Digital Commons Network^™

Bridging Big Data In The Enigma Consortium To Combine Non-Equivalent Cognitive Measures, Eamonn Kennedy, Shashank Vadlamani, Hannah M Lindsey, Pui-Wa Lei, Mary Jo-Pugh, David F Tate, Emily L Dennis, Elisabeth A Wilde, Enigma Clinical Endpoints Working Group Collaborators

Faculty, Staff and Student Publications

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample size. These efforts unveil new questions about how to integrate data across distinct sources and instruments. The goal of this study was to link scores across common auditory verbal learning tasks (AVLTs). This international secondary analysis aggregated multisite raw data for AVLTs across 53 studies totaling 10,505 individuals. Using the ComBat-GAM algorithm, we isolated and removed the component of memory scores associated with site effects while preserving instrumental effects. After adjustment, a continuous item response theory model used multiple memory items of varying …

Trends In Gaps Of Care For Patients With Congenital Heart Disease: Implications For Social Determinants Of Health And Child Opportunity Index, Abbas H. Zaidi, Adam Alberts, Devyani Chowdhury, Claude Beaty, Benjamin Brewer, Ming Hui Chen, Sarah D. De Ferranti

Department of Surgery Faculty Papers

BACKGROUND: Lifelong continuity of care is essential for patients with congenital heart disease (CHD) to maximize health outcomes; unfortunately, gaps in care (GIC) are common. Trends in GIC and of social determinants of health factors contributing to GIC are poorly understood.

METHODS AND RESULTS: This retrospective cohort study included patients with CHD, aged 0 to 34 years, who underwent surgery between January 2003 and May 2020, followed up at a pediatric subspeciality hospital. Patients were categorized as having simple, moderate, and complex CHD based on 2018 American Heart Association and American College of Cardiology guidelines. Social determinants of health, such …

Institutional Experience Of Lymphoproliferative Disorders With Initial Diagnosis Made Via Fine Needle Aspiration At Otolaryngology Clinic, Alaa S. Hrizat, Jerald Gong, Stacey M. Gargano

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: This study characterizes lymphomas presenting as palpable head and neck masses and evaluates the role of fine needle aspiration (FNA) and flow cytometry (FC) in diagnosis.

DESIGN: A 5-year retrospective review of FNAs performed by pathologists in an ENT clinic identified cases with a predominant lymphoid population that lacked an epithelial component. Cytology, FC, and subsequent surgical pathology diagnoses were correlated.

RESULTS: Of 821 FNAs, 154 (19%) met selection criteria. Reactive lymph nodes accounted for 43% (67/154), with most diagnosed as 'negative for malignancy,' except one 'atypical' (ATY) case. Lymphoma was confirmed in 57% (87/154) of cases, categorized as …

Exposure To Per- And Polyfluoroalkyl Substances And Alterations In Plasma Microrna Profiles In Children, Jesse A Goodrich, Haotian Wu, Shelley H Liu, Hongxu Wang, Emily Beglarian, Scott M Bartell, Sandrah Proctor Eckel, Douglas Walker, Damaskini Valvi, Michele Andrea La Merrill, Thomas H Inge, Todd Jenkins, Justin R Ryder, Stephanie Sisley, Rohit Kohli, Stavra A Xanthakos, Marina Vafeiadi, Aikaterini Margetaki, Theano Roumeliotaki, Max Aung, Rob Mcconnell, Andrea Baccarelli, David Conti, Lida Chatzi

Faculty, Staff and Students Publications

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that persist in the environment and can accumulate in humans, leading to adverse health effects. MicroRNAs (miRNAs) are emerging biomarkers that can advance the understanding of the mechanisms of PFAS effects on human health. However, little is known about the associations between PFAS exposures and miRNA alterations in humans.

OBJECTIVE: To investigate associations between PFAS concentrations and miRNA levels in children.

