Digital Commons Network^™

Hydraulic Permeability And Compressive Properties Of Porcine And Human Synovium, Milad Rohanifar, Benjamin B Johnston, Alexandra L Davis, Young Guang, Kayla Nommensen, James A J Fitzpatrick, Christine N Pham, Lori A Setton

2020-Current year OA Pubs

The synovium is a multilayer connective tissue separating the intra-articular spaces of the diarthrodial joint from the extra-synovial vascular and lymphatic supply. Synovium regulates drug transport into and out of the joint, yet its material properties remain poorly characterized. Here, we measured the compressive properties (aggregate modulus, Young's modulus, and Poisson's ratio) and hydraulic permeability of synovium with a combined experimental-computational approach. A compressive aggregate modulus and Young's modulus for the solid phase of synovium were quantified from linear regression of the equilibrium confined and unconfined compressive stress upon strain, respectively (H

Stain-Free Detection Of Embryo Polarization Using Deep Learning, Cheng Shen, Adiyant Lamba, Meng Zhu, Ray Zhang, Magdalena Zernicka-Goetz, Changhuei Yang

Open Access Publications

Polarization of the mammalian embryo at the right developmental time is critical for its development to term and would be valuable in assessing the potential of human embryos. However, tracking polarization requires invasive fluorescence staining, impermissible in the in vitro fertilization clinic. Here, we report the use of artificial intelligence to detect polarization from unstained time-lapse movies of mouse embryos. We assembled a dataset of bright-field movie frames from 8-cell-stage embryos, side-by-side with corresponding images of fluorescent markers of cell polarization. We then used an ensemble learning model to detect whether any bright-field frame showed an embryo before or after …

Iκb-Ζ Signaling Promotes Chondrocyte Inflammatory Phenotype, Senescence, And Erosive Joint Pathology, Manoj Arra, Gaurav Swarnkar, Yael Alippe, Gabriel Mbalaviele, Yousef Abu-Amer

Open Access Publications

Osteoarthritis is a joint disease characterized by a poorly-defined inflammatory response that does not encompass a massive immune cell infiltration yet contributes to cartilage degradation and loss of joint mobility, suggesting a chondrocyte intrinsic inflammatory response. Using primary chondrocytes from joints of osteoarthritic mice and patients, we first show that these cells express ample pro-inflammatory markers and RANKL in an NF-κB dependent manner. The inflammatory phenotype of chondrocytes was recapitulated by exposure of chondrocytes to IL-1β and bone particles, which were used to model bone matrix breakdown products revealed to be present in synovial fluid of OA patients, albeit their …

Apparent Sunk Cost Effect In Rational Agents, Torben Ott, Paul Masset, Thiago S Gouvêa, Adam Kepecs

Open Access Publications

Rational decision makers aim to maximize their gains, but humans and other animals often fail to do so, exhibiting biases and distortions in their choice behavior. In a recent study of economic decisions, humans, mice, and rats were reported to succumb to the sunk cost fallacy, making decisions based on irrecoverable past investments to the detriment of expected future returns. We challenge this interpretation because it is subject to a statistical fallacy, a form of attrition bias, and the observed behavior can be explained without invoking a sunk cost-dependent mechanism. Using a computational model, we illustrate how a rational decision …

The Association Between Hiv Status, Estradiol, And Sex Hormone Binding Globulin Among Premenopausal Women In The Women's Interagency Hiv Study, Sally B Coburn, Jodie Dionne-Odom, Maria L Alcaide, Caitlin A Moran, Lisa Rahangdale, Elizabeth T Golub, Leslie Stewart Massad, Dominika Seidman, Katherine G Michel, Howard Minkoff, Kerry Murphy, Todd T Brown, Kala Visvanathan, Bryan Lau, Keri N Althoff

Open Access Publications

No abstract provided.

