tbuckley/cabot-search huggingface dataset:
Association of Visitor Contact Precautions With Estimated Hospital-Onset <i>Clostridioides difficile</i> Infection Rates in Acute Care Hospitals
Authors: Elizabeth Scaria, Anna K. Barker, Oguzhan Alagoz, Nasia Safdar
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Visitor contact precautions (VCPs) are commonly used to reduce the transmission of<i>Clostridioides difficile</i>at health care institutions. Implementing VCPs requires considerable personnel and personal protective equipment resources. However, it is unknown whether VCPs are associated with reduced hospital-onset<i>C difficile</i>infection (HO-CDI) rates. <h3>Objective</h3> To estimate the association between VCPs and HO-CDI rates using simulation modeling. <h3>Design, Setting, and Participants</h3> This simulation study, conducted between July 27, 2020, and August 11, 2020, used an established agent-based simulation model of<i>C difficile</i>transmission in a 200-bed acute care adult hospital to estimate the association between VCPs and HO-CDI while varying assumptions about factors such as patient susceptibility, behavior, and<i>C difficile</i>transmission. The model simulated hospital activity for 1 year among a homogeneous, simulated adult population. <h3>Interventions</h3> No VCP use vs ideal use of VCPs under different hospital configurations. <h3>Main Outcomes and Measures</h3> The rate of HO-CDI per 10 000 patient-days according to the Centers for Disease Control and Prevention's definition of HO-CDI. <h3>Results</h3> With use of the simulation model, the baseline rate of HO-CDI was 7.94 10 000 patient-days (95% CI, 7.91-7.98 per 10 000 patient-days) with no VCP use compared with 7.97 per 10 000 patient-days (95% CI, 7.93-8.01 per 10 000 patient-days) with ideal VCP use. Visitor contact precautions were not associated with a reduction of more than 1% in HO-CDI rates in any of the tested scenarios and hospital settings. Independently increasing the hand-hygiene compliance of the average health care worker and environmental cleaning compliance by no more than 2% each was associated with greater HO-CDI reduction compared with all other scenarios, including VCPs. <h3>Conclusions and Relevance</h3> In this simulation study, the association between VCPs and HO-CDI was minimal, but improvements in health care worker hand hygiene and environmental cleaning were associated with greater reductions in estimated HO-CDI. Hospitals may achieve a higher rate of reduction for HO-CDI by focusing on making small improvements in compliance with interventions other than VCP.
Overcoming the Market Dominance of Hospitals
Authors: Robert P. Kocher, Soleil Shah, Amol S. Navathe
Journal: JAMA (2021)

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Cardiac Involvement in Fabry Disease
Authors: Maurizio Pieroni, James C. Moon, Eloisa Arbustini, Roberto Barriales-Villa, Antonia Camporeale, Andreja Cokan Vujkovac, Perry M. Elliott, Albert Hagege, Johanna Kuusisto, Aleš Linhart, Peter Nordbeck, Iacopo Olivotto, Päivi Pietilä-Effati, Mehdi Namdar
Journal: Journal of the American College of Cardiology (2021)
Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors
Authors: Jason J Luke, Fabrice Barlesi, Ki Chung, Anthony W Tolcher, Karen Kelly, Antoine Hollebecque, Christophe Le Tourneau, Vivek Subbiah, Frank Tsai, Steven Kao, Philippe A Cassier, Mustafa Khasraw, Hedy L Kindler, Hua Fang, Frances Fan, Kathryn Allaire, Maulik Patel, Shiming Ye, Debra T Chao, William R Henner, Joel S Hayflick, Michael A McDevitt, Lawrence Fong