METHODS: Data from two distinct cohorts were utilized: 176 participants (average age 17.1 years; 75.6% female) from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort in the United States, and …

Npm1-Mutated Myeloid Neoplasms Are A Unique Entity Not Defined By Bone Marrow Blast Percentage, Georgina Gener-Ricos, Alex Bataller, Juan Jose Rodriguez-Sevilla, Kelly S Chien, Andres E Quesada, Danielle Hammond, Courtney Dinardo, Tapan Kadia, Naval Daver, Gautam Borthakur, Ghayas C Issa, Nicholas J Short, Rashmi Kanagal-Shamanna, Hagop M Kantarjian, Guillermo Garcia-Manero, Guillermo Montalban-Bravo

Faculty, Staff and Student Publications

Introduction: NPM1-mutated (NPM1mut) myeloid neoplasms (MNs) with < 20% bone marrow (BM) blasts (NPM1mut MNs< 20) are uncommon, and their classification remains inconsistent.

Methods: The clinicopathologic features of 54 patients with NPM1mut MNs < 20 were evaluated and compared with wild-type NPM1 MNs < 20 and NPM1mut MNs≥20, respectively.

Results: NPM1mut MNs had similar features regardless of blast percentage, except for higher IDH2 (29% vs 7%, p = .023) and FLT3 (70% vs 11%, p < .001) frequency in patients with ≥20% BM blasts. Thirty-three (61%) patients with NPM1mut MNs < 20 received low-intensity chemotherapy (LIC) and 12 (22%) received intensive chemotherapy (IC). Higher complete remission rates (75% vs 27%, p = .006) and median overall survival (mOS) (not reached vs 30.4 months, p = .06) were observed with IC compared to LIC. Young patients (age < 60 years) did not reach mOS either when treated with LIC or IC. Stem cell transplant was associated with increased survival only in patients treated with LIC (HR, 0.24; p = .025). No differences in mOS were observed by BM blast strata (32.2 months, not reached and 46.9 months for < 10%, 10%-19%, and ≥20% blasts, p = .700) regardless of treatment modality (LIC: p = .900; IC: p = .360). Twenty-three patients (43%) with NPM1mut MNs < 20 had marrow blast progression to ≥20%.

Conclusions: Overall, NPM1mut MNs define a unique entity independent of BM blast percentage.

Cdk12 Loss Drives Prostate Cancer Progression, Transcription-Replication Conflicts, And Synthetic Lethality With Paralog Cdk13, Jean Ching-Yi Tien, Jie Luo, Yu Chang, Yuping Zhang, Yunhui Cheng, Jianzhang Yang, Somnath Mahapatra, Palak Shah, Xiao-Ming Wang, Abigail J Todd, Sanjana Eyunni, Caleb Cheng, Ryan J Rebernick, Lanbo Xiao, Yi Bao, James Neiswender, Rachel Brough, Stephen J Pettitt, Xuhong Cao, Stephanie J Miner, Licheng Zhou, Yi-Mi Wu, Estefania Labanca, Yuzhuo Wang, Abhijit Parolia, Marcin Cieslik, Dan R Robinson, Zhen Wang, Felix Y Feng, Jonathan Chou, Christopher J Lord, Ke Ding, Arul M Chinnaiyan

Faculty, Staff and Student Publications

Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a metastatic castration-resistant prostate cancer (mCRPC) subtype. It remains unclear, however, whether CDK12 loss drives prostate cancer (PCa) development or uncovers pharmacologic vulnerabilities. Here, we show Cdk12 ablation in murine prostate epithelium is sufficient to induce preneoplastic lesions with lymphocytic infiltration. In allograft-based CRISPR screening, Cdk12 loss associates positively with Trp53 inactivation but negatively with Pten inactivation. Moreover, concurrent Cdk12/Trp53 ablation promotes proliferation of prostate-derived organoids, while Cdk12 knockout in Pten-null mice abrogates prostate tumor growth. In syngeneic systems, Cdk12/Trp53-null allografts exhibit luminal morphology and immune checkpoint blockade sensitivity. Mechanistically, Cdk12 inactivation …

Biochemical And Structural Insights Into A 5′ To 3′ Rna Ligase Reveal A Potential Role In Trna Ligation, Yingjie Hu, Victor A Lopez, Hengyi Xu, James P Pfister, Bing Song, Masahiro Sakurai, Joshua T Mendell, Tao Wang, Jun Wu, Alan M Lambowitz, Diana R Tomchick, Krzysztof Pawłowski, Vincent S Tagliabracci