Single-Agent Mosunetuzumab Shows Durable Complete Responses In Patients With Relapsed Or Refractory B-Cell Lymphomas: Phase I Dose-Escalation Study, Lihua E Budde, Nancy L Bartlett, Et Al

2020-Current year OA Pubs

PURPOSE: Mosunetuzumab is a bispecific antibody targeting CD20 and CD3 that redirects T cells to engage and eliminate malignant B cells and is being developed for relapsed or refractory (R/R) B-cell non-Hodgkin lymphomas (B-NHLs).

METHODS: This first-in-human trial (ClinicalTrials.gov identifier: NCT02500407) evaluated the safety and tolerability and efficacy of mosunetuzumab in patients with R/R B-NHL and established the recommended phase II dose. Data from dose escalation are presented. Single-agent mosunetuzumab was administered intravenously in 3-week cycles, at full dose in cycle 1 day 1 (group A) or with ascending (step-up) doses during cycle 1 on days 1, 8, and 15 …

Spatiotemporal Expression Of Regulatory Kinases Directs The Transition From Mitosis To Cellular Morphogenesis In Drosophila, Shuo Yang, Jennifer Mcadow, Yingqiu Du, Jennifer Trigg, Paul H Taghert, Aaron N Johnson

Open Access Publications

Embryogenesis depends on a tightly regulated balance between mitosis, differentiation, and morphogenesis. Understanding how the embryo uses a relatively small number of proteins to transition between growth and morphogenesis is a central question of developmental biology, but the mechanisms controlling mitosis and differentiation are considered to be fundamentally distinct. Here we show the mitotic kinase Polo, which regulates all steps of mitosis in Drosophila, also directs cellular morphogenesis after cell cycle exit. In mitotic cells, the Aurora kinases activate Polo to control a cytoskeletal regulatory module that directs cytokinesis. We show that in the post-mitotic mesoderm, the control of Polo …

A Dominant Negative Variant Of Rab5b Disrupts Maturation Of Surfactant Protein B And Surfactant Protein C, Huiyan Huang, Jiehong Pan, Ariz Mohammad, Tao Huang, Anika G Lindsey, Hyori Kim, Jian Chen, Avinash Ramu, Stephanie A Morrison, Zachary D Dawson, Alex Z Hu, Eric Tycksen, Gary A Silverman, Dustin Baldridge, Jennifer A Wambach, Stephen C. Pak, Steven L Brody, Tim Schedl, Et Al

Open Access Publications

Pathogenic variants in surfactant proteins SP-B and SP-C cause surfactant deficiency and interstitial lung disease. Surfactant proteins are synthesized as precursors (proSP-B, proSP-C), trafficked, and processed via a vesicular-regulated secretion pathway; however, control of vesicular trafficking events is not fully understood. Through the Undiagnosed Diseases Network, we evaluated a child with interstitial lung disease suggestive of surfactant deficiency. Variants in known surfactant dysfunction disorder genes were not found in trio exome sequencing. Instead, a de novo heterozygous variant in

Outcome Of Allogeneic Transplantation For Mature T-Cell Lymphomas: Impact Of Donor Source And Disease Characteristics, Mehdi Hamadani, Amanda F Cashen, Et Al

Open Access Publications

Mature T-cell lymphomas constitute the most common indication for allogeneic hematopoietic cell transplantation (allo-HCT) of all lymphomas. Large studies evaluating contemporary outcomes of allo-HCT in mature T-cell lymphomas relative to commonly used donor sources are not available. Included in this registry study were adult patients who had undergone allo-HCT for anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) between 2008 and 2018. Hematopoietic cell transplantation (HCT) platforms compared were posttransplant cyclophosphamide-based haploidentical (haplo-)HCT, matched sibling donor (MSD) HCT, matched unrelated donor HCT with in vivo T-cell depletion (MUD TCD+), and matched unrelated …

Ddr1 Contributes To Kidney Inflammation And Fibrosis By Promoting The Phosphorylation Of Bcr And Stat3, Corina M. Borza, Gema Bolas, Fabian Bock, Xiuqi Zhang, Favour C Akabogu, Ming-Zhi Zhang, Mark De Caestecker, Min Yang, Haichun Yang, Ethan Lee, Leslie Gewin, Agnes B Fogo, W Hayes Mcdonald, Roy Zent, Ambra Pozzi

