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Neurotoxicity: A Rare Side Effect Of Programmed Cell Death 1 (Pd-1) Inhibitors, Syed Ehsanullah, Syed Hasan, Faran S Polani, Syeda Zarmeena Rashid, Syed Ijlal Ahmed

Open Access Publications

Immunotherapy is a biological therapy that helps the body's immune system to fight against cancer cells. The Food and Drug Administration (FDA) approved the first immune checkpoint inhibitor in 2011. Since 2011, many immune checkpoint inhibitors have been approved. Programmed cell death 1 (PD-1) inhibitors are now commonly used in multiple malignancies due to their remarkable response. Thus, immune-related adverse events are now coming into the limelight due to the increasing use of PD-1 inhibitors. Here, we present a case of a 54-year-old female with non-small cell lung cancers (NSCLC) treated with pembrolizumab and later presented with severe neurotoxicity.

Identification Of Novel Mitochondrial Pyruvate Carrier Inhibitors By Homology Modeling And Pharmacophore-Based Virtual Screening, Lamees Hegazy, Lauren Gill, Kelly Pyles, Christopher Kaiho, Sophia Kchouk, Brian Finck, Kyle Mccommis, Bahaa Elgendy

Open Access Publications

No abstract provided.

Prevalence Of Borderline Acetabular Dysplasia In Symptomatic And Asymptomatic Populations: A Systematic Review And Meta-Analysis, Serena Freiman, Maria Schwabe, Lucas Fowler, John Clohisy, Jeffrey Nepple

Open Access Publications

Background: Patients with borderline acetabular dysplasia are a controversial patient population in hip preservation, as some have primarily impingement-based symptoms and others have instability-based symptoms. Borderline dysplasia is most commonly defined as a lateral center-edge angle (LCEA) of 20° to 25°. However, its prevalence has not been well established in the literature.

Purpose: To (1) define the prevalence of borderline hip dysplasia in the general population as well as in populations presenting with hip pain using a systematic review and meta-analysis of the literature and (2) describe differences between male and female patients as well as differences in prevalence from …

Rxra Dt448/9pp Generates A Dominant Active Variant Capable Of Inducing Maturation In Acute Myeloid Leukemia Cells, Orsola Di Martino, Margaret A. Ferris, Gayla Hadwiger, Soyi Sarkar, Anh Vu, María P. Menéndez-Gutiérrez, Mercedes Ricote, John S Welch

Open Access Publications

RARA and RXRA contribute to myeloid maturation in both mice and humans, and deletion of Rxra and Rxrb augments leukemic growth in mice. While defining the domains of RXRA that are required for anti-leukemic effects in murine KMT2A-MLLT3 leukemia cells, we unexpectedly identified RXRA DT448/9PP as a constitutively active variant capable of inducing maturation and loss of their proliferative phenotype. RXRA DT448/9PP was associated with ligand-independent activity in reporter assays, with enhanced co-activator interactions, reduced engraftment in vivo, and activation of myeloid maturation transcriptional signatures that overlapped with those of cells treated with the potent RXRA agonist bexarotene, suggestive of …

Alterations Of Host-Gut Microbiome Interactions In Multiple Sclerosis, Claudia Cantoni, Laura Ghezzi, Emily Evans, Li Deng, Alberto Locca, Robert Mikesell, Kathleen Obert, Amber Salter, Anne H Cross, Phillip I Tarr, Laura Piccio, Yanjiao Zhou, Et Al

Open Access Publications

BACKGROUND: Multiple sclerosis (MS) has a complex genetic, immune and metabolic pathophysiology. Recent studies implicated the gut microbiome in MS pathogenesis. However, interactions between the microbiome and host immune system, metabolism and diet have not been studied over time in this disorder.