Faculty, Staff and Student Publications

ATP-grasp superfamily enzymes contain a hand-like ATP-binding fold and catalyze a variety of reactions using a similar catalytic mechanism. More than 30 protein families are categorized in this superfamily, and they are involved in a plethora of cellular processes and human diseases. Here, we identify C12orf29 (RLIG1) as an atypical ATP-grasp enzyme that ligates RNA. Human RLIG1 and its homologs autoadenylate on an active site Lys residue as part of a reaction intermediate that specifically ligates RNA halves containing a 5’-phosphate and a 3’-hydroxyl. RLIG1 binds tRNA in cells and can ligate tRNA within the anticodon loop in vitro. Transcriptomic …

Development And Validation Of A Machine Learning Model To Predict Myocardial Blood Flow And Clinical Outcomes From Patients’ Electrocardiogram, Fares Alahdab, Maliazurina Binti Saad, Ahmed Ibrahim Ahmed, Qasem Al Tashi, Muhammad Aminu, Jonathan B Moody, Jia Wu, Mouaz H Al-Mallah

Faculty, Staff and Student Publications

We develop a machine learning (ML) model using electrocardiography (ECG) to predict myocardial blood flow reserve (MFR) and assess its prognostic value for major adverse cardiovascular events (MACEs). Using 3,639 ECG-positron emission tomography (PET) and 17,649 ECG-single-photon emission computed tomography (SPECT) data pairs, the ML model is trained with a swarm intelligence approach and support vector regression (SVR). The model achieves a receiver-operator curve (ROC) area under the curve (AUC) of 0.83, with a sensitivity and specificity of 0.75. An ECG-MFR value below 2 is significantly associated with MACE, with hazard ratios (HRs) of 3.85 and 3.70 in the discovery …

A Phase Ib/Ii Randomized Clinical Trial Of Oleclumab With Or Without Durvalumab Plus Chemotherapy In Patients With Metastatic Pancreatic Ductal Adenocarcinoma, Andrew L Coveler, Matthew J Reilley, Mark Zalupski, Teresa Macarulla, Christos Fountzilas, Adnan Nagrial, Sophia Frentzas, Michael Overman, Anne Noonan, Wells A Messersmith, Nick Pavlakis, Niharika B Mettu, Ina Bisha, Ying Wang, Paul Smith, Elina Murtomaki, Agata A Bielska, Veronique Bragulat, Zachary A Cooper, Rakesh Kumar, David R Spigel

Faculty, Staff and Student Publications

Purpose: Pancreatic ductal adenocarcinoma upregulates CD73, potentially contributing to immune surveillance evasion. Combining oleclumab (CD73 inhibitor) and durvalumab with chemotherapy may identify an effective treatment option.

Patients and methods: We describe a multicenter phase Ib/II randomized clinical trial in patients with metastatic pancreatic ductal adenocarcinoma, untreated (cohort A) or previously received gemcitabine-based chemotherapy (cohort B; NCT03611556). During escalation, patients received oleclumab 1,500 or 3,000 mg, durvalumab 1,500 mg, and gemcitabine plus nab-paclitaxel (GnP; cohort A; n = 14) or modified FOLFOX (cohort B; n = 11). During expansion, cohort A patients (n = 170) were randomized to GnP (arm …

First-In-Human Clinical Outcomes With Ng-350a, An Anti-Cd40 Expressing Tumor-Selective Vector Designed To Remodel Immunosuppressive Tumor Microenvironments, Aung Naing, Danny Khalil, Oliver Rosen, D Ross Camidge, Tom Lillie, Andrea Stacey, Lee Rosen

Faculty, Staff and Student Publications

Background: Tumor-selective oncolytic viral vectors are promising anticancer therapeutics; however, challenges with dosing and potency in advanced/metastatic cancers have limited efficacy and usage. NG-350A is a next-generation blood-stable adenoviral vector engineered to express an agonist anti-cluster of differentiation (CD)40 antibody without affecting tumor-selectivity and oncolytic potency.