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background CD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Systemic administration of CD40 agonists has historically been associated with considerable toxicity, providing the rationale for development of tumor-targeted immunomodulators to improve clinical safety and efficacy. This phase I study assessed the safety, tolerability, preliminary antitumor activity, and preliminary biomarkers of ABBV-428, a first-in-class, mesothelin-targeted, bispecific antibody designed for tumor microenvironment-dependent CD40 activation with limited systemic toxicity. Methods ABBV-428 was administered intravenously every 2 weeks to patients with advanced solid tumors. An accelerated titration (starting at a 0.01 mg/kg dose) and a 3+3 dose escalation scheme were used, followed by recommended phase II dose cohort expansions in ovarian cancer and mesothelioma, tumor types associated with high mesothelin expression. Results Fifty-nine patients were treated at doses between 0.01 and 3.6 mg/kg. The maximum tolerated dose was not reached, and 3.6 mg/kg was selected as the recommended phase II dose. Seven patients (12%) reported infusion-related reactions. Treatment-related grade ≥3 treatment-emergent adverse events were pericardial effusion, colitis, infusion-related reaction, and pleural effusion (n=1 each, 2%), with no cytokine release syndrome reported. The pharmacokinetic profile demonstrated roughly dose-proportional increases in exposure from 0.4 to 3.6 mg/kg. Best response was stable disease in 9/25 patients (36%) treated at the recommended phase II dose. CD40 receptor occupancy &gt;90% was observed on peripheral B-cells starting from 0.8 mg/kg; however, no consistent changes from baseline in intratumoral CD8+ T-cells, programmed death ligand-1 (PD-L1+) cells, or immune-related gene expression were detected post-ABBV-428 treatment (cycle 2, day 1). Mesothelin membrane staining showed greater correlation with progression-free survival in ovarian cancer and mesothelioma than in the broader dose escalation population. Conclusions ABBV-428 monotherapy exhibited dose-proportional pharmacokinetics and an acceptable safety profile, particularly for toxicities characteristic of CD40 agonism, illustrating that utilization of a tumor-targeted, bispecific antibody can improve the safety of CD40 agonism as a therapeutic approach. ABBV-428 monotherapy had minimal clinical activity in dose escalation and in a small expansion cohort of patients with advanced mesothelioma or ovarian cancer. Trial registration number NCT02955251 .
Upgrading the evidence for the use of ambroxol in Gaucher disease and <scp>GBA</scp> related Parkinson: Investigator initiated registry based on real life data
Authors: Majdolen Istaiti, Shoshana Revel‐Vilk, Michal Becker‐Cohen, Tama Dinur, Uma Ramaswami, Daniela Castillo‐Garcia, Magdalena Ceron‐Rodriguez, Alicia Chan, Predrag Rodic, Radka Stefanova Tincheva, Walla Al‐Hertani, Beom Hee Lee, Chia‐Feng Yang, Beata Kiec‐Wilk, Agata Fiumara, Barbara Rubio, Ari Zimran
Journal: American Journal of Hematology (2021)

Ambroxol hydrochloride is an oral mucolytic drug available over-the-counter for many years as cough medicine. In 2009 it was identified as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several-fold higher dose. Unfortunately, there have been no pharma-driven clinical trials to establish its use. Thus, real-world observational data are needed on the safety and efficacy of ambroxol for patients with Gaucher disease (GD) and GBA-Parkinson disease (GBA-PD). Clinicians treating patients with ambroxol for GD and GBA-PD were approached to collaborate in an investigator-initiated registry. Anonymized data were collected, including demographics, GD type, GD-specific therapy (when applicable), adverse events (AEs), and, when available, efficacy data. We report the data of the first 41 patients (25 females) at a median (range) age 17 (1.5-74) from 13 centers; 11 with GD type 1(four diagnosed with PD), 27 with neuronopathic GD (nGD), and three GBA mutation carriers with PD. The median (range) treatment period and maximum dose of ambroxol were 19 (1-76) months and 435 (75-1485) mg/day, respectively. One patient with type 2 GD died of her disease. No other severe AEs were reported. Twelve patients experienced AE, including minor bowel discomfort, cough, allergic reaction, mild proteinuria, dizziness and disease progression. Clinical benefits were reported in 25 patients, including stable or improved neurological status, increased physical activity, and reduced fatigue. Until the approval of specific therapies for nGD and disease-modification for GBA-PD, these preliminary data may be encouraging to physicians and patients who consider an off-label use of ambroxol.
