tbuckley/cabot-search huggingface dataset:
Abstract 17047: Nintedanib And Cardiomyopathy: A Vascular Failure?
Authors: Alexander J Lu, Li Lai, Hyeon-Ju R Ali, Guha Ashrith, John P Cooke
Journal: Circulation (2021)

Description of the Case: Patient 1 is a 61-year-old woman with a history of rheumatoid arthritis-related interstitial lung disease (ILD). Six months after initiation of nintedanib, she was diagnosed with new-onset heart failure. Cardiac magnetic resonance imaging (CMR) was consistent with nonischemic cardiomyopathy (NICM) with ejection fraction (EF) of 15-25%. EKG showed new bifascicular block (right bundle branch block and left anterior fascicular block). Nintedanib was discontinued, and four months later, echocardiogram showed recovered EF (50-54%). EKG abnormalities resolved with biventricular pacing. Patient 2 is a 57-year-old-man with a history of scleroderma-related ILD and stable diastolic heart failure (EF = 55-60%). Six months after initiation of nintedanib, he was admitted for heart failure exacerbation. CMR showed NICM with EF = 35%, and EKG showed prolonged QRS (130 ms). Given the rapid progression of cardiomyopathy, nintedanib was discontinued. Discussion: We report two patients with underlying connective tissue disease who developed significant nonischemic cardiomyopathy in temporal association with initiation of nintedanib. Nintedanib is a tyrosine kinase inhibitor, antagonizing three angiogenic signaling pathways mediated by vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet derived growth factor receptor (PDGFR). The nintedanib-treated cohorts of the TOMORROW and INPULSIS trials for idiopathic pulmonary fibrosis showed a high incidence of myocardial infarction (MI). With the recent SCENSIS trial, nintedanib was approved in 2019 for ILD associated with systemic sclerosis. There are likely multifactorial effects of this triple angiokinase inhibitor, seeing that it inhibits multiple growth factors essential for vascular homeostasis, the balance between mesenchymal and endothelial cell fates. Thus, there may be multiple pathways for cardiomyopathy due to “vascular failure,” including MI and importantly, cardiac fibrosis. Based on our observations, we urge other clinicians to report their experience with nintedanib use in patients with underlying connective tissue disease and to carefully monitor these patients for adverse cardiovascular effects.
Early Hospital Discharge Following PCI for Patients With STEMI
Authors: Krishnaraj S. Rathod, Katrina Comer, Oliver Casey-Gillman, Lizzie Moore, Gordon Mills, Gordon Ferguson, Sotiris Antoniou, Riyaz Patel, Sadeer Fhadil, Tasleem Damani, Paul Wright, Mick Ozkor, Debashish Das, Oliver P. Guttmann, Andreas Baumbach, R. Andrew Archbold, Andrew Wragg, Ajay K. Jain, Fizzah A. Choudry, Anthony Mathur, Daniel A. Jones
Journal: Journal of the American College of Cardiology (2021)
Multifunctional Single‐Component Polypeptide Hydrogels: The Gelation Mechanism, Superior Biocompatibility, High Performance Hemostasis, and Scarless Wound Healing
Authors: Qian Bai, Lin Teng, Xueliang Zhang, Chang‐Ming Dong
Journal: Advanced Healthcare Materials (2021)

Polymeric hydrogels have been increasingly studied for wound sealants, adhesives, hemostats, and dressings, however, multi-component gelation, adhesion-causing tissue damage, inefficient hemostasis, and skin scarring in wound healing hamper their advances. So it is urgent to develop multifunctional single-component polymeric hydrogels with benign tissue detachment, high performance hemostasis, and scarless wound healing attributes. Herein, a dopamine-modified poly(l-glutamate) hydrogel at an ultralow concentration of 0.1 wt% is serendipitously constructed by physical treatments, in which a gelation mechanism is disclosed via oxidative catechol-crosslinking and sequential dicatechol-carboxyl hydrogen-bonding interactions. The covalent/H-bonding co-crosslinked and highly negative-charged networks enable the polypeptide hydrogels thermo-, salt-, urea-resistant, self-healing, injectable, and adhesive yet detachable. In vitro and in vivo assays demonstrate they have superior biocompatibility with ≈0.5% hemolysis and negligible inflammation. The polypeptide/graphene oxide hybrid hydrogel performs fast and efficient hemostasis of 12 s and 1.4% blood loss, surpassing some hydrogels and commercial counterparts. Remarkably, the polypeptide hydrogels achieve scarless and full wound healing and regenerate thick dermis with some embedded hair follicles within 14 days, presenting superior full-thickness wound healing and skin scar-preventing capabilities. This work provides a simple and practicable method to construct multifunctional polypeptide hemostatic and healing hydrogels that overcome some above-mentioned hurdles.
<i>TP53</i> and CD19-Directed Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Large B-Cell Lymphoma
Authors: Roni Shouval, Ana Alarcon Tomas, Joshua A Fein, Jessica Flynn, Ettai Markovits, Shimrit Mayer, Aishat Olaide Afuye, Anna Alperovich, Theodora Anagnostou, Connie Lee Batlevi, Parastoo B. Dahi, Sean M Devlin, Warren Fingrut, Sergio A Giralt, Richard J Lin, Gilles Salles, Craig S. Sauter, Michael Scordo, Gunjan L Shah, Nishi Shah, Ruth Scherz Shouval, Marcel van den Brink, Miguel-Angel Perales, Maria Lia Palomba
Journal: Blood (2021)
Chronic calcium signaling in IgE+ B cells limits plasma cell differentiation and survival
Authors: Rebecca Newman, Pavel Tolar
Journal: Immunity (2021)