Methods: Intravenous and intratumoral (IT) administration of NG-350A was assessed in a phase Ia/Ib study in patients with metastatic/advanced epithelial tumors (NCT03852511). Dose-escalation was performed separately for intravenous (four dose levels available, each with infusions on Days 1, 3 and 5 of a 57-day treatment period) and IT (single injection on D1 …

Evaluating Debio 1347 In Patients With Fgfr Fusion-Positive Advanced Solid Tumors From The Fuze Multicenter, Open-Label, Phase Ii Basket Trial, Petros Grivas, Elena Garralda, Funda Meric-Bernstam, Ingo K Mellinghoff, Lipika Goyal, E Claire Dees, Nilofer S Azad, Asha Karippot, Razelle Kurzrock, Josep Tabernero, Juha Kononen, Matthew C H Ng, Rutika Mehta, Nataliya V Uboha, Frédéric Bigot, Valentina Boni, Samantha E Bowyer, Valeriy Breder, Andrés Cervantes, Nancy Chan, James M Cleary, Mallika Dhawan, Rikke L Eefsen, James Ewing, Donna M Graham, Tormod K Guren, Jin Won Kim, Krassimir Koynov, Do-Youn Oh, Rebecca Redman, Chia-Jui Yen, David Spetzler, Marie-Claude Roubaudi-Fraschini, Valerie Nicolas-Metral, Rafik Ait-Sarkouh, Claudio Zanna, Abdallah Ennaji, Anna Pokorska-Bocci, Keith T Flaherty

Faculty, Staff and Student Publications

Purpose: This multicenter phase II basket trial investigated the efficacy, safety, and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1-3, in patients with solid tumors harboring a functional FGFR1-3 fusion.

Patients and methods: Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2), or another histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of …

Genotype And Phenotype Of 21-Hydroxylase Deficiency: A Single Center Experience From Western India, Manjiri Karlekar, Rohit Barnabas, Vijaya Sarathi, Anurag Lila, Sneha Arya, Samiksha Hegishte, Vishwambhar V Bhandare, Saba Samad Memon, Virendra Patil, Tushar Bandgar, Ambarish Kunwar, Nalini Shah

Faculty, Staff and Student Publications

Objective: To describe the genotype-phenotype characteristics of patients with 21-hydroxylase deficiency from western India and ascertain the prevalence of various phenotypes of 21-hydroxylase deficiency.

Methods: Patients with 21-hydroxylase deficiency, diagnosed clinically and biochemically, were prospectively enrolled and classified into salt wasting (SW), simple virilizing (SV), and non-classic (NC) phenotypes and were subjected to genetic testing of CYP21A2 by targeted sequencing and multiplex ligation-dependent probe amplification (MLPA).

Results: Eighty (64; 46, XX) probands with 21-hydroxylase deficiency were analyzed. 41 had SW, 34 had SV, and 5 had NC phenotype. Disease-causing mutations were identified in 158/160 alleles. The common mutations were Deletions/Large …

Multicenter Pivotal Study Of The Alterra Adaptive Prestent For The Treatment Of Pulmonary Regurgitation, D Scott Lim, Gareth Morgan, Thomas K Jones, Aimee K Armstrong, Darren Berman, Jamil Aboulhosn, Vaikom S Mahadevan, Matthew J Gillespie, David Balzer, Thomas Zellers, Xiao Yu, Girish Shirali, Anitha Parthiban, Jonathan Leipsic, Philipp Blanke, Evan Zahn, Shabana Shahanavaz

Faculty, Staff and Students Publications

Background: A dilated native right ventricular outflow tract (RVOT) presents unique challenges for transcatheter management using balloon-expandable valves. The Alterra Adaptive Prestent was designed to expand transcatheter therapy to treat patients with dilated RVOTs.

Objectives: The aim of this study was to report 2-year outcomes of the main cohort of the ALTERRA (Multicenter Study of Congenital Pulmonic Valve Dysfunction Studying the SAPIEN 3 THV With the Alterra Adaptive Prestent) pivotal trial using the prestent with transcatheter pulmonary valve replacement.