Patient perspectives and involvement in precision medicine research
Authors: Katherine R. Tuttle, Jack Bebiak, Keith Brown, Catherine Campbell, Ashveena Dighe, Lynda Hyashi, Nichole Jefferson, Glenda V. Roberts, Christy Stutzke, Richard Knight, Richard Knight, Stewart Lecker, Isaac Stillman, Sushrut Waikar, Gearoid Mcmahon, Astrid Weins, Samuel Short, Nir Hacohen, Paul Hoover, Mark Aulisio, Leslie Cooperman, Leal Herlitz, John O’Toole, Emilio Poggio, John Sedor, Stacey Jolly, Paul Appelbaum, Olivia Balderes, Jonathan Barasch, Andrew Bomback, Pietro A. Canetta, Vivette D. d’Agati, Krzysztof Kiryluk, Satoru Kudose, Karla Mehl, Jai Radhakrishnan, Chenhua Weng, Laura Barisoni, Theodore Alexandrov, Tarek Ashkar, Daria Barwinska, Pierre Dagher, Kenneth Dunn, Michael Eadon, Michael Ferkowicz, Katherine Kelly, Timothy Sutton, Seth Winfree, Steven Menez, Chirag Parikh, Avi Rosenberg, Pam Villalobos, Rubab Malik, Derek Fine, Mohammed Atta, Jose Manuel Monroy Trujillo, Alison Slack, Sylvia Rosas, Mark Williams, Evren Azeloglu, Cijang (John) He, Ravi Iyengar, Jens Hansen, Samir Parikh, Brad Rovin, Chris Anderton, Ljiljana Pasa-Tolic, Dusan Velickovic, Jessica Lukowski, George (Holt) Oliver, Joseph Ardayfio, Jack Bebiak, Keith Brown, Taneisha Campbell, Catherine Campbell, Lynda Hayashi, Nichole Jefferson, Robert Koewler, Glenda Roberts, John Saul, Anna Shpigel, Edith Christine Stutzke, Lorenda Wright, Leslie Miegs, Roy Pinkeney, Rachel Sealfon, Olga Troyanskaya, Katherine Tuttle, Dejan Dobi, Yury Goltsev, Blue Lake, Kun Zhang, Maria Joanes, Zoltan Laszik, Andrew Schroeder, Minnie Sarwal, Tara Sigdel, Ulysses Balis, Victoria Blanc, Oliver He, Jeffrey Hodgin, Matthias Kretzler, Laura Mariani, Rajasree Menon, Edgar Otto, Jennifer Schaub, Becky Steck, Chrysta Lienczewski, Sean Eddy, Michele Elder, Daniel Hall, John Kellum, Mary Kruth, Raghav Murugan, Paul Palevsky, Parmjeet Randhawa, Matthew Rosengart, Sunny Sims-Lucas, Mary Stefanick, Stacy Stull, Mitchell Tublin, Charles Alpers, Ian de Boer, Ashveena Dighe, Jonathan Himmelfarb, Robyn Mcclelland, Sean Mooney, Stuart Shankland, Kayleen Williams, Kristina Blank, Jonas Carson, Frederick Dowd, Zach Drager, Christopher Park, Kumar Sharma, Guanshi Zhang, Shweta Bansal, Manjeri Venkatachalam, Asra Kermani, Simon Lee, Christopher Lu, Tyler Miller, Orson Moe, Harold Park, Kamalanathan Sambandam, Francisco Sanchez, Jose Torrealba, Toto Robert, Miguel Vazquez, Nancy Wang, Joe Gaut, Sanjay Jain, Anitha Vijayan, Randy Luciano, Dennis Moledina, Ugwuowo Ugochukwu, Francis Perry Wilson, Sandy Alfano
Journal: Kidney International (2021)
Platelet-derived growth factor C signaling is a potential therapeutic target for radiation proctopathy
Authors: Weisi Lu, Yunling Xie, Binjie Huang, Tenghui Ma, Huaiming Wang, Boxiong Deng, Shaomin Zou, Wencong Wang, Qin Tang, Ziqing Yang, Xuri Li, Lei Wang, Lekun Fang
Journal: Science Translational Medicine (2021)

Platelet-derived growth factor C signaling promotes radiation proctopathy development and can be inhibited in a mouse model.