Open Access Publications

Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase activated by collagen, contributes to chronic kidney disease. However, its role in acute kidney injury and subsequent development of kidney fibrosis is not clear. Thus, we performed a model of severe ischemia/reperfusion-induced acute kidney injury that progressed to kidney fibrosis in WT and Ddr1-null mice. We showed that Ddr1-null mice had reduced acute tubular injury, inflammation, and tubulointerstitial fibrosis with overall decreased renal monocyte chemoattractant protein (MCP-1) levels and STAT3 activation. We identified breakpoint cluster region (BCR) protein as a phosphorylated target of DDR1 that controls MCP-1 production in renal proximal …

Stromal Architecture Directs Early Dissemination In Pancreatic Ductal Adenocarcinoma, Arja Ray, Mackenzie K. Callaway, Nelson J. Rodríguez-Merced, Alexandra L. Crampton, Marjorie Carlson, Kenneth B. Emme, Ethan A. Ensminger, Alexander A. Kinne, Jonathan H. Schrope, Haley R. Rasmussen, Hong Jiang, David G. Denardo, David K. Wood, Paolo P. Provenzano

Open Access Publications

Pancreatic ductal adenocarcinoma (PDA) is an extremely metastatic and lethal disease. Here, in both murine and human PDA, we demonstrate that extracellular matrix architecture regulates cell extrusion and subsequent invasion from intact ductal structures through tumor-associated collagen signatures (TACS). This results in early dissemination from histologically premalignant lesions and continual invasion from well-differentiated disease, and it suggests TACS as a biomarker to aid in the pathologic assessment of early disease. Furthermore, we show that pancreatitis results in invasion-conducive architectures, thus priming the stroma prior to malignant disease. Analysis in potentially novel microfluidic-derived microtissues and in vivo demonstrates decreased extrusion and …

Regulation Of The Double-Stranded Rna Response Through Adar1 Licenses Metaplastic Reprogramming In Gastric Epithelium, José B. Sáenz, Nancy Vargas, Charles J. Cho, Jason C. Mills

2020-Current year OA Pubs

Cells recognize both foreign and host-derived double-stranded RNA (dsRNA) via a signaling pathway that is usually studied in the context of viral infection. It has become increasingly clear that the sensing and handling of endogenous dsRNA is also critical for cellular differentiation and development. The adenosine RNA deaminase, ADAR1, has been implicated as a central regulator of the dsRNA response, but how regulation of the dsRNA response might mediate cell fate during injury and whether such signaling is cell intrinsic remain unclear. Here, we show that the ADAR1-mediated response to dsRNA was dramatically induced in 2 distinct injury models of …

Live-Dead Assay On Unlabeled Cells Using Phase Imaging With Computational Specificity, Chenfei Hu, Shenghua He, Young Jae Lee, Yuchen He, Edward M Kong, Hua Li, Mark A Anastasio, Gabriel Popescu

Open Access Publications

Existing approaches to evaluate cell viability involve cell staining with chemical reagents. However, the step of exogenous staining makes these methods undesirable for rapid, nondestructive, and long-term investigation. Here, we present an instantaneous viability assessment of unlabeled cells using phase imaging with computation specificity. This concept utilizes deep learning techniques to compute viability markers associated with the specimen measured by label-free quantitative phase imaging. Demonstrated on different live cell cultures, the proposed method reports approximately 95% accuracy in identifying live and dead cells. The evolution of the cell dry mass and nucleus area for the labeled and unlabeled populations reveal …

Protocol For Development Of A Core Outcome Set For Clinical Trials In Melasma, Sarah Ibrahim, Bianca Kang, Daniel Schlessinger, Sarah Chiren, Jennifer Tang, Jamie Kirkham, Jochen Schmitt, Emily Poon, Ian Maher, Joseph Sobanko, Todd Cartee, Murad Alam