Methods: The prestent device used with the 29 mm SAPIEN 3 transcatheter heart valve (THV) was evaluated for the management of …

Clean Intermittent Catheterisation Determinants And Caregiver Adherence In Paediatric Patients With Spinal Dysraphism And Spinal Cord Injury In A Paediatric Spinal Differences Clinic: A Mixed Methods Study Protocol., Azadeh Wickham, Cynthia L. Russell, John Gatti

Manuscripts, Articles, Book Chapters and Other Papers

INTRODUCTION: Clean intermittent catheterisation (CIC) is the standard of care for treating neurogenic lower urinary tract dysfunction (NLUTD), the most common bladder dysfunction in children diagnosed with spinal dysraphism (SD) and spinal cord injury (SCI). Failure to follow the prescribed CIC regimen results in urinary tract infections, incontinence and renal insufficiency. Adherence to CIC is suboptimal, with reported non-adherence rates of 18%-66%. Despite the efficacy of CIC, the research on CIC adherence is not well defined in the literature and even less for caregivers of children on CIC protocols.

METHODS: This proposed study aims to identify caregiver CIC adherence and …

Memory Modulation: Dominance Of Negative Visual Context Over Neutral Verbal Memory, Stas Kozak, Noa Herz, Maya Tocker, Yair Bar-Haim, Nitzan Censor

Department of Neurology Faculty Papers

Neutral memories can be modulated via intentional memory control paradigms such as directed forgetting. In addition, previous studies have shown that neutral visual memories can be modulated indirectly, via remember and forget instructions towards competing verbal memories. Here we show that direct modulation of neutral verbal memory strength is impaired by negative visual context, and that negative visual context is resistant to indirect memory modulation. Participants were directly instructed to intentionally remember or forget newly encoded neutral verbal information. Importantly, this verbal information was interleaved with embedded negative visual context. Results showed that negative visual context eliminated the well-documented effect …

Left Ventricular Diastolic Dysfunction With Elevated Filling Pressures Is Associated With Embolic Stroke Of Undetermined Source And Atrial Fibrillation, Zubair Bashir, Liqi Shu, Yuqian Guo, Edward W Chen, Shuyuan Wang, Maheen Rana, Xing Dai, Daniel Mandel, Shadi Yaghi, Phinnara Has, Mingxing Xie, Tao Wang, James Simmons, Christopher Song, Philip Haines

Faculty, Staff and Student Publications

Background/Objectives: Left ventricular diastolic dysfunction (LVDD) and elevated left ventricular filling pressure (LVFP) are strong predictors of clinical outcomes across various populations. However, their diagnostic utility in embolic stroke of undetermined source (ESUS) remains unclear. We hypothesized that LVDD with elevated LVFP (based on echocardiography) was more likely to be prevalent in ESUS compared to non-cardioembolic stroke (NCE) and to be associated with atrial fibrillation (AF) on follow-up monitoring.

Methods: This is a single-center retrospective study that included adult patients with a diagnosis of acute ischemic stroke between January 2016 and June 2017. LV function was assessed by …

Regular Nonsteroidal Anti-Inflammatory Drug Use Increases Stress Fracture Risk In The General Population: A Retrospective Case-Control Study, Alexandra Ciuciu, Chris Mulholland, Michael A. Bozzi, Chris C. Frymoyer, Leonardo Cavinatto, David Yaron, Marc I. Harwood, Jeremy D. Close, Christopher J. Mehallo, Ryan E. Tomlinson

Department of Orthopaedic Surgery Faculty Papers

Previous studies have shown that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with increased stress fracture risk. This phenomenon has been studied predominantly in high-activity individuals, so data regarding the general population are limited despite the substantial economic and resource burden of stress fracture injuries within the general US population. Furthermore, our preclinical studies demonstrate that regular use of NSAIDs also diminishes the intrinsic ability of bone to resist fracture. To determine the association of regular NSAID use with stress fractures in the general population, we surveyed subjects presenting with either stress fracture or uncomplicated ankle sprain to …

Pain After Licorice Or Sugar-Water Gargling In Patients Recovering From Oropharyngeal Surgery-A Randomized, Double-Blind Trial, Marita Windpassinger, Michal Prusak, Jana Gemeiner, Olga Plattner, Stefan Janik, Gerold Besser, Wolfgang Gstoettner, Pu Xuan, Daniel I Sessler, Kurt Ruetzler

Faculty, Staff and Student Publications

Background: Glycyrrhiza glabrata (licorice) is used in traditional medicine and herbal remedies and reduces sore throats consequent to intubation, but whether it is protective for more intense pain after oropharyngeal surgery remains unclear. We thus tested the joint hypothesis that gargling with licorice, which has anti-inflammatory and antioxidant properties, reduces postoperative pain and morphine consumption.