METHODS: We performed a six-month longitudinal multi-omics study of 49 participants (24 untreated relapse remitting MS patients and 25 age, sex, race matched healthy control individuals. Gut microbiome composition and function were characterized using 16S and metagenomic shotgun sequencing. Flow cytometry was used to characterize blood immune cell populations and cytokine profiles. Circulating metabolites were profiled by untargeted …

Mitochondrial Pyruvate Carrier Inhibitors Improve Metabolic Parameters In Diet-Induced Obese Mice, Wesley T Hodges, Chaowapong Jarasvaraparn, Daniel Ferguson, Kristine Griffett, Lauren E Gill, Yana Chen, Ma Xenia G Ilagan, Lamees Hegazy, Bahaa Elgendy, Kevin Cho, Gary J Patti, Kyle S Mccommis, Brian N Finck

Open Access Publications

The mitochondrial pyruvate carrier (MPC) is an inner mitochondrial membrane complex that plays a critical role in intermediary metabolism. Inhibition of the MPC, especially in liver, may have efficacy for treating type 2 diabetes mellitus. Herein, we examined the antidiabetic effects of zaprinast and 7ACC2, small molecules which have been reported to act as MPC inhibitors. Both compounds activated a bioluminescence resonance energy transfer-based MPC reporter assay (reporter sensitive to pyruvate) and potently inhibited pyruvate-mediated respiration in isolated mitochondria. Furthermore, zaprinast and 7ACC2 acutely improved glucose tolerance in diet-induced obese mice in vivo. Although some findings were suggestive of improved …

Safety And Efficacy Of Mass Drug Administration With A Single-Dose Triple-Drug Regimen Of Albendazole + Diethylcarbamazine + Ivermectin For Lymphatic Filariasis In Papua New Guinea: An Open-Label, Cluster-Randomised Trial, Livingstone Tavul, Kobie O'Brian, Gary J. Weil, Charles W. Goss, Et Al

Open Access Publications

BACKGROUND: Papua New Guinea (PNG) has a high burden of lymphatic filariasis (LF) caused by Wuchereria bancrofti, with an estimated 4.2 million people at risk of infection. A single co-administered dose of ivermectin, diethylcarbamazine and albendazole (IDA) has been shown to have superior efficacy in sustained clearance of microfilariae compared to diethylcarbamazine and albendazole (DA) in small clinical trials. A community-based cluster-randomised trial of DA versus IDA was conducted to compare the safety and efficacy of IDA and DA for LF in a moderately endemic, treatment-naive area in PNG.

METHODOLOGY: All consenting, eligible residents of 24 villages in Bogia district, …

The Foundations And Development Of Lipidomics, Xianlin Han, Richard W Gross

Open Access Publications

For over a century, the importance of lipid metabolism in biology was recognized but difficult to mechanistically understand due to the lack of sensitive and robust technologies for identification and quantification of lipid molecular species. The enabling technological breakthroughs emerged in the 1980s with the development of soft ionization methods (Electrospray Ionization and Matrix Assisted Laser Desorption/Ionization) that could identify and quantify intact individual lipid molecular species. These soft ionization technologies laid the foundations for what was to be later named the field of lipidomics. Further innovative advances in multistage fragmentation, dramatic improvements in resolution and mass accuracy, and multiplexed …

Coronavirus Disease 2019 (Covid-19) Research Agenda For Healthcare Epidemiology, Lona Mody, Hilary M Babcock, Jennie H Kwon, Et Al

Open Access Publications

This SHEA white paper identifies knowledge gaps and challenges in healthcare epidemiology research related to coronavirus disease 2019 (COVID-19) with a focus on core principles of healthcare epidemiology. These gaps, revealed during the worst phases of the COVID-19 pandemic, are described in 10 sections: epidemiology, outbreak investigation, surveillance, isolation precaution practices, personal protective equipment (PPE), environmental contamination and disinfection, drug and supply shortages, antimicrobial stewardship, healthcare personnel (HCP) occupational safety, and return to work policies. Each section highlights three critical healthcare epidemiology research questions with detailed description provided in supplementary materials. This research agenda calls for translational studies from laboratory-based …

Antiretroviral Therapy Timing Impacts Latent Tuberculosis Infection Reactivation In A Mycobacterium Tuberculosis/Siv Coinfection Model, Riti Sharan, Allison N Bucsan, Shabaana A Khader, Et Al

Open Access Publications

Studies using the nonhuman primate model of Mycobacterium tuberculosis/simian immunodeficiency virus coinfection have revealed protective CD4+ T cell-independent immune responses that suppress latent tuberculosis infection (LTBI) reactivation. In particular, chronic immune activation rather than the mere depletion of CD4+ T cells correlates with reactivation due to SIV coinfection. Here, we administered combinatorial antiretroviral therapy (cART) 2 weeks after SIV coinfection to study whether restoration of CD4+ T cell immunity occurred more broadly, and whether this prevented reactivation of LTBI compared to cART initiated 4 weeks after SIV. Earlier initiation of cART enhanced survival, led to better control of viral replication, …