Open Access Publications

INTRODUCTION: Melasma is a pigmentation disorder of the skin. Characterised by brown to gray-brown patches on the face and neck, the condition predominantly affects women and has been associated with pregnancy, hormonal variation and sun exposure. Melasma can be disfiguring and anxiety-provoking, and quality of life is often adversely impacted. Management includes sun protection, laser and energy device therapy, topical and oral skin-bleaching agents and chemical peels. While clinical trials of melasma exist, there is a lack of consistency in reported outcomes, which has been a barrier to the aggregation of data in systematic reviews and meta-analyses. This protocol describes …

Using Smartphones To Reduce Research Burden In A Neurodegenerative Population And Assessing Participant Adherence: A Randomized Clinical Trial And Two Observational Studies, Anna L Beukenhorst, Katherine M Burke, Zoe Scheier, Timothy M Miller, Sabrina Paganoni, Mackenzie Keegan, Ella Collins, Kathryn P Connaghan, Anna Tay, James Chan, James D Berry, Jukka-Pekka Onnela

Open Access Publications

BACKGROUND: Smartphone studies provide an opportunity to collect frequent data at a low burden on participants. Therefore, smartphones may enable data collection from people with progressive neurodegenerative diseases such as amyotrophic lateral sclerosis at high frequencies for a long duration. However, the progressive decline in patients' cognitive and functional abilities could also hamper the feasibility of collecting patient-reported outcomes, audio recordings, and location data in the long term.

OBJECTIVE: The aim of this study is to investigate the completeness of survey data, audio recordings, and passively collected location data from 3 smartphone-based studies of people with amyotrophic lateral sclerosis.

METHODS: …

Highly Reliable Creation Of Floxed Alleles By Electroporating Single-Cell Embryos, Monica F Sentmanat, J Michael White, Evguenia Kouranova, Xiaoxia Cui

2020-Current year OA Pubs

BACKGROUND: Floxed (flanked by loxP) alleles are a crucial portion of conditional knockout mouse models. However, an efficient and reliable strategy to flox genomic regions of any desired size is still lacking.

RESULTS: Here, we demonstrate that the method combining electroporation of fertilized eggs with gRNA/Cas9 complexes and single-stranded oligodeoxynucleotides (ssODNs), assessing phasing of loxP insertions in founders using an in vitro Cre assay and an optional, highly specific and efficient second-round targeting ensures the generation of floxed F1 animals in roughly five months for a wide range of sequence lengths (448 bp to 160 kb reported here).

CONCLUSIONS: Floxed …

Genetically Stable Crispr-Based Kill Switches For Engineered Microbes, Austin G Rottinghaus, Aura Ferreiro, Skye R S Fishbein, Gautam Dantas, Tae Seok Moon

Open Access Publications

Microbial biocontainment is an essential goal for engineering safe, next-generation living therapeutics. However, the genetic stability of biocontainment circuits, including kill switches, is a challenge that must be addressed. Kill switches are among the most difficult circuits to maintain due to the strong selection pressure they impart, leading to high potential for evolution of escape mutant populations. Here we engineer two CRISPR-based kill switches in the probiotic Escherichia coli Nissle 1917, a single-input chemical-responsive switch and a 2-input chemical- and temperature-responsive switch. We employ parallel strategies to address kill switch stability, including functional redundancy within the circuit, modulation of the …

Constitutive Activation Of Canonical Wnt Signaling Disrupts Choroid Plexus Epithelial Fate, Arpan Parichha, Varun Suresh, Mallika Chatterjee, Aditya Kshirsagar, Lihi Ben-Reuven, Tsviya Olender, M Mark Taketo, Velena Radosevic, Mihaela Bobic-Rasonja, Sara Trnski, Michael J Holtzman, Nataša Jovanov-Milosevic, Orly Reiner, Shubha Tole

Open Access Publications

The choroid plexus secretes cerebrospinal fluid and is critical for the development and function of the brain. In the telencephalon, the choroid plexus epithelium arises from the Wnt- expressing cortical hem. Canonical Wnt signaling pathway molecules such as nuclear β-CATENIN are expressed in the mouse and human embryonic choroid plexus epithelium indicating that this pathway is active. Point mutations in human β-CATENIN are known to result in the constitutive activation of canonical Wnt signaling. In a mouse model that recapitulates this perturbation, we report a loss of choroid plexus epithelial identity and an apparent transformation of this tissue to a …