Methods: We enrolled patients having elective oropharyngeal surgery. Participants were randomly allocated to gargle with either 1 g licorice or a sugar placebo before and for up to three days after surgery. A numerical rating scale (NRS) for pain along with morphine consumption was evaluated …

Long Covid Among Undocumented Latino Immigrant Populations In The Emergency Department., Karen P. Reyes, Zubaid Rafique, Brian Chinnock, Vijaya Arun Kumar, Michael Gottlieb, Kristin L. Rising, Robert M. Rodriguez

Department of Emergency Medicine Faculty Papers

Although many investigators have examined post–COVID-19 condition (long COVID) and its effects in the general population, to our knowledge, no studies have investigated its effect on one of the largest underserved US populations: undocumented Latino immigrants.¹ This group comprises 7% of the US population and has high rates of uninsurance, limited access to primary care, and language barriers when seeking health care.^2-4 Anti-immigrant political rhetoric and immigrants’ fear of discovery of their undocumented status when accessing health care make evaluation of this population more challenging.⁵ We leveraged emergency departments (EDs) as the primary health care …

A Complex Eprescribing Antimicrobial Stewardship-Based (Epams+) Intervention For Hospitals: Mixed-Methods Feasibility Trial Results, Rona Sharp, Holly Ennis, Andrew Heed, Robin Williams, Kathrin Cresswell, Omara Dogar, Sarah Pontefract, Jamie Coleman, Richard Lilford, Neil Watson, Ann Slee, Antony Chuter, Jillian Beggs, Sarah Slight, James Mason, David W Bates, Aziz Sheikh

Faculty, Staff and Students Publications

Background: Antibiotic resistant infections cause over 700,000 deaths worldwide annually. As antimicrobial stewardship (AMS) helps minimise the emergence of antibiotic resistance resulting from inappropriate use of antibiotics in healthcare, we developed ePAMS+ (ePrescribing-based Anti-Microbial Stewardship), an ePrescribing and Medicines Administration (EPMA) system decision-support tool complemented by educational, behavioural and organisational elements.

Methods: We conducted a non-randomised before-and-after feasibility trial, implementing ePAMS+ in two English hospitals using the Cerner Millennium EPMA system. Wards of several specialties were included. Patient participants were blinded to whether ePAMS+ was in use; prescribers were not. A mixed-methods evaluation aimed to establish: acceptability and usability of …

Larp1 Haploinsufficiency Is Associated With An Autosomal Dominant Neurodevelopmental Disorder, Robert Best, Kevin Chen, Josephine Morris, Zinaida Dedeic, Anna Childers, R Curtis Rogers, Barbara R Dupont, Cindy Skinner, Sébastien Küry, Kevin Uguen, Marc Planes, Danielle Monteil, Megan Li, Aviva Eliyahu, Lior Greenbaum, Nofar Mor, Thomas Besnard, Bertrand Isidor, Benjamin Cogné, Alyssa Blesson, Anne Comi, Ingrid M Wentzensen, Blake Vuocolo, Seema R Lalani, Roberta Sierra, Lori Berry, Kent Carter, Stephan J Sanders, Sarah P Blagden

Faculty, Staff and Students Publications

Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and …

Impact Of Age On Pharmacogenomics And Treatment Outcomes Of B-Cell Acute Lymphoblastic Leukemia, Satoshi Yoshimura, Zhenhua Li, Yoshihiro Gocho, Wenjian Yang, Kristine R Crews, Kathryn G Roberts, Mary V Relling, Jiyang Yu, Allen E J Yeoh, Mignon L Loh, Caner Saygin, Mark R Litzow, Sima Jeha, Seth E Karol, Hiroto Inaba, Ching-Hon Pui, Marina Konopleva, Nitin Jain, Wendy Stock, Elisabeth Paietta, Elias Jabbour, Steven M Kornblau, William E Evans, Jun J Yang

Faculty, Staff and Student Publications

Purpose: Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear.

