tbuckley/cabot-search huggingface dataset:
Comparative study of lung ultrasound and chest computed tomography scan in the assessment of severity of confirmed COVID-19 pneumonia
Authors: Laurent Zieleskiewicz, Thibaut Markarian, Alexandre Lopez, Chloé Taguet, Neyla Mohammedi, Mohamed Boucekine, Karine Baumstarck, Guillaume Besch, Gautier Mathon, Gary Duclos, Lionel Bouvet, Pierre Michelet, Bernard Allaouchiche, Kathia Chaumoître, Mathieu Di Bisceglie, Marc Leone
Journal: Intensive Care Medicine (2020)
Molecular Engineering of Ultrasmall Silica Nanoparticle–Drug Conjugates as Lung Cancer Therapeutics
Authors: Brian Madajewski, Feng Chen, Barney Yoo, Melik Z. Turker, Kai Ma, Li Zhang, Pei-Ming Chen, Rupa Juthani, Virginia Aragon-Sanabria, Mithat Gonen, Charles M. Rudin, Ulrich Wiesner, Michelle S. Bradbury, Cameron Brennan
Journal: Clinical Cancer Research (2020)

Small-molecule inhibitors have had a major impact on cancer care. While treatments have demonstrated clinically promising results, they suffer from dose-limiting toxicities and the emergence of refractory disease. Considerable efforts made to address these issues have more recently focused on strategies implementing particle-based probes that improve drug delivery and accumulation at target sites, while reducing off-target effects.Ultrasmall (<8 nm) core-shell silica nanoparticles, C' dots, were molecularly engineered to function as multivalent drug delivery vehicles for significantly improving key in vivo biological and therapeutic properties of a prototype epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib. Novel surface chemical components were used to conjugate gefitinib-dipeptide drug-linkers and deferoxamine (DFO) chelators for therapeutic delivery and PET imaging labels, respectively.Gefitinib-bound C' dots (DFO-Gef-C' dots), synthesized using the gefitinib analogue, APdMG, at a range of drug-to-particle ratios (DPR; DPR = 11-56), demonstrated high stability for DPR values≤ 40, bulk renal clearance, and enhanced in vitro cytotoxicity relative to gefitinib (LD50 = 6.21 nmol/L vs. 3 μmol/L, respectively). In human non-small cell lung cancer mice, efficacious Gef-C' dot doses were at least 200-fold lower than that needed for gefitinib (360 nmoles vs. 78 μmoles, respectively), noting fairly equivalent tumor growth inhibition and prolonged survival. Gef-C' dot-treated tumors also exhibited low phosphorylated EFGR levels, with no appreciable wild-type EGFR target inhibition, unlike free drug.Results underscore the clinical potential of DFO-Gef-C' dots to effectively manage disease and minimize off-target effects at a fraction of the native drug dose.
COVID-19 and School Closures
Authors: Julie M. Donohue, Elizabeth Miller
Journal: JAMA (2020)