Measurement Matters: An Individual Differences Examination Of Family Socioeconomic Factors, Latent Dimensions Of Children's Experiences, And Resting State Functional Brain Connectivity In The Abcd Sample, Meriah L Dejoseph, Max P Herzberg, Robin D Sifre, Daniel Berry, Kathleen M Thomas

Open Access Publications

The variation in experiences between high and low-socioeconomic status contexts are posited to play a crucial role in shaping the developing brain and may explain differences in child outcomes. Yet, examinations of SES and brain development have largely been limited to distal proxies of these experiences (e.g., income comparisons). The current study sought to disentangle the effects of multiple socioeconomic indices and dimensions of more proximal experiences on resting-state functional connectivity (rsFC) in a sample of 7834 youth (aged 9-10 years) from the Adolescent Brain Cognitive Development (ABCD) study. We applied moderated nonlinear factor analysis (MNLFA) to establish measurement invariance …

Dear Reviewers: Responses To Common Reviewer Critiques About Infant Neuroimaging Studies, Marta Korom, M Catalina Camacho, Courtney A Filippi, Roxane Licandro, Lucille A Moore, Alexander Dufford, Lilla Zöllei, Alice M Graham, Marisa Spann, Brittany Howell, Fit'ng, Sarah Shultz, Dustin Scheinost

Open Access Publications

The field of adult neuroimaging relies on well-established principles in research design, imaging sequences, processing pipelines, as well as safety and data collection protocols. The field of infant magnetic resonance imaging, by comparison, is a young field with tremendous scientific potential but continuously evolving standards. The present article aims to initiate a constructive dialog between researchers who grapple with the challenges and inherent limitations of a nascent field and reviewers who evaluate their work. We address 20 questions that researchers commonly receive from research ethics boards, grant, and manuscript reviewers related to infant neuroimaging data collection, safety protocols, study planning, …

Liposomal Phytohemagglutinin: In Vivo T-Cell Activator As A Novel Pan-Cancer Immunotherapy, Kinan Alhallak, Jennifer Sun, Barbara Muz, Amanda Jeske, Julie O'Neal, Julie K Ritchey, Samuel Achilefu, John F Dipersio, Abdel Kareem Azab

Open Access Publications

Immunotherapy is an attractive approach for treating cancer. T-cell engagers (TCEs) are a type of immunotherapy that are highly efficacious; however, they are challenged by weak T-cell activation and short persistence. Therefore, alternative solutions to induce greater activation and persistence of T cells during TCE immunotherapy is needed. Methods to activate T cells include the use of lectins, such as phytohemagglutinin (PHA). PHA has not been used to activate T cells in vivo, for immunotherapy, due to its biological instability and toxicity. An approach to overcome the limitations of PHA while also preserving its function is needed. In this study, …

Depression Is Transiently Increased In Patients Undergoing Two-Stage Revision Arthroplasty, Ryan J Furdock, Bharadwaj Jilakara, Tyler J Moon, Neelansh Bute, Lee Rhea, Douglas Mcdonald, Cara A Cipriano

Open Access Publications

Background: The implications of two-stage revision on mental health are poorly understood. The purpose of this study is to determine (1) whether patients undergoing two-stage revision total hip and knee arthroplasty for prosthetic joint infection were more likely to get Patient-Reported Outcomes Measurement Information System (PROMIS) Depression scores consistent with major depressive disorder (MDD) than those undergoing aseptic revision and (2) whether these symptoms resolved after the procedure.