Methods: Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations …

Forecasting The Effects Of Smoking Prevalence Scenarios On Years Of Life Lost And Life Expectancy From 2022 To 2050: A Systematic Analysis For The Global Burden Of Disease Study 2021

Faculty, Staff and Students Publications

BACKGROUND: Smoking is the leading behavioural risk factor for mortality globally, accounting for more than 175 million deaths and nearly 4·30 billion years of life lost (YLLs) from 1990 to 2021. The pace of decline in smoking prevalence has slowed in recent years for many countries, and although strategies have recently been proposed to achieve tobacco-free generations, none have been implemented to date. Assessing what could happen if current trends in smoking prevalence persist, and what could happen if additional smoking prevalence reductions occur, is important for communicating the effect of potential smoking policies.

METHODS: In this analysis, we use …

Rare Variant Contribution To The Heritability Of Coronary Artery Disease, Alanna C Morrison, Kruthika R Iyer, Erica P Young, Nathan O Stitziel, Goo Jun, Cecelia Laurie, Jai G Broome, Alyna T Khan, Donna K Arnett, Lewis C Becker, Joshua C Bis, Eric Boerwinkle, Donald W Bowden, April P Carson, Patrick T Ellinor, Myriam Fornage, Nora Franceschini, Barry I Freedman, Lifang Hou, Yii-Der Ida Chen, Eimear E Kenny, Charles Kooperberg, Brian G Kral, Ruth J F Loos, Sharon M Lutz, Joann E Manson, Lisa W Martin, Braxton D Mitchell, Rami Nassir, Nicholette D Palmer, Wendy S Post, Michael H Preuss, Bruce M Psaty, Laura M Raffield, Elizabeth A Regan, Stephen S Rich, Jennifer A Smith, Kent D Taylor, Lisa R Yanek, Kendra A Young, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Austin T Hilliard, Catherine Tcheandjieu, Patricia A Peyser, Ramachandran S Vasan, Jerome I Rotter, Clint L Miller, Themistocles L Assimes, Paul S De Vries, Ron Do

Faculty, Staff and Student Publications

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin …

Pandemic Perspectives From Detained Youth During Covid-19: Bridging The Knowledge Gap For Future Safeguards., April Mcneill-Johnson, Zuri Hudson, Brittany Moore, Dumebi Okocha, Megha Ramaswamy, Kimberly Randell

Manuscripts, Articles, Book Chapters and Other Papers

Despite the worsening health disparities among youth in detention during the COVID-19 pandemic, there has been minimal exploration into the pandemic experiences of detained youth and opportunities for pandemic mitigation. This paper analyzes the perspectives of youth in detention on the pandemic, including the effect of the pandemic on their detention experience and their perceptions about COVID-19 vaccination. The study used purposive sampling to recruit 16 participants (aged 14-17 years) from two juvenile detention centers in the urban Midwest. We conducted semi-structured interviews and analyzed verbatim transcripts using a hybrid deductive-inductive approach and thematic analysis. Four themes emerged: 1) personal …

Phase I/Ii Study Of Bms-986156 With Ipilimumab Or Nivolumab With Or Without Stereotactic Ablative Radiotherapy In Patients With Advanced Solid Malignancies, Joe Y Chang, Xinyan Xu, Girish S Shroff, Nathan I Comeaux, Wei Li, Daniel D Karp, Vivek Verma, Aileen Chen, James Welsh, David S Hong

Faculty, Staff and Student Publications

Background: BMS-986156 is an agonist of the glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) and promotes increased effector T-cell activation. Combined anti-GITR, anti-programmed death-1, anti-cytotoxic T-lymphocyte-associated protein 4 antibodies and radiotherapy improve tumor control in preclinical studies. Herein we describe the results of the safety and efficacy of BMS-986156+ipilimumab or nivolumab with/without stereotactic ablative radiotherapy (SABR) in patients with advanced solid cancers (NCT04021043).