In contrast to other antibody isotypes, B cells switched to IgE respond transiently and do not give rise to long-lived plasma cells (PCs) or memory B cells. To better understand IgE-BCR-mediated control of IgE responses, we developed whole-genome CRISPR screening that enabled comparison of IgE+ and IgG1+ B cell requirements for proliferation, survival, and differentiation into PCs. IgE+ PCs exhibited dependency on the PI3K-mTOR axis that increased protein amounts of the transcription factor IRF4. In contrast, loss of components of the calcium-calcineurin-NFAT pathway promoted IgE+ PC differentiation. Mice bearing a B cell-specific deletion of calcineurin B1 exhibited increased production of IgE+ PCs. Mechanistically, sustained elevation of intracellular calcium in IgE+ PCs downstream of the IgE-BCR promoted BCL2L11-dependent apoptosis. Thus, chronic calcium signaling downstream of the IgE-BCR controls the self-limiting character of IgE responses and may be relevant to the accumulation of IgE-producing cells in allergic disease.
IL-26 inhibits hepatitis C virus replication in hepatocytes
Authors: Élodie Beaumont, Vincent Larochette, Laurence Preisser, Charline Miot, Pascale Pignon, Simon Blanchard, Björn-Thore Hansen, Jonathan Dauvé, Caroline Poli, Minna M. Poranen, Patricia Lamourette, Marc Plaisance, Alain Morel, Helmut Fickenscher, Pascale Jeannin, Philippe Roingeard, Yves Delneste
Journal: Journal of Hepatology (2021)
Comments on Study About US Female Surgeons
Authors: Emily Shin Chwa
Journal: JAMA Surgery (2021)

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瑞典掌跖脓疱病的发病率有多高?
Journal: British Journal of Dermatology (2021)

掌跖 (手掌和足底) 脓疱病 (PPP) 是一种持续性 (慢性) 疾病, 表现为手掌和足底出现充满液体的水疱。手掌和足底的皮肤会非常痒和疼痛, 特别是皮肤有深裂时。这种病症是持续性的, 但症状可能有所不同, 随着时间的推移而好转和恶化, 通常没有明显的原因。
49P A phase II randomized trial with adjuvant autologous tumor lysate-pulsed dendritic cells (DC) in resected stage III-IV melanoma patients: Preliminary immunological results
Authors: L. Ridolfi, J. Bulgarelli, C. Piccinini, S. Carloni, A. Granato, M. Petrini, F. De Rosa, M. Tazzari, E. Pancisi, V. Ancarani, L. Turci, G. Gentili, L. Valmorri, M. Guidoboni
Journal: Annals of Oncology (2021)
Soluble antigens derived from Coxiella burnetii elicit protective immunity in three animal models without inducing hypersensitivity
Authors: Anthony E. Gregory, Erin J. van Schaik, Alycia P. Fratzke, Kasi E. Russell-Lodrigue, Christina M. Farris, James E. Samuel
Journal: Cell Reports Medicine (2021)