Methods: Records of all 366 patients that underwent revision total hip or knee arthroplasty from January 1, 2015, - June 20, 2019, were reviewed. Forty-two patients were excluded for missing PROMIS Depression …

Quantifying Regional Α -Synuclein, Amyloid Β, And Tau Accumulation In Lewy Body Dementia, Rebecca L Miller, Dhruva D Dhavale, Jennifer Y O'Shea, Kristin M Andruska, Jialu Liu, Erin E Franklin, Chandana Buddhala, Susan K Loftin, John R Cirrito, Richard J Perrin, Nigel J Cairns, Meghan C Campbell, Joel S Perlmutter, Paul T Kotzbauer

Open Access Publications

OBJECTIVE: Parkinson disease (PD) is defined by the accumulation of misfolded α-synuclein (α-syn) in Lewy bodies and Lewy neurites. It affects multiple cortical and subcortical neuronal populations. The majority of people with PD develop dementia, which is associated with Lewy bodies in neocortex and referred to as Lewy body dementia (LBD). Other neuropathologic changes, including amyloid β (Aβ) and tau accumulation, occur in some LBD cases. We sought to quantify α-syn, Aβ, and tau accumulation in neocortical, limbic, and basal ganglia regions.

METHODS: We isolated insoluble protein from fresh frozen postmortem brain tissue samples for eight brains regions from 15 …

Incidence Of Emergency Department Visits For Electric Rental Scooters Using Detailed Ridership Data, Chelsea Williams, Cindy C Bitter, Steven Lorber, Caleb R Overfelt, Holly Zehfus, Andrea Spangler, Valerie Lew, Lawrence M Lewis, Rosanne S Naunheim

Open Access Publications

INTRODUCTION: Electric scooter (e-scooter) rental usage has increased exponentially around the country, expanding to more than 120 cities by the end of 2018. Early attempts to capture the safety effects of widespread adoption of this technology have been hampered by lack of accurate ridership data. Here we describe a 17-month evolution of ridership characteristics in St. Louis, Missouri, and the frequency of e-scooter rental-related injuries serious enough to require an emergency department (ED) visit over this time frame; we also provide estimates of incidence rates of injuries based on company ridership data.

METHODS: We performed a combination retrospective chart review …

Racial And Ethnic Minorities Have A Lower Prevalence Of Airflow Obstruction Than Non-Hispanic Whites, Akshay Sood, Hans Petersen, Congjian Liu, Orrin Myers, Xin Wang Shore, Bobbi A Gore, Rodrigo Vazquez-Guillamet, Linda S Cook, Paula Meek, Yohannes Tesfaigzi

Open Access Publications

Racial and ethnic disparities in chronic obstructive pulmonary disease (COPD) are not well-studied. Our objective was to examine differences in limited COPD-related outcomes between three minority groups-African Americans (AAs), Hispanics, and American Indians (AIs) versus non-Hispanic Whites (NHWs), as the referent group, in separate cohorts. Separate cross-sectional evaluations were performed of three US-based cohorts of subjects at risk for COPD: COPDGene Study with 6,884 NHW and 3,416 AA smokers; Lovelace Smokers' Cohort with 1,598 NHW and 378 Hispanic smokers; and Mining Dust Exposure in the United States Cohort with 2,115 NHW, 2,682 Hispanic, and 2,467 AI miners. Prebronchodilator spirometry tests …

Computational Genomics In The Era Of Precision Medicine: Applications To Variant Analysis And Gene Therapy, Yung-Chun Wang, Julie Choi, Shujuan Zhao, Mariam Khanfar, Kuangying Yang, Po-Ying Fu, Max Wrubel, Xiaobing Yu, Sheng Chih Jin, Et Al

Open Access Publications

Rapid methodological advances in statistical and computational genomics have enabled researchers to better identify and interpret both rare and common variants responsible for complex human diseases. As we continue to see an expansion of these advances in the field, it is now imperative for researchers to understand the resources and methodologies available for various data types and study designs. In this review, we provide an overview of recent methods for identifying rare and common variants and understanding their roles in disease etiology. Additionally, we discuss the strategy, challenge, and promise of gene therapy. As computational and statistical approaches continue to …

Whole-Exome Analysis Of Adolescents With Low Vwf And Heavy Menstrual Bleeding Identifies Novel Genetic Associations, Brooke Sadler, Christina A Gurnett, Jorge Di Paola, Et Al

