, Eran Shlomovitz, Richard A Kozarek, Joyce A Peetermans, Edmund Mcmullen, Evelyne Ho, Schalk W Van Der Merwe

Other Specialties

OBJECTIVE: To evaluate the safety and efficacy of endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) using a lumen-apposing metal stent (LAMS).

BACKGROUND: For patients with acute cholecystitis who are poor surgical candidates, EUS-GBD using a LAMS is an important treatment alternative to percutaneous gallbladder drainage.

METHODS: We conducted a regulatory-compliant, prospective multicenter trial at 7 tertiary referral centers in the United States of America and Belgium. Thirty consecutive patients with mild or moderate acute cholecystitis who were not candidates for cholecystectomy were enrolled between September 2019 and August 2021. Eligible patients had a LAMS placed transmurally with 30 to 60-day indwell if …

Case Study: The Elusive Vaginal Leiomyoma, Fiona Hodges, Roziya Tursunova, Kelly Nagy, Halei Wong, Wright State University Boonshoft Som Department Of Obstetrics And Gynecology, Wright Patterson Air Force Base Department Of Obstetrics And Gynecology

Obstetrics and Gynecology Faculty Publications

This poster was presented at the September 2023 Armed Forces District Meeting.

A Perspective On In Vitro Developmental Neurotoxicity Test Assay Results: An Expert Panel Review, D. R. Juberg, D. A. Fox, P. A. Forcelli, S. Kacew, J. C. Lipscomb, S. A. Saghir, Catherine M. Sherwin, C. M. Koenig, S. M. Hays, C. R. Kirman

Pediatrics Faculty Publications

For decades, there has been increasing concern about the potential developmental neurotoxicity (DNT) associated with chemicals. Regulatory agencies have historically utilized standardized in vivo testing to evaluate DNT. Owing to considerations including higher-throughput screening for DNT, reduction in animal use, and potential cost efficiencies, the development of alternative new approach methods (NAMs) occurred; specifically, the advent of the DNT in vitro test battery (DNT IVB). SciPinion convened an expert panel to address specific questions related to the interpretation of in vitro DNT test data. The consensus of the expert panel was that the DNT IVB might be used during initial …

Abnormal Motion Capture In Acute Stroke (Bionics): A Low-Cost Tele-Evaluation Tool For Automated Assessment Of Upper Extremity Function In Stroke Patients, Syed A Zamin, Kaichen Tang, Emily A Stevens, Melissa Howard, Dorothea M Parker, Allyson Seals, Xiaoqian Jiang, Sean Savitz, Shayan Shams

Faculty, Staff and Student Publications

BACKGROUND: The incidence of stroke and stroke-related hemiparesis has been steadily increasing and is projected to become a serious social, financial, and physical burden on the aging population. Limited access to outpatient rehabilitation for these stroke survivors further deepens the healthcare issue and estranges the stroke patient demographic in rural areas. However, new advances in motion detection deep learning enable the use of handheld smartphone cameras for body tracking, offering unparalleled levels of accessibility.

METHODS: In this study we want to develop an automated method for evaluation of a shortened variant of the Fugl-Meyer assessment, the standard stroke rehabilitation scale …

Contraceptive Counseling For Adolescents In The Emergency Department: A Novel Curriculum For Nurse Practitioners And Physician Assistants., Laurel S. Gabler, Michelle Shankar, Tara Ketterer, Jennifer Molnar, Amber Adams, Jungwon Min, Elizabeth Miller, Romina Barral, Aletha Akers, Melissa K. Miller, Cynthia Mollen

Manuscripts, Articles, Book Chapters and Other Papers

Many adolescents use the emergency department (ED) as their primary source of health care. As a result, the ED serves as a unique opportunity to reach adolescents. Although many adolescent visits to the ED are related to reproductive health, ED providers report barriers to providing this care, including lack of training. Nurse practitioners (NPs) and physician assistants (PAs) serve a vital role in the provision of consistent care to adolescents in the ED. The purpose of this study was to create a curriculum to train NPs and PAs at two pediatric institutions to provide patient-centered contraceptive counseling to adolescents in …

Committing To Genomic Answers For All Kids: Evaluating Inequity In Genomic Research Enrollment., Natalie J. Kane, Ana S A Cohen, Courtney D. Berrios, Bridgette Jones, T Pastinen, Mark A. Hoffman

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: Persistent inequities in genomic medicine and research contribute to health disparities. This analysis uses a context-specific and equity-focused strategy to evaluate enrollment patterns for Genomic Answers for Kids (GA4K), a large, metropolitan-wide genomic study on children.

METHODS: Electronic health records for 2247 GA4K study participants were used to evaluate the distribution of individuals by demographics (race, ethnicity, and payor type) and location (residential address). Addresses were geocoded to produce point density and 3-digit zip code maps showing local and regional enrollment patterns. Health system reports and census data were used to compare participant characteristics with reference populations at different …

Barriers And Facilitators Of Family Rules And Routines During Pediatric Cancer Treatment., Carolyn R. Bates, Isabella K. Pallotto, Rachel Moore, Lynne Covitz, Meredith Dreyer

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: Pediatric nurses work closely with families of children with new cancer diagnoses and can provide essential supports to promote coping and adjustment. This cross-sectional qualitative study aimed to gather caregiver perspectives on barriers and facilitators to adaptive family functioning during the early phases of cancer treatment, with a focus on family rules and routines.

METHODS: Caregivers (N = 44) of a child diagnosed with cancer and receiving active treatment completed a semi-structured interview about their engagement in family rules and routines. Time since diagnosis was abstracted from the medical record. A multi-pass inductive coding strategy was utilized to extract …

Efficient Targeted Learning Of Heterogeneous Treatment Effects For Multiple Subgroups, Waverly Wei, Maya Petersen, Mark J Van Der Laan, Zeyu Zheng, Chong Wu, Jingshen Wang

Faculty, Staff and Student Publications

In biomedical science, analyzing treatment effect heterogeneity plays an essential role in assisting personalized medicine. The main goals of analyzing treatment effect heterogeneity include estimating treatment effects in clinically relevant subgroups and predicting whether a patient subpopulation might benefit from a particular treatment. Conventional approaches often evaluate the subgroup treatment effects via parametric modeling and can thus be susceptible to model mis-specifications. In this paper, we take a model-free semiparametric perspective and aim to efficiently evaluate the heterogeneous treatment effects of multiple subgroups simultaneously under the one-step targeted maximum-likelihood estimation (TMLE) framework. When the number of subgroups is large, we …

Mpla Case: How Do You Lead As A Lead Physicist?, Patricia Sansourekidou, Leonard Kim, Lee Xu, Mary Gronberg, Cassandra Stambaugh, Dongxu Wang

Faculty, Staff and Student Publications

This work of fiction is part of a case study series developed by the Medical Physics Leadership Academy (MPLA). It is intended to facilitate the discussion of the managerial and leadership challenges faced by a clinical medical physicist. In this case, a physicist David used to work in a clinic where he thrived and felt like a leader, despite not having the title. After a job change, he is now officially the "Lead Physicist" at a hospital newly affiliated with a large academic healthcare system. He believes he will be equally successful. Yet he struggles to bring about changes and …