Therapeutically Increasing MHC-I Expression Potentiates Immune Checkpoint Blockade
Authors: Shengqing Stan Gu, Wubing Zhang, Xiaoqing Wang, Peng Jiang, Nicole Traugh, Ziyi Li, Clifford Meyer, Blair Stewig, Yingtian Xie, Xia Bu, Michael P. Manos, Alba Font-Tello, Evisa Gjini, Ana Lako, Klothilda Lim, Jake Conway, Alok K. Tewari, Zexian Zeng, Avinash Das Sahu, Collin Tokheim, Jason L. Weirather, Jingxin Fu, Yi Zhang, Benjamin Kroger, Jin Hua Liang, Paloma Cejas, Gordon J. Freeman, Scott Rodig, Henry W. Long, Benjamin E. Gewurz, F. Stephen Hodi, Myles Brown, X. Shirley Liu
Journal: Cancer Discovery (2021)

Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR screens with a data-mining approach to identify drugs that can upregulate MHC-I without inducing PD-L1. CRISPR screening identified TRAF3, a suppressor of the NFκB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout gene expression signature is associated with better survival in ICB-naïve patients with cancer and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified Second Mitochondria-derived Activator of Caspase (SMAC) mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T cell-dependent killing, and adds to ICB efficacy. Our findings provide preclinical rationale for treating tumors expressing low MHC-I expression with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy. SIGNIFICANCE: MHC-I loss or downregulation in cancer cells is a major mechanism of resistance to T cell-based immunotherapies. Our study reveals that birinapant may be used for patients with low baseline MHC-I to enhance ICB response. This represents promising immunotherapy opportunities given the biosafety profile of birinapant from multiple clinical trials.This article is highlighted in the In This Issue feature, p. 1307.
Abstract 23931: Selective Inhibition Of Hdac3 Prevents Diabetic Cardiomyopathy In Ove26 Mice Via Mir-200a-mediated Nrf2 Activation
Authors: zheng xu, yang zheng, zhiguo zhang, JIAN SUN, Lu Cai
Journal: Circulation (2017)

Although histone deacetylases (HDACs) was are the promising target for the initiation and development of diabetic cardiomyopathy (DCM), which isoform of them plays the key role remains unclear. The present study was designed to determine whether DCM could be prevented by selective inhibition of HDAC3 and the underlying mechanism. Male type 1 diabetic OVE26 and age-matched wild-type mice were given the selective HDAC3 inhibitor (HDAC3i) RGFP966 or vehicle for 3 months before the cardiac function was examined with Echo. Results indicated that HDAC3i treatment improved cardiac function in the diabetes group. HDAC3 activity was significantly increased in the heart of diabetic mice, which was blocked by the treatment of HDAC3i. Oxidative stress as a major cause of DCM is also inhibited by HDAC3i. Mechanistically cardiac miR-200a, which targets and destabilizes kelch-like ECH-associated protein 1 (KEAP1) mRNA, was significantly up-regulated and KEAP1 expression was markedly inhibited by HDAC3i in the diabetic mouse. Immunoprecipitation shows that the binding of KEAP1 in the diabetic heart was decreased by the treatment of HDAC3i when we pull down nuclear factor-E2-related factor 2 (NRF2). Meanwhile, the nuclear localization of NRF2 and its downstream anti-oxidative stress genes, NADPH quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), were markedly up-regulated in the HDAC3i treated diabetic mouse group. These results suggest that HDAC3i prevents DCM likely via miR-200a-mediated degradation of KEAP1 and consequently activation of the Nrf2-regulated antioxidant pathway.