Open Access Publications

Adolescents with low von Willebrand factor (VWF) levels and heavy menstrual bleeding (HMB) experience significant morbidity. There is a need to better characterize these patients genetically and improve our understanding of the pathophysiology of bleeding. We performed whole-exome sequencing on 86 postmenarchal patients diagnosed with low VWF levels (30-50 IU/dL) and HMB and compared them with 660 in-house controls. We compared the number of rare stop-gain/stop-loss and rare ClinVar "pathogenic" variants between cases and controls, as well as performed gene burden and gene-set burden analyses. We found an enrichment in cases of rare stop-gain/stop-loss variants in genes involved in bleeding …

T Cell Subtype Profiling Measures Exhaustion And Predicts Anti-Pd-1 Response, Ian Schillebeeckx, Jon Earls, Kevin C Flanagan, Jeffrey Hiken, Alex Bode, Jon R Armstrong, David N Messina, Douglas Adkins, Jessica Ley, Ilaria Alborelli, Philip Jermann, Jarret I Glasscock

Open Access Publications

Anti-PD-1 therapy can provide long, durable benefit to a fraction of patients. The on-label PD-L1 test, however, does not accurately predict response. To build a better biomarker, we created a method called T Cell Subtype Profiling (TCSP) that characterizes the abundance of T cell subtypes (TCSs) in FFPE specimens using five RNA models. These TCS RNA models are created using functional methods, and robustly discriminate between naïve, activated, exhausted, effector memory, and central memory TCSs, without the reliance on non-specific, classical markers. TCSP is analytically valid and corroborates associations between TCSs and clinical outcomes. Multianalyte biomarkers based on TCS estimates …

Longitudinal Study After Sputnik V Vaccination Shows Durable Sars-Cov-2 Neutralizing Antibodies And Reduced Viral Variant Escape To Neutralization Over Time, María M Gonzalez Lopez Ledesma, Paul W Rothlauf, Zhuoming Liu, Louis-Marie Bloyet, Marjorie Cornejo Pontelli, Et Al

Open Access Publications

Recent studies have shown a temporal increase in the neutralizing antibody potency and breadth to SARS-CoV-2 variants in coronavirus disease 2019 (COVID-19) convalescent individuals. Here, we examined longitudinal antibody responses and viral neutralizing capacity to the B.1 lineage virus (Wuhan related), to variants of concern (VOC; Alpha, Beta, Gamma, and Delta), and to a local variant of interest (VOI; Lambda) in volunteers receiving the Sputnik V vaccine in Argentina. Longitudinal serum samples (

Inhibiting Mycobacterium Abscessus Cell Wall Synthesis: Using A Novel Diazabicyclooctane Β-Lactamase Inhibitor To Augment Β-Lactam Action, Khalid M Dousa, David C Nguyen, Sebastian G Kurz, Magdalena A Taracila, Christopher R Bethel, William Schinabeck, Barry N Kreiswirth, Sheldon T Brown, W Henry Boom, Richard S Hotchkiss, Kenneth E Remy, Frank J Jacono, Charles L Daley, Steven M Holland, Alita A Miller, Robert A Bonomo

Open Access Publications

Mycobacterium abscessus (

Neural Signatures Of Data-Driven Psychopathology Dimensions At The Transition To Adolescence, Amirhossein Modabbernia, Giorgia Michelini, Abraham Reichenberg, Roman Kotov, Deanna Barch, Sophia Frangou

Open Access Publications

BACKGROUND: One of the challenges in human neuroscience is to uncover associations between brain organization and psychopathology in order to better understand the biological underpinnings of mental disorders. Here, we aimed to characterize the neural correlates of psychopathology dimensions obtained using two conceptually different data-driven approaches.

METHODS: Dimensions of psychopathology that were either maximally dissociable or correlated were respectively extracted by independent component analysis (ICA) and exploratory factor analysis (EFA) applied to the Childhood Behavior Checklist items from 9- to 10-year-olds (n = 9983; 47.8% female, 50.8% white) participating in the Adolescent Brain Cognitive Development study. The patterns of brain …

American Society Of Hematology Living Guidelines On The Use Of Anticoagulation For Thromboprophylaxis In Patients With Covid-19: July 2021 Update On Postdischarge Thromboprophylaxis, Adam Cuker, Kristen M. Sanfilippo, Et Al

Open Access Publications

No abstract provided.

