tbuckley/cabot-search huggingface dataset:
JAK2V617F variant allele frequency &gt;50% identifies patients with polycythemia vera at high risk for venous thrombosis
Authors: Paola Guglielmelli, Giuseppe G. Loscocco, Carmela Mannarelli, Elena Rossi, Francesco Mannelli, Francesco Ramundo, Giacomo Coltro, Silvia Betti, Chiara Maccari, Sara Ceglie, Patrizia Chiusolo, Chiara Paoli, Tiziano Barbui, Ayalew Tefferi, Valerio De Stefano, Alessandro M. Vannucchi
Journal: Blood Cancer Journal (2021)

Arterial (AT) and venous (VT) thrombotic events are the most common complications in patients with polycythemia vera (PV) and are the leading causes of morbidity and mortality. In this regard, the impact of JAK2V617F variant allele frequency (VAF) is still debated. The purpose of the current study was to analyze the impact of JAK2V617F VAF in the context of other established risk factors for thrombosis in a total of 865 2016 WHO-defined PV patients utilizing two independent cohorts: University of Florence (n = 576) as a training cohort and Policlinico Gemelli, Catholic University, Rome (n = 289) as a validation cohort. In the training cohort VT free-survival was significantly shorter in the presence of a JAK2V617F VAF > 50% (HR 4; p < 0.0001), whereas no difference was found for AT (HR 0.9; p = 0.8). Multivariable analysis identified JAK2V617F VAF > 50% (HR 3.8, p = 0.001) and previous VT (HR 2.2; p = 0.04) as independent risk factors for future VT whereas diabetes (HR 2.4; p = 0.02), hyperlipidemia (HR 2.3; p = 0.01) and previous AT (HR 2; p = 0.04) were independent risk factors for future AT. Similarly, JAK2V617F VAF > 50% (HR 2.4; p = 0.01) and previous VT (HR 2.8; p = 0.005) were confirmed as independent predictors of future VT in the validation cohort. Impact of JAK2V617F VAF > 50% on VT was particularly significant in conventional low-risk patients, both in Florence (HR 10.6, p = 0.005) and Rome cohort (HR 4; p = 0.02). In conclusion, we identified JAK2V617F VAF > 50% as an independent strong predictor of VT, supporting that AT and VT are different entities which might require distinct management.
Programmed genomic instability regulates neural transdifferentiation of human brain microvascular pericytes
Authors: Saba Rezaei-Lotfi, Filip Vujovic, Mary Simonian, Neil Hunter, Ramin M. Farahani
Journal: Genome biology (2021)

Transdifferentiation describes transformation in vivo of specialized cells from one lineage into another. While there is extensive literature on forced induction of lineage reprogramming in vitro, endogenous mechanisms that govern transdifferentiation remain largely unknown. The observation that human microvascular pericytes transdifferentiate into neurons provided an opportunity to explore the endogenous molecular basis for lineage reprogramming.
Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant
Authors: Emmanuel de Billy, Marsha Pellegrino, Domenico Orlando, Giulia Pericoli, Roberta Ferretti, Pietro Businaro, Maria Antonietta Ajmone-Cat, Sabrina Rossi, Lucia Lisa Petrilli, Nicola Maestro, Francesca Diomedi-Camassei, Marco Pezzullo, Cristiano De Stefanis, Paola Bencivenga, Alessia Palma, Rossella Rota, Francesca Del Bufalo, Luca Massimi, Gerrit Weber, Chris Jones, Andrea Carai, Simona Caruso, Biagio De Angelis, Ignazio Caruana, Concetta Quintarelli, Angela Mastronuzzi, Franco Locatelli, Maria Vinci
Journal: Neuro-Oncology (2021)