Q fever is caused by the intracellular bacterium Coxiella burnetii, for which there is no approved vaccine in the United States. A formalin-inactivated whole-cell vaccine (WCV) from virulent C. burnetii NMI provides single-dose long-lived protection, but concerns remain over vaccine reactogenicity. We therefore sought an alternate approach by purifying native C. burnetii antigens from the clonally derived avirulent NMII strain. A soluble bacterial extract, termed Sol II, elicits high-titer, high-avidity antibodies and induces a CD4 T cell response that confers protection in naive mice. In addition, Sol II protects against pulmonary C. burnetii challenge in three animal models without inducing hypersensitivity. An NMI-derived extract, Sol I, enhances protection further and outperforms the WCV gold standard. Collectively, these data represent a promising approach to design highly effective, non-reactogenic Q fever vaccines.
Abstract 14171: Prehospital Outcomes and Patient Characteristics Associated With PulsePoint Dispatches for Out-of-Hospital Cardiac Arrest in Pittsburgh, Pennsylvania
Authors: David Salcido, Christian Martin-Gill, LEONARD WEISS, David D Salcido
Journal: Circulation (2021)

Background: Mobile phone-based dispatch of volunteers to out-of-hospital cardiac arrest (OHCA) has been shown to increase the likelihood of early chest compressions and AED application. In the United States, limited characterization of patients encountered as a result of such systems exists, including PulsePoint Respond, a smartphone-based volunteer dispatch system. Objective: Examine prehospital case characteristics and outcomes from a multi-year deployment of PulsePoint in Pittsburgh, Pennsylvania. Methods: Case data, including PulsePoint determinant triggers and timing, prehospital electronic health records (EHRs), and computer aided dispatch records were obtained for suspected EMS-treated OHCA cases that did and did not generate PulsePoint alerts within the service area of Pittsburgh EMS for the period July 2016 to October 2020. EHRs were reviewed to determine true OHCA status, and OHCA case characteristics were extracted according to the Utstein template. Key characteristics and the outcome of prehospital return of spontaneous circulation (ROSC) were summarized and compared between cases with and without PulsePoint dispatches. Chi-squared tests were used to determine statistical significance of relationships. Results: There were 1229 OHCA cases overall in the capture period, with an estimated 29.6% occurring in public. Of 840 total PulsePoint dispatches, 68 (8.1%) were for true OHCA. Forty-five (66.2%) of these were witnessed, 43 (63.2%) received bystander CPR, and 17 (25%) had an AED applied prior to first responder arrival. Twenty-seven (39.7%) had an initial shockable rhythm, and 34 (50%) achieved ROSC in the field. Compared to non-PulsePoint dispatch generating OHCA, PulsePoint alert-associated patients were significantly more likely to be male (p=0.024), have bystander CPR/AED application performed (p&lt;0.001), have an initial shockable rhythm (p&lt;0.001), and achieve ROSC (p&lt;0.001). EMS response time, age, ALS response time, and witnessed status were not significantly different. Conclusions: A minority of PulsePoint dispatches in Pittsburgh were triggered by true OHCA. Among cases that did generate a PulsePoint dispatch, case characteristics were prognostically favorable.
Alveolar, Endothelial, and Organ Injury Marker Dynamics in Severe COVID-19
Authors: Daniel E. Leisman, Arnav Mehta, B. Taylor Thompson, Nicole C. Charland, Anna L. K. Gonye, Irena Gushterova, Kyle R. Kays, Hargun K. Khanna, Thomas J. LaSalle, Kendall M. Lavin-Parsons, Brendan M. Lilley, Carl L. Lodenstein, Kasidet Manakongtreecheep, Justin D. Margolin, Brenna N. McKaig, Maricarmen Rojas-Lopez, Brian C. Russo, Nihaarika Sharma, Jessica Tantivit, Molly F. Thomas, Blair Alden Parry, Alexandra-Chloé Villani, Moshe Sade-Feldman, Nir Hacohen, Michael R. Filbin, Marcia B. Goldberg
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Alveolar and endothelial injury may be differentially associated with coronavirus disease (COVID-19) severity over time. Objectives: To describe alveolar and endothelial injury dynamics and associations with COVID-19 severity, cardiorenovascular injury, and outcomes. Methods: This single-center observational study enrolled patients with COVID-19 requiring respiratory support at emergency department presentation. More than 40 markers of alveolar (including receptor for advanced glycation endproducts [RAGE]), endothelial (including angiopoietin-2), and cardiorenovascular injury (including renin, kidney injury molecule-1, and troponin-I) were serially compared between invasively and spontaneously ventilated patients using mixed-effects repeated-measures models. Ventilatory ratios were calculated for intubated patients. Associations of biomarkers with modified World Health Organization scale at Day 28 were determined with multivariable proportional-odds regression. Measurements and Main Results: Of 225 patients, 74 (33%) received invasive ventilation at Day 0. RAGE was 1.80-fold higher in invasive ventilation patients at Day 0 (95% confidence interval [CI], 1.50-2.17) versus spontaneous ventilation, but decreased over time in all patients. Changes in alveolar markers did not correlate with changes in endothelial, cardiac, or renal injury markers. In contrast, endothelial markers were similar to lower at Day 0 for invasive ventilation versus spontaneous ventilation, but then increased over time only among intubated patients. In intubated patients, angiopoietin-2 was similar (fold difference, 1.02; 95% CI, 0.89-1.17) to nonintubated patients at Day 0 but 1.80-fold higher (95% CI, 1.56-2.06) at Day 3; cardiorenovascular injury markers showed similar patterns. Endothelial markers were not consistently associated with ventilatory ratios. Endothelial markers were more often significantly associated with 28-day outcomes than alveolar markers. Conclusions: Alveolar injury markers increase early. Endothelial injury markers increase later and are associated with cardiorenovascular injury and 28-day outcome. Alveolar and endothelial injury likely contribute at different times to disease progression in severe COVID-19.
Salvage technique for endoscopic stent removal using a thin-tipped balloon catheter during endoscopic ultrasound-guided hepaticoduodenostomy
Authors: Tomohiro Ishii, Takashi Kaneko, Yuichi Suzuki, Masaki Nishimura, Kazuya Sugimori, Ichiro Kawana, Shin Maeda
Journal: Endoscopy (2021)