Katherine A. Auger, MD, MSc; Samir S. Shah, MD, MSCE; Troy Richardson, PhD; David Hartley, PhD, MPH; Matthew Hall, PhD; Amanda Warniment, MD; Kristen Timmons, MS; Dianna Bosse, BA; Sarah A. Ferris, BA; Patrick W. Brady, MD, MSc; Amanda C. Schondelmeyer, MD, MSc; Joanna E. Thomson, MD, MPH
Respiratory Tract Dysbiosis Is Associated with Worse Outcomes in Mechanically Ventilated Patients
Authors: Georgios D. Kitsios, Haopu Yang, Libing Yang, Shulin Qin, Adam Fitch, Xiao-Hong Wang, Katherine Fair, John Evankovich, William Bain, Faraaz Shah, Kelvin Li, Barbara Methé, Panayiotis V. Benos, Alison Morris, Bryan J. McVerry
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Host inflammatory responses have been strongly associated with adverse outcomes in critically ill patients, but the biologic underpinnings of such heterogeneous responses have not been defined.Objectives: We examined whether respiratory tract microbiome profiles are associated with host inflammation and clinical outcomes of acute respiratory failure.Methods: We collected oral swabs, endotracheal aspirates (ETAs), and plasma samples from mechanically ventilated patients. We performed 16S ribosomal RNA gene sequencing to characterize upper and lower respiratory tract microbiota and classified patients into host-response subphenotypes on the basis of clinical variables and plasma biomarkers of innate immunity and inflammation. We derived diversity metrics and composition clusters with Dirichlet multinomial models and examined our data for associations with subphenotypes and clinical outcomes.Measurements and Main Results: Oral and ETA microbial communities from 301 mechanically ventilated subjects had substantial heterogeneity in α and β diversity. Dirichlet multinomial models revealed a cluster with low α diversity and enrichment for pathogens (e.g., high Staphylococcus or Pseudomonadaceae relative abundance) in 35% of ETA samples, associated with a hyperinflammatory subphenotype, worse 30-day survival, and longer time to liberation from mechanical ventilation (adjusted P < 0.05), compared with patients with higher α diversity and relative abundance of typical oral microbiota. Patients with evidence of dysbiosis (low α diversity and low relative abundance of "protective" oral-origin commensal bacteria) in both oral and ETA samples (17%, combined dysbiosis) had significantly worse 30-day survival and longer time to liberation from mechanical ventilation than patients without dysbiosis (55%; adjusted P < 0.05).Conclusions: Respiratory tract dysbiosis may represent an important, modifiable contributor to patient-level heterogeneity in systemic inflammatory responses and clinical outcomes.
Association of Mortality with Neuromuscular Blockade Differs according to Baseline Diaphragm Thickness
Authors: Jose Dianti, Federico Angriman, Bruno L. Ferreyro, Michael C. Sklar, Laurent Brochard, Niall D. Ferguson, Ewan C. Goligher
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

"Association of Mortality with Neuromuscular Blockade Differs according to Baseline Diaphragm Thickness." American Journal of Respiratory and Critical Care Medicine, 202(12), pp. 1717–1720
New insights into the evasion of host innate immunity by Mycobacterium tuberculosis
Authors: Qiyao Chai, Lin Wang, Cui Hua Liu, Baoxue Ge
Journal: Cellular and Molecular Immunology (2020)

Abstract Mycobacterium tuberculosis (Mtb) is an extremely successful intracellular pathogen that causes tuberculosis (TB), which remains the leading infectious cause of human death. The early interactions between Mtb and the host innate immune system largely determine the establishment of TB infection and disease development. Upon infection, host cells detect Mtb through a set of innate immune receptors and launch a range of cellular innate immune events. However, these innate defense mechanisms are extensively modulated by Mtb to avoid host immune clearance. In this review, we describe the emerging role of cytosolic nucleic acid-sensing pathways at the host – Mtb interface and summarize recently revealed mechanisms by which Mtb circumvents host cellular innate immune strategies such as membrane trafficking and integrity, cell death and autophagy. In addition, we discuss the newly elucidated strategies by which Mtb manipulates the host molecular regulatory machinery of innate immunity, including the intranuclear regulatory machinery, the ubiquitin system, and cellular intrinsic immune components. A better understanding of innate immune evasion mechanisms adopted by Mtb will provide new insights into TB pathogenesis and contribute to the development of more effective TB vaccines and therapies.
Ethics and injury risk in World Rugby and England Rugby tackle-height trial
Authors: Adam John White, Joe Piggin, John Batten, Gary Turner, Alan Pearce, Rachael Bullingham, Eric Anderson
Journal: British Journal of Sports Medicine (2020)

Concerns about concussion in contact sport have permeated debate within sports medicine.1–4 Considerable scientific attention has been focussed on the short-term and long-term outcomes of concussions, as well as the strategies to reduce the risk of traumatic brain injury. The practicalities and impact of altering rules (laws) in sport—including the evaluation of outcomes—are often considered.

In the elite setting, World Rugby recently opted to lower the permitted tackle height in Championship Rugby.5 6 We believe this research intervention7 raises some ethical questions around informed consent and the right to withdraw, since the players were contractually compelled to participate. Unfortunately, rather than reducing injury risk, this research intervention also resulted in an increased risk of concussion.