Single Circulating-Tumor-Cell-Targeted Sequencing To Identify Somatic Variants In Liquid Biopsies In Non-Small-Cell Lung Cancer Patients, Mouadh Barbirou, Amanda Miller, Yariswamy Manjunath, Arturo B Ramirez, Nolan G Ericson, Kevin F Staveley-O'Carroll, Jonathan B Mitchem, Wesley C Warren, Aadel A Chaudhuri, Yi Huang, Guangfu Li, Peter J Tonellato, Jussuf T Kaifi

2020-Current year OA Pubs

Non-small-cell lung cancer (NSCLC) accounts for most cancer-related deaths worldwide. Liquid biopsy by a blood draw to detect circulating tumor cells (CTCs) is a tool for molecular profiling of cancer using single-cell and next-generation sequencing (NGS) technologies. The aim of the study was to identify somatic variants in single CTCs isolated from NSCLC patients by targeted NGS. Thirty-one subjects (20 NSCLC patients, 11 smokers without cancer) were enrolled for blood draws (7.5 mL). CTCs were identified by immunofluorescence, individually retrieved, and DNA-extracted. Targeted NGS was performed to detect somatic variants (single-nucleotide variants (SNVs) and insertions/deletions (Indels)) across 65 oncogenes and …

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.

Macrophage Global Metabolomics Identifies Cholestenone As Host/Pathogen Cometabolite Present In Human Mycobacterium Tuberculosis Infection, Pallavi Chandra, Héloise Coullon, Mansi Agarwal, Charles W Goss, Jennifer A Philips

Open Access Publications

Mycobacterium tuberculosis (M. tuberculosis) causes an enormous burden of disease worldwide. As a central aspect of its pathogenesis, M. tuberculosis grows in macrophages, and host and microbe influence each other's metabolism. To define the metabolic impact of M. tuberculosis infection, we performed global metabolic profiling of M. tuberculosis-infected macrophages. M. tuberculosis induced metabolic hallmarks of inflammatory macrophages and a prominent signature of cholesterol metabolism. We found that infected macrophages accumulate cholestenone, a mycobacterial-derived, oxidized derivative of cholesterol. We demonstrated that the accumulation of cholestenone in infected macrophages depended on the M. tuberculosis enzyme 3β-hydroxysteroid dehydrogenase (3β-Hsd) and correlated with pathogen …

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.

Ras And Beyond: The Many Faces Of The Neurofibromatosis Type 1 Protein, Corina Anastasaki, Paola Orozco, David H Gutmann

Open Access Publications

Neurofibromatosis type 1 is a rare neurogenetic syndrome, characterized by pigmentary abnormalities, learning and social deficits, and a predisposition for benign and malignant tumor formation caused by germline mutations in the NF1 gene. With the cloning of the NF1 gene and the recognition that the encoded protein, neurofibromin, largely functions as a negative regulator of RAS activity, attention has mainly focused on RAS and canonical RAS effector pathway signaling relevant to disease pathogenesis and treatment. However, as neurofibromin is a large cytoplasmic protein the RAS regulatory domain of which occupies only 10% of its entire coding sequence, both canonical and …

Hypoxia Inhibits Colonic Uptake Of The Microbiota-Generated Forms Of Vitamin B1 Via Hif-1Α-Mediated Transcriptional Regulation Of Their Transporters, Subrata Sabui, Kalidas Ramamoorthy, Jose M Romero, Rita D Simoes, James M Fleckenstein, Hamid M Said

Open Access Publications

Hypoxia exerts profound effects on cell physiology, but its effect on colonic uptake of the microbiota-generated forms of vitamin B1 (i.e., thiamin pyrophosphate [TPP] and free thiamine) has not been described. Here, we used human colonic epithelial NCM460 cells and human differentiated colonoid monolayers as in vitro and ex vivo models, respectively, and were subjected to either chamber (1% O

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 …

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, …