Endoscopic ultrasound-guided hepaticoduodenostomy (EUS-HDS) is sometimes performed for right intrahepatic duct drainage after failure of endoscopic retrograde cholangiopancreatography (ERCP) [1]. We experienced difficulty in removing a plastic stent, during EUS-HDS. Here, we describe a salvage technique for endoscopic stent removal using a thin-tipped balloon catheter during EUS-HDS.
Stereotactic Radiotherapy and Short-course Pembrolizumab for Oligometastatic Renal Cell Carcinoma—The RAPPORT Trial
Authors: Shankar Siva, Mathias Bressel, Simon T. Wood, Mark G. Shaw, Sherene Loi, Shahneen K. Sandhu, Ben Tran, Arun A. Azad, Jeremy H. Lewin, Katharine E. Cuff, Howard Y. Liu, Daniel Moon, Jeremy Goad, Lih-Ming Wong, Michael LimJoon, Jennifer Mooi, Sarat Chander, Declan G. Murphy, Nathan Lawrentschuk, David Pryor
Journal: European Urology (2021)
Error in Box
Authors: Dimitri Drekonja, Barbara Trautner, James Johnson
Journal: JAMA (2021)

We agree and note that this trial's design started as a superiority trial but emerged with a noninferiority design after 3 successive rounds of Veterans Affairs scientific review.The Veterans Affairs reviewers recommended this change, noting that the bulk of the published studies of antimicrobial duration have been noninferiority trials.Because antimicrobial therapy is superior to no antimicrobial therapy for UTI, 2 we strongly doubt that 7 and 14 days of antimicrobial therapy yielded similar outcomes because neither duration is effective.Mr Yap raises concerns that inclusion criteria were insufficiently stringent and that E coli susceptibility to ciprofloxacin vs trimethoprim-sulfamethoxazole differs.The dilemma of whether to use more restrictive eligibility criteria vs a pragmatic approach is an ongoing challenge for trialists.Although a restrictive approach provides greater certainty that study participants have the condition of interest, a pragmatic approach is more applicable to nonstudy settings, in which clinicians must treat patients who do not fit neatly into established diagnostic categories based on strict inclusion criteria.We opted for a pragmatic approach and are reassured by exploratory analyses that treatment effect did not differ based on urine culture status.The reference provided by Yap for the concern about poorer treatment outcomes with trimethoprim-sulfamethoxazole is a study that examined individual-and group-level factors associated with the probability of a resistant organism in a multilevel model and did not address outcomes, so it is noncontributory. 3Furthermore, in our trial, all E coli isolates were known to be susceptible to the prescribed antimicrobial.Dr Ahmed and colleagues question the inclusion of ciprofloxacin as a study drug and note that since 2018, UK and European guidelines have recommended a 7-day course of treatment for afebrile men with UTI, which makes our work unlikely to change practice there.We note that 1 of their 2 cited references 4 states that for men with cystitis, "a treatment duration of at least seven days is recommended, preferably with trimethoprim sulfamethoxazole or a fluoroquino-lone… [italics added]."This recommendation for "at least seven days" therapy with either of our 2 study drugs supports the relevance of our findings for UK and European clinicians and may affect future European guidelines.In addition, regarding the comment by Ahmed and colleagues that no patient or public involvement was sought, we would like to clarify that our study was reviewed and modified by 3 successive scientific review panels and underwent further review with the institutional review boards at 2 academic institutions.These institutional review boards included com
Bortezomib-Pomalidomide-Dexamethasone (VPD) As Novel Induction Therapy in Newly-Diagnosed Multiple Myeloma: Early Safety Data from an Ongoing Single Arm Phase-II Investigator-Initiated Clinical Trial (PRIME Study)
Authors: Vivek S Radhakrishnan, Naveed Tamboli, Shreya Das, Jeevan Kumar Garg, Arijit Nag, Saurabh J Bhave, Mayur Parihar, Sushant Vinarkar, Sumit Mukhopadhyay, Subhosmito Chakraborty, Deepak K Mishra, Reena Nair, Mammen Chandy
Journal: Blood (2021)
Platelets mediate inflammatory monocyte activation by SARS-CoV-2 spike protein
Authors: Tianyang Li, Yang Yang, Yongqi Li, Zhengmin Wang, Faxiang Ma, Runqi Luo, Xiaoming Xu, Guo Zhou, Jianhua Wang, Junqi Niu, Guoyue Lv, Ian N. Crispe, Zhengkun Tu
Journal: Journal of Clinical Investigation (2021)