Thus, we alert the reader to issues relating to the ethics and increased risk of injury following this research intervention and make some recommendations for the future.

We are concerned by the ethical approval and participant selection processes employed in this research intervention. Indeed, this trial was conducted by World Rugby following research published by World Rugby employees.5 …
Successful and Safe Treatment With 177Lu-DOTATATE (Lutathera) of Progressive Metastatic Pancreatic Neuroendocrine Tumor Under Hemodialysis
Authors: Lawrence O. Dierickx, Brillouet Séverine, Mokrane Fatima, Bensafi Amel, Guimbaud Rosine
Journal: Clinical Nuclear Medicine (2020)

Abstract 177 Lu-DOTATATE is an effective treatment for inoperable metastatic well-differentiated pancreatic neuroendocrine tumors. There are no guidelines for patients with terminal renal failure. We present the case of a 74-year-old woman who received different lines of treatment: analogs of somatostatin, chemotherapy, a first series of peptide receptor radionuclide therapy (PRRT), and finally chemoembolization. Because of persistent hepatic progression, a safe and successful administration of 4 cycles of a second series of PRRT under hemodialysis was administered. Patient was in scintigraphic complete remission at 12 months with normal hematological parameters at 12 and 30 months after PRRT.
Correction: Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS
Authors: G. J. Ossenkoppele, D. A. Breems, G. Stuessi, Y. van Norden, M. Bargetzi, B. J. Biemond, P. A von dem Borne, Y. Chalandon, J. Cloos, D. Deeren, M. Fehr, B. Gjertsen, C. Graux, G. Huls, J. J. J. W. Janssen, A. Jaspers, M. Jongen-Lavrencic, E. de Jongh, S. K. Klein, M. van der Klift, M. van Marwijk Kooy, J. Maertens, L. Michaux, M. W. M. van der Poel, A. van Rhenen, L. Tick, P. Valk, M. C. Vekemans, W. J. F. M. van der Velden, O. de Weerdt, T. Pabst, M. Manz, B. Löwenberg, D. A. Breems, None Havelange, M-C Vekemans, I. Moors, F. van Obberg, J. A. Maertens, B. Hodossy, S. Vansteenweghen, L. Lammertijn, D. Deeren, C. Graux, A. Sonet, A. Triffet, B. T. Gjertsen, M. Bargetzi, J. Passweg, D. Heim, San Giovanni, Georg Stuessi, T. Pabst, D. Betticher, Y. Chalandon, O. Spertini, M. Gregor, U. Hess, M. Fehr, M. G. Manz, S. K. Klein, B. J. Biemond, G J Ossenkoppele, A. van de Loosdrecht, J J W M Janssen, J. W. J. van Esser, M. Van der Klift, R. E. Brouwer, D. Van Lammeren-Venema, M. D. Levin, L. W. Tick, M. C. J. C. Legdeur, G. Huls, E. Vellenga, M. Hoogendoorn, J. H. Veelken, P. A. von dem Borne, H. C. Schouten, O. de Weerdt, W. J. F. M. van der Velden, J. Cornelissen, M. Jongen-Lavrencic, B. Wouters, H. G. M. Raaijmakers, B. Löwenberg, J. Kuball, A. Van Rhenen, M. Van Marwijk Kooy
Journal: Leukemia (2020)
DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance
Authors: Flora D’Anna, Laurien Van Dyck, Jieyi Xiong, Hui Zhao, Rebecca V. Berrens, Junbin Qian, Pawel Bieniasz-Krzywiec, Vikas Chandra, Luc Schoonjans, Jason Matthews, Julie De Smedt, Liesbeth Minnoye, Ricardo Amorim, Sepideh Khorasanizadeh, Qian Yu, Liyun Zhao, Marie De Borre, Savvas N. Savvides, M. Celeste Simon, Peter Carmeliet, Wolf Reik, Fraydoon Rastinejad, Massimiliano Mazzone, Bernard Thienpont, Diether Lambrechts
Journal: Genome biology (2020)