Abstract 16164: Left Ventricular Ejection Fraction Matters in Transthyretin Amyloidosis Cardiomyopathy
Authors: Lana Rashdan, Pranav Chandrashekar, Zack Dale, Miriam Elman, Babak Nazer, Stephen B Heitner, Ahmad Masri
Journal: Circulation (2020)

Introduction: Patients with transthyretin cardiac amyloidosis (ATTR-CM) are risk stratified using the Mayo Clinic Prognostic Model. Prior studies showed global longitudinal strain’s (GLS) role in predicting mortality. However, frequently, arrythmias and poor image quality limit GLS quantification. Given GLS and LVEF correlation, we sought to assess the prognostic value of LVEF in addition to Mayo staging in patients with ATTR-CM. Methods: A single center observational cohort study of patients who had been seen at our Amyloidosis Center with ATTR-CM diagnosed between 2005-2019. LVEF was assessed using Simpson’s bi-plane method. Mayo Stages were classified as follows (NTproBNP and Troponin I thresholds 3000 pg/ml and 0.1 ng/ml, respectively): Stage I (both values &lt; threshold), Stage II (either ≥ threshold) and Stage III (both ≥ threshold). The primary outcome was all-cause mortality. Results: Ninety-one patients with ATTR-CM (mean age 73±10 years, 92% male) had a median (IQR) follow-up of 28 (15, 45) months, and 25 (28%) patients died. Mayo Stage distribution in patients with LVEF &lt;50% vs LVEF ≥50% was 33% vs 66% (Stage I), 40% vs 24% (Stage II), and 27% vs 10% (Stage III) (Fisher’s exact, p=0.03). Thirty-seven (41%) had LVEF &lt;50% of whom 35% died as compared to 53 (59%) with LVEF ≥50% of whom 23% died, (log-rank, p=0.02; Figure). Results from univariable and multivariable Cox Proportional Hazard models are shown in Table. Conclusions: LVEF provides incremental prognostic information to the Mayo classification.
'Off-the-shelf’ allogeneic antigen-specific adoptive T-cell therapy for the treatment of multiple EBV-associated malignancies
Authors: Debottam Sinha, Sriganesh Srihari, Kirrliee Beckett, Laetitia Le Texier, Matthew Solomon, Archana Panikkar, George R Ambalathingal, Lea Lekieffre, Pauline Crooks, Sweera Rehan, Michelle A. Neller, Corey Smith, Rajiv Khanna
Journal: Journal for ImmunoTherapy of Cancer (2021)

Epstein-Barr virus (EBV), an oncogenic human gammaherpesvirus, is associated with a wide range of human malignancies of epithelial and B-cell origin. Recent studies have demonstrated promising safety and clinical efficacy of allogeneic 'off-the-shelf' virus-specific T-cell therapies for post-transplant viral complications.Taking a clue from these studies, we developed a highly efficient EBV-specific T-cell expansion process using a replication-deficient AdE1-LMPpoly vector that specifically targets EBV-encoded nuclear antigen 1 (EBNA1) and latent membrane proteins 1 and 2 (LMP1 and LMP2), expressed in latency II malignancies.These allogeneic EBV-specific T cells efficiently recognized human leukocyte antigen (HLA)-matched EBNA1-expressing and/or LMP1 and LMP2-expressing malignant cells and demonstrated therapeutic potential in a number of in vivo models, including EBV lymphomas that emerged spontaneously in humanized mice following EBV infection. Interestingly, we were able to override resistance to T-cell therapy in vivo using a 'restriction-switching' approach, through sequential infusion of two different allogeneic T-cell therapies restricted through different HLA alleles. Furthermore, we have shown that inhibition of the programmed cell death protein-1/programmed death-ligand 1 axis in combination with EBV-specific T-cell therapy significantly improved overall survival of tumor-bearing mice when compared with monotherapy.These findings suggest that restriction switching by sequential infusion of allogeneic T-cell therapies that target EBV through distinct HLA alleles may improve clinical response.