Infection with SARS-CoV-2, the causative agent of COVID-19, causes mild to moderate disease in most patients but carries a risk of morbidity and mortality. Seriously affected individuals manifest disorders of hemostasis and a cytokine storm, but it is not understood how these manifestations of severe COVID-19 are linked. Here, we showed that the SARS-CoV-2 spike protein engaged the CD42b receptor to activate platelets via 2 distinct signaling pathways and promoted platelet-monocyte communication through the engagement of P selectin/PGSL-1 and CD40L/CD40, which led to proinflammatory cytokine production by monocytes. These results explain why hypercoagulation, monocyte activation, and a cytokine storm are correlated in patients severely affected by COVID-19 and suggest a potential target for therapeutic intervention.
Plasticity of Extrachromosomal and Intrachromosomal<i>BRAF</i>Amplifications in Overcoming Targeted Therapy Dosage Challenges
Authors: Kai Song, Jenna K. Minami, Arthur Huang, Siavash R. Dehkordi, Shirley H. Lomeli, Jens Luebeck, Mark H. Goodman, Gatien Moriceau, Oscar Krijgsman, Prashanthi Dharanipragada, Trevor Ridgley, William P. Crosson, Jesus Salazar, Eli Pazol, Gabriel Karin, Rachana Jayaraman, Nikolas G. Balanis, Salwan Alhani, Kyle Sheu, Johanna ten Hoeve, Amelia Palermo, Stephen E. Motika, T. Niroshi Senaratne, Kim H. Paraiso, Paul J. Hergenrother, P. Nagesh Rao, Asha S. Multani, Daniel S. Peeper, Vineet Bafna, Roger S. Lo, Thomas G. Graeber
Journal: Cancer Discovery (2021)

Focal amplifications (FA) can mediate targeted therapy resistance in cancer. Understanding the structure and dynamics of FAs is critical for designing treatments that overcome plasticity-mediated resistance. We developed a melanoma model of dual MAPK inhibitor (MAPKi) resistance that bears BRAFV600 amplifications through either extrachromosomal DNA (ecDNA)/double minutes (DM) or intrachromosomal homogenously staining regions (HSR). Cells harboring BRAFV600E FAs displayed mode switching between DMs and HSRs, from both de novo genetic changes and selection of preexisting subpopulations. Plasticity is not exclusive to ecDNAs, as cells harboring HSRs exhibit drug addiction-driven structural loss of BRAF amplicons upon dose reduction. FA mechanisms can couple with kinase domain duplications and alternative splicing to enhance resistance. Drug-responsive amplicon plasticity is observed in the clinic and can involve other MAPK pathway genes, such as RAF1 and NRAS. BRAF FA-mediated dual MAPKi-resistant cells are more sensitive to proferroptotic drugs, extending the spectrum of ferroptosis sensitivity in MAPKi resistance beyond cases of dedifferentiation. Understanding the structure and dynamics of oncogene amplifications is critical for overcoming tumor relapse. BRAF amplifications are highly plastic under MAPKi dosage challenges in melanoma, through involvement of de novo genomic alterations, even in the HSR mode. Moreover, BRAF FA-driven, dual MAPKi-resistant cells extend the spectrum of resistance-linked ferroptosis sensitivity. This article is highlighted in the In This Issue feature, p. 873.