Hypoxia is pervasive in cancer and other diseases. Cells sense and adapt to hypoxia by activating hypoxia-inducible transcription factors (HIFs), but it is still an outstanding question why cell types differ in their transcriptional response to hypoxia.
Legionella pneumonia: increased risk after COVID-19 lockdown? Italy, May to June 2020
Authors: Claudia Palazzolo, Gaetano Maffongelli, Alessandra D’Abramo, Luciana Lepore, Andrea Mariano, Antonella Vulcano, Tommaso Ascoli Bartoli, Nazario Bevilacqua, Maria Letizia Giancola, Enrico Di Rosa, Emanuele Nicastri
Journal: Eurosurveillance (2020)

We report a case of Legionella pneumonia in a dishwasher of a restaurant in Rome, Italy, just after the end of the lockdown that was in place to control the SARS-CoV-2 epidemic. The case highlights the importance of strict monitoring of water and air systems immediately before reopening business or public sector buildings, and the need to consider Legionella infections among the differential diagnosis of respiratory infections after lockdown due to the ongoing COVID-19 pandemic.
Time for a change: anticipating the diagnosis and treatment of COPD
Authors: Alvar Agusti, Bernardino Alcazar, Borja Cosio, Jose Maria Echave, Rosa Faner, Jose Luis Izquierdo, Jose Maria Marin, Juan Jose Soler-Cataluña, Bartolome Celli
Journal: European Respiratory Journal (2020)

COPD is a major public health problem because of its high prevalence (about 10% of the adult population), rising incidence (likely related to the ageing of the population), associated morbi-mortality (it is currently the third leading cause of death globally), and personal, social and economic costs [1]. The traditional way to address this problem has been to reduce smoking exposure, the main environmental risk factor for COPD [1]. Although this was, is and will be, a key public-health strategy, we argue here that it is not enough. If we want to eradicate COPD [2], it is time for a change that anticipates the diagnosis and treatment of the disease. COPD is often not diagnosed, or is diagnosed too late. It is time for a change that anticipates both diagnosis and treatment. <https://bit.ly/2BrDSv1> ANTES is supported by GSK and run by an independent academic scientific committee, which includes the authors of this article and, in addition, Julio Ancochea, Ciro Casanova, Alberto Fernandez Villar, Juan Luis Garcia Rivero, Cruz Gonzalez, Jose Luis Lopez Campos, Francisco Javier Martin-Sanchez, Jesus Molina, German Peces-Barba, Miguel Roman and Felipe Villar.
Stem Cell Transplantation and Vinblastine Monotherapy for Relapsed Pediatric Anaplastic Large Cell Lymphoma: Results of the International, Prospective ALCL-Relapse Trial
Authors: Fabian Knörr, Laurence Brugières, Marta Pillon, Martin Zimmermann, Stephanie Ruf, Andishe Attarbaschi, Karin Mellgren, G. Amos A. Burke, Anne Uyttebroeck, Grażyna Wróbel, Auke Beishuizen, Nathalie Aladjidi, Alfred Reiter, Wilhelm Woessmann
Journal: Journal of Clinical Oncology (2020)