Abstract PS3-27: 18F-FDG-PET/CT and MRI in the assessment of neoadjuvant chemotherapy treatment response in breast cancer. Correlation with pathological response
Authors: Marco Guarin, M. Eugenia Azar, Carolina Tinetti, M. Dolores Mansilla F., Mauro Namias, Pilar Carballo, Lucia Santamarina, Jorgelina Cavallero, Romina Moreau, Christian Gonzalez, Valeria Caceres, Eduardo Gonzalez, Gabriel Bruno
Journal: Cancer Research (2021)

Abstract Introduction: Residual cancer burden (RCB) after neoadjuvant chemotherapy (NAC) can accurately predict disease recurrence and survival in breast cancer. In this context, end of treatment (EOT) image-guided response assessment could be useful to adapt treatment for individual patients. Our main objective was to assess the effectiveness of 18F-FDG PET/CT and MRI in determining NAC response. Methods: Patients with surgically resectable breast cancer (stages II-III) were prospectively included and evaluated with 18F-FDG-PET/CT and MRI before and after standard-of-care neoadjuvant chemotherapy (NAC). Ultrasound guided breast biopsy was performed before NAC and pathologic examination with residual cancer burden (RCB) scoring was performed after surgery. Standard uptake values (SUVmax and SUVmean) from baseline PET scans were measured. EOT images results were compared with RCB scores to assess the sensitivity and specificity of (EOT) 18F-FDG-PET/CT and MRI images. A multinomial logistic regression was performed to assess predictors of pathological response. A p-value of 0.05 was considered significant. Results: 30 patients were included, with 25% showing complete pathological response. EOT 18F-FDG-PET/CT images had a sensitivity of 55% and specificity of 100% to predict RCB &amp;gt; 0, while EOT MRI had a sensitivity of 65% and specificity of 66,6%. Luminal tumors showed significant lower baseline SUVmean and SUVmax values than triple-negative tumors. Ki67 expression didn´t correlate with treatment outcome. High estrogen receptor expression level was significantly associated with non-complete pathological response and higher false negative rates in both EOT 18F-FDG-PET and MRI images (7/8 in PET and 6/7 in MRI). Conclusions: 18F-FDG-PET / CT could be a useful diagnostic tool to assess neoadjuvant chemotherapy treatment response in breast cancer, showing greater specificity than MRI to predict pathological response. A high expression of estrogen receptors could lead to a high rate of false negative findings, both in PET and MRI. A greater number of cases is required to validate these findings. Citation Format: Marco Guarin, M. Eugenia Azar, Carolina Tinetti, M. Dolores Mansilla F., Mauro Namias, Pilar Carballo, Lucia Santamarina, Jorgelina Cavallero, Romina Moreau, Christian Gonzalez, Valeria Caceres, Eduardo Gonzalez, Gabriel Bruno. 18F-FDG-PET/CT and MRI in the assessment of neoadjuvant chemotherapy treatment response in breast cancer. Correlation with pathological response [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS3-27.
ACC Health Policy Statement on Cardiovascular Disease Considerations for COVID-19 Vaccine Prioritization
Authors: Elissa Driggin, Thomas M. Maddox, Keith C. Ferdinand, James N. Kirkpatrick, Bonnie Ky, Alanna A. Morris, J. Brendan Mullen, Sahil A. Parikh, Daniel M. Philbin, Muthiah Vaduganathan
Journal: Journal of the American College of Cardiology (2021)