Abstract Background Diffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although GD2-CAR T-cells demonstrated significant anti-tumor activity against DMG H3K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. We investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy. Methods Immunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models, and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function. Results GD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual IGF1R/IR antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo, and in vivo. Conclusion Our study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for treating patients affected by DMG/DIPG and, potentially, by pHGG.
A novel endoscopic shield: a barrier device to minimize virus transmission during endoscopy
Authors: Hiroya Ueyama, Yoichi Akazawa, Toshio Fujisawa, Hiroyuki Isayama, Akihito Nagahara
Journal: Endoscopy (2021)

In this era, where medical staff are at risk of contracting an emerging infectious disease from patients, such as with the current COVID-19 pandemic situation, it has been strongly recommended that effective infection prevention measures are established within an endoscopy unit to protect both patients and medical staff [1]. However, only a few barrier devices have been reported and determining which device is effective remains a notable issue [2] [3] [4] [5].
Representation of Women in Ophthalmology Subspecialty Societies over 20 Years
Authors: Amee D. Azad, Arthika Chandramohan, Angela S. Li, Tatiana R. Rosenblatt, Mary-Grace R. Reeves, Malini Veerappan-Pasricha, Cassie A. Ludwig, Angeline Nguyen, Kimberly M. Winges, Sophia Y. Wang, Carolyn K. Pan, Heather E. Moss, Diana V. Do, Tamara R. Fountain, Andrea L. Kossler
Journal: Ophthalmology (2021)
EPID-08. IMPORTANCE OF THE INTERSECTION OF AGE AND SEX TO UNDERSTAND VARIATION IN INCIDENCE AND SURVIVAL FOR PRIMARY MALIGNANT GLIOMAS
Authors: Gi-Ming Wang, Gino Cioffi, Nirav Patil, Kristin Waite, Robert Lanese, Quinn Ostrom, Carol Kruchko, Michael Berens, James Connor, Justin Lathia, Joshua Rubin, Jill Barnholtz-Sloan
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Gliomas are the most common type of malignant brain and other CNS tumors, accounting for 80.8% of malignant primary brain and CNS tumors. They cause significant morbidity and mortality. This study investigates the intersection between age and sex to better understand variation of incidence and survival for glioma in the United States. METHODS Incidence data from 2000-2017 were obtained from the Central Crain Tumor Registry of the United States, which obtains data from the CDC’s National Program of Cancer Registries and NCI’s Surveillance Epidemiology and End Results Program (SEER), and survival data from the CDC’s NPCR Registries. Age-adjusted incidence rates and rate ratios per 100,000 were generated to compare male-to-female incidence by age group. Cox proportional hazard models were performed by age group, generating hazard ratios to assess male-to-female survival differences. RESULTS Overall, glioma incidence was higher in males. Male-to-female incidence was lowest in ages 0-9 years (IRR: 1.04, 95% CI:1.01 - 1.07, p=0.003), increasing with age, peaking at 50-59 years (IRR:1.56, 95% CI: 1.53 - 1.59, p&amp;lt; 0.001). Females had worse survival for ages 0-9 (HR:0.93, 95% CI:0.87-0.99), though male survival was worse for all other age groups, with the difference highest in those 20-29 years (HR:1.36, 95% CI:1.28-1.44). Incidence and survival differences by age and sex also varied by histological subtype of glioma. CONCLUSION To better understand the variation in glioma incidence and survival, investigating the intersection of age and sex is key. The current work shows that the combined impact of these variables is dependent on glioma subtype. These results contribute to the growing understanding of sex and age differences that impact cancer incidence and survival.
Impact of Reverse Triggering Dyssynchrony during Lung-Protective Ventilation on Diaphragm Function: An Experimental Model
Authors: L. Felipe Damiani, Doreen Engelberts, Luca Bastia, Kohei Osada, Bhushan H. Katira, Gail Otulakowski, Ewan C. Goligher, W. Darlene Reid, Sebastián Dubo, Alejandro Bruhn, Martin Post, Brian P. Kavanagh, Laurent J. Brochard
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Reverse triggering dyssynchrony (RT) is a patient-ventilator interaction where a respiratory muscle contraction is triggered by