Methods: This open-label, multigroup, single-center phase I/II study enrolled patients with histologically-confirmed stage IV solid cancers resistant to standard treatments. Group 1 (G1, n=20) received four cycles of ipilimumab (3 mg/kg) plus BMS-986156 (30 …

Promoting Healthful And Diverse Eating Behaviours Through An Extracurricular Culinary Skills Intervention In Philadelphia, Matthew D. Kearney, Arlene R. Maheu, Madalyn Booth, Andrew B. Newberg, Peter F. Cronholm, Soussan Ayubcha

SKMC Student Presentations and Publications

In the current study we evaluated an afterschool nutrition education programme, called Vetri Cooking Lab (VCL), for promoting healthy and diverse eating habits among at-risk children in the Greater Philadelphia area. To understand potential programme impacts, we conducted a longitudinal analysis of survey data collected before and after participation in VCL. Main study included cooking confidence, cooking knowledge, changes in dietary consumption behaviours, and changes in vegetable preferences. Participants included students in grades 3-11 enrolled in VCL during the 2018-19 school year at VCL sites (n = 60) throughout Philadelphia, PA, and Camden, NJ. Eligible participants completed surveys both before …

Gender And Sexuality Awareness In Medical Education And Practice: Mixed Methods Study, Ruba Tuma, Hisham Atwan, Anna Siri, Manlio Converti, Francesco Chirico, Łukasz Szarpak, Carlo Biz, Raymond Farah, Nicola Bragazzi

Faculty, Staff and Students Publications

BACKGROUND: The integration of gender and sexuality awareness in health care is increasingly recognized as vital for patient outcomes. Despite this, there is a notable lack of comprehensive data on the current state of physicians' training and perceptions in these areas, leading to a gap in targeted educational interventions and optimal health care delivery.

OBJECTIVE: The study's aim was to explore the experiences and perceptions of attending and resident physicians regarding the inclusion of gender and sexuality content in medical school curricula and professional practice in Israel.

METHODS: This cross-sectional survey targeted a diverse group of physicians across various specializations …

Impact Of Cancer Therapy On Clonal Hematopoiesis Mutations And Subsequent Clinical Outcomes, Kevin T Nead, Taebeom Kim, Lijin Joo, Tina L Mcdowell, Justin W Wong, Elizabeth Brock, Ting Xu, Chad Tang, Chang-Lung Lee, Jun-Ichi Abe, Kelly L Bolton, Zhongxing Liao, Paul A Scheet, Steven H Lin

Faculty, Staff and Student Publications

Exposure to cancer therapies is associated with an increased risk of clonal hematopoiesis (CH). The objective of our study was to investigate the genesis and evolution of CH after cancer therapy. In this prospective study, we undertook error-corrected duplex DNA sequencing in blood samples collected before and at 2 time points after chemoradiation in patients with esophageal or lung cancer recruited from 2013 to 2018. We applied a customized workflow to identify the earliest changes in CH mutation count and clone size and determine their association with clinical outcomes. Our study included 29 patients (87 samples). Their median age was …

Ct Strain Metrics Allow For Earlier Diagnosis Of Bronchiolitis Obliterans Syndrome After Hematopoietic Cell Transplant, Husham Sharifi, Christopher D Bertini, Mansour Alkhunaizi, Maria Hernandez, Zayan Musa, Ihsan Turk, Burton F Dickey, Guang-Shing Cheng, Gregory Yanik, Craig J Galban, Huawei Henry Guo, Myrna C B Godoy, Joseph M Reinhardt, Eric A Hoffman, Mario Castro, Gabriela Rondon, Amin M Alousi, Richard E Champlin, Elizabeth J Shpall, Ying Lu, Samuel Peterson, Keshav Datta, Mark R Nicolls, Joe Hsu, Ajay Sheshadri

Faculty, Staff and Student Publications

Bronchiolitis obliterans syndrome (BOS) after hematopoietic cell transplantation (HCT) is associated with substantial morbidity and mortality. Quantitative computed tomography (qCT) can help diagnose advanced BOS meeting National Institutes of Health (NIH) criteria (NIH-BOS) but has not been used to diagnose early, often asymptomatic BOS (early BOS), limiting the potential for early intervention and improved outcomes. Using pulmonary function tests (PFTs) to define NIH-BOS, early BOS, and mixed BOS (NIH-BOS with restrictive lung disease) in patients from 2 large cancer centers, we applied qCT to identify early BOS and distinguish between types of BOS. Patients with transient impairment or healthy lungs …