To analyze the efficacy of a risk-stratified treatment of children with relapsed anaplastic large cell lymphoma (ALCL). The ALCL-Relapse trial (ClinicalTrials.gov identifier: NCT00317408) stratified patients according to the time of relapse and CD3 expression to prospectively test reinduction approaches combined with consolidation by allogeneic or autologous hematopoietic stem cell transplantation (SCT) and vinblastine monotherapy.Patients with progression during frontline therapy (very high risk) or a CD3-positive relapse (high risk) were scheduled for allogeneic SCT after reinduction chemotherapy. Patients with a CD3-negative relapse within 1 year after initial diagnosis or prior exposure to vinblastine (intermediate risk) received autologous SCT after carmustine-etoposide-cytarabine-melphalan. This arm was terminated prematurely, and subsequent patients received vinblastine monotherapy instead. Patients with a CD3-negative relapse > 1 year after initial diagnosis (low risk) received vinblastine monotherapy.One hundred sixteen patients met the inclusion criteria; 105 evaluable patients with CNS-negative disease had a 5-year event-free survival (EFS) of 53% ± 5% and a 5-year overall survival (OS) of 78% ± 4%. Before termination of autologous SCT, EFS rates of patients in the very-high- (n = 17), high- (n = 26), intermediate- (n = 32), and low- (n = 21) risk groups were 41% ± 12%, 62% ± 10%, 44% ± 9%, and 81% ± 9%; the respective OS rates were 59% ± 12%, 73% ± 9%, 78% ± 7%, and 90% ± 6%. Analyzing only the patients in the intermediate-risk group consolidated per protocol by autologous SCT, EFS and OS of 23 patients were 30% ± 10% and 78% ± 9%, respectively. All 5 patients with intermediate risk receiving vinblastine monotherapy after the amendment experienced relapse again.Shorter time to relapse was the strongest predictor of subsequent relapse. Allogeneic SCT offers a chance for cure in patients with high-risk ALCL relapse. For early relapsed ALCL autologous SCT was not effective. Vinblastine monotherapy achieved cure in patients with late relapse; however, it was not effective for early relapses.
Conversion of T Follicular Helper Cells to T Follicular Regulatory Cells by Interleukin‐2 Through Transcriptional Regulation in Systemic Lupus Erythematosus
Authors: He Hao, Shingo Nakayamada, Kaoru Yamagata, Naoaki Ohkubo, Shigeru Iwata, Yoshino Inoue, Mingzeng Zhang, Tong Zhang, Yurie Kanda Satoh, Yu Shan, Takashi Otsuka, Yoshiya Tanaka
Journal: Arthritis & Rheumatology (2020)

This study was undertaken to identify characteristics of follicular regulatory T (Tfr) cells and elucidate the mechanisms by which follicular helper T (Tfh) cells convert to Tfr cells. We probed the phenotype of T helper cells in patients with systemic lupus erythematosus (SLE) and underlying transcriptional regulation using cytokine-induced STAT family factors.Peripheral blood mononuclear cells from 41 patients with SLE and 26 healthy donors were used to sort out the memory Tfh cell subset, and Tfh cells were cultured under various conditions. The phenotype of T helper cells and underlying mechanisms of transcriptional regulation were probed using flow cytometry and quantitative polymerase chain reaction analyses. These analyses evaluated the expression of characteristic markers and phosphorylation of STATs. Chromatin immunoprecipitation was used to evaluate histone modifications.In patients with SLE, the proportion of CD4+CXCR5+FoxP3-PD-1high Tfh cells was increased (P < 0.01), whereas the proportion of CD4+CXCR5+CD45RA-FoxP3high activated Tfr cells was decreased (P < 0.05). Serum interleukin-2 (IL-2) levels were also reduced in patients with SLE. IL-2 induced conversion of memory Tfh cells to functional Tfr cells, which was characterized by CXCR5+Bcl-6+FoxP3high pSTAT3+pSTAT5+ cells. The loci of FOXP3 and BCL6 at STAT binding sites were marked by bivalent histone modifications. Following IL-2 stimulation, STAT3 and STAT5 selectively bound to FOXP3 and BCL6 gene loci accompanied by suppression of H3K27me3. Finally, IL-2 stimulation suppressed the generation of CD38+CD27high plasmablasts in Tfh and B cell coculture assays ex vivo.Impaired function of Tfr cells might be attributed to defective IL-2 production. Exogenous IL-2 restores the function of Tfr cells through the conversion of Tfh cells to Tfr cells in patients with SLE. Thus, restoring balance between Tfh and Tfr cells may provide new therapeutic approaches in SLE.
Radioligand Therapy With 177Lu–Prostate-Specific Membrane Antigen in a Patient With Non–Prostate-Specific Antigen–Secreting Metastatic Prostate Cancer
Authors: Elahe Pirayesh
Journal: Clinical Nuclear Medicine (2020)

Abstract Progression of prostate cancer and prostate-specific antigen (PSA) elevation are closely associated. In fewer than 1% of all cases, disease progression may occur despite low or undetectable PSA levels. In these conditions, androgen deprivation therapy is relatively ineffective, and the prostate cancer progresses very quickly. We present a 65-year-old man with non–PSA-secreting prostate cancer and widespread metastases with rather fair response to 177 Lu-prostate-specific membrane antigen radioligand therapy.
Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants
Authors: M. Pamela Griffin, Yuan Yuan, Therese Takas, Joseph B. Domachowske, Shabir A. Madhi, Paolo Manzoni, Eric A.F. Simões, Mark T. Esser, Anis A. Khan, Filip Dubovsky, Tonya Villafana, John P. DeVincenzo
Journal: New England Journal of Medicine (2020)

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants, and a need exists for prevention of RSV in healthy infants. Nirsevimab is a monoclonal antibody with an extended half-life that is being developed to protect infants for an entire RSV season with a single intramuscular dose.
Assembly of alternative prothrombinase by extracellular histones initiates and disseminates intravascular coagulation
Authors: Simon T. Abrams, Dunhao Su, Yasmina Sahraoui, Ziqi Lin, Zhenxing Cheng, Kate Nesbitt, Yasir Alhamdi, Micaela Harrasser, Min Du, Jonathan H. Foley, David Lillicrap, Guozheng Wang, Cheng-Hock Toh
Journal: Blood (2020)
Mechanism of lung development in the aetiology of adult congenital pulmonary airway malformations
Authors: Bethany Taylor, Alexandra Rice, Andrew G Nicholson, Matthew Hind, Charlotte H Dean
Journal: Thorax (2020)

Congenital pulmonary airway malformations (CPAMs) are rare lung abnormalities that result in cyst formation and are associated with respiratory distress in infants and malignant potential in adults. The pathogenesis of CPAMs remains unknown but data suggest disruption of the normal proximo-distal programme of airway branching and differentiation. Here, we demonstrate that adult human CPAM are lined with epithelium that retains SOX-2 and thyroid transcription factor-1 immunohistochemical markers, characteristic of the developing lung. However, RALDH-1, another key marker, is absent. This suggests a more complex aetiology for CPAM than complete focal arrest of lung development and may provide insight to the associated risk of malignancy.
Postmarketing Safety of Vaccines Approved by the U.S. Food and Drug Administration
Authors: Noam Tau, Dafna Yahav, Daniel Shepshelovich
Journal: Annals of Internal Medicine (2020)

Background: Vaccines are one of the greatest achievements in public health. Prevalence and clinical significance of emerging postapproval, vaccine-related safety issues have not been systematically studied. Objective: To explore postmarketing safety modifications in U.S. Food and Drug Administration (FDA)–approved vaccine labels. Design: Retrospective cohort study. Setting: United States. Participants: Initial and subsequent labels of all vaccines that were FDA-approved between 1 January 1996 and 31 December 2015. Measurements: The primary aim was a descriptive analysis of the prevalence and characteristics of postapproval, safety-related label changes. The secondary aim was to describe the distribution of data sources triggering these modifications. Results: The study cohort comprised 57 FDA-approved vaccines. Initial approval for 53 (93%) of the vaccines was supported by randomized controlled trials, with a median cohort size of 4161 participants (interquartile range, 2204 to 8634 participants). There were 58 postapproval, safety-related label modifications associated with 25 vaccines (49 warnings and precautions, 8 contraindications, and 1 safety-related withdrawal). The initial approval trial characteristics were similar in vaccines with and without postmarketing, safety-related label modifications. The most common safety issue triggering label modifications was expansion of population restrictions (n = 21 [36%]), followed by allergies (n = 13 [22%]). The most common source of safety data was postmarketing surveillance (n = 28 of 58 [48%]). Limitation: The data source of the initial signal triggering safety-related label changes may not necessarily represent all safety data received and processed by the FDA. Conclusion: Over a 20-year period, vaccines were found to be remarkably safe. A large proportion of safety issues were identified through existing postmarketing surveillance programs and were of limited clinical significance. These findings confirm the robustness of the vaccine approval system and postmarketing surveillance. Primary Funding Source: None.