Improving The Diagnosis Of Menstrual Dysfunction Through Quality Improvement, Kayla Daniel, Anastasia Fischer, Michael Welty, Amy E Valasek

Open Access Publications

Introduction: Prevalence of menstrual dysfunction (MD) in high school athletes ranges from 7% to 54%. Early recognition and intervention are crucial to prevent future consequences. The purpose of this Quality Improvement project was to optimize the institution's Epic Best Practice Advisory (BPA) screening tool and synthesize new patient questionnaires to diagnose MD in athletes greater than 12 years of age presenting to a pediatric sports medicine clinic.

Methods: Using Quality Improvement methodology, we evaluated clinic flow, the Epic BPA tool, and actions by the physician following the appropriate triggering of the BPA. Diagnoses targeted were primary amenorrhea, oligomenorrhea, or irregular …

Enrichment Of The Exocytosis Protein Stx4 In Skeletal Muscle Remediates Peripheral Insulin Resistance And Alters Mitochondrial Dynamics Via Drp1, Karla E Merz, Jinhee Hwang, Chunxue Zhou, Rajakrishnan Veluthakal, Erika M Mccown, Angelica Hamilton, Eunjin Oh, Wenting Dai, Patrick T Fueger, Lei Jiang, Janice M Huss, Debbie C Thurmond

Open Access Publications

Mitochondrial dysfunction is implicated in skeletal muscle insulin resistance. Syntaxin 4 (STX4) levels are reduced in human diabetic skeletal muscle, and global transgenic enrichment of STX4 expression improves insulin sensitivity in mice. Here, we show that transgenic skeletal muscle-specific STX4 enrichment (skmSTX4tg) in mice reverses established insulin resistance and improves mitochondrial function in the context of diabetogenic stress. Specifically, skmSTX4tg reversed insulin resistance caused by high-fat diet (HFD) without altering body weight or food consumption. Electron microscopy of wild-type mouse muscle revealed STX4 localisation at or proximal to the mitochondrial membrane. STX4 enrichment prevented HFD-induced mitochondrial fragmentation and dysfunction through …

The Immunoregulatory Landscape Of Human Tuberculosis Granulomas, Erin F. Mccaffrey, Shabaana A. Khader, Et Al

Open Access Publications

No abstract provided.

The Gut Microbiota Of Chickens In A Commercial Farm Treated With A Salmonella Phage Cocktail, Viviana Clavijo, Tatiana Morales, Martha Josefina Vives-Flores, Alejandro Reyes Muñoz

Open Access Publications

The microbiota in broiler chicken intestines affects the animals' health, metabolism, and immunity both positively and negatively. Accordingly, it has a significant impact on animal productivity. Phages, host-specific parasites of bacterial cells, are a promising antimicrobial alternative that selectively target pathogens without disturbing the microbiota. The purpose of this study is to further characterize the commensal microbial community at production scale in broiler chickens treated with a Salmonella phage treatment. We evaluated the cecal microbiota of broilers reared in a commercial farming system where a phage cocktail against Salmonella, SalmoFree was supplied to animals. To do so, two field trials …

Jib-04 Has Broad-Spectrum Antiviral Activity And Inhibits Sars-Cov-2 Replication And Coronavirus Pathogenesis, Juhee Son, Shimeng Huang, Qiru Zeng, Traci L Bricker, James Brett Case, Ruochen Zang, Zhuoming Liu, Tamarand L Darling, Jian Xu, Houda H Harastani, Maria Florencia Gomez Castro, Hinissan P Kohio, Gaopeng Hou, Paul W Rothlauf, Adam L Bailey, Steven L Brody, Sean P J Whelan, Michael S Diamond, Adrianus C M Boon, Siyuan Ding, Et Al

Open Access Publications

Pathogenic coronaviruses are a major threat to global public health. Here, using a recombinant reporter virus-based compound screening approach, we identified small-molecule inhibitors that potently block the replication of severe acute respiratory syndrome virus 2 (SARS-CoV-2). Among them, JIB-04 inhibited SARS-CoV-2 replication in Vero E6 cells with a 50% effective concentration of 695 nM, with a specificity index of greater than 1,000. JIB-04 showed

Spotlight On Nociceptin/Orphanin Fq Receptor In The Treatment Of Pain, Amal El Daibani, Tao Che

Open Access Publications

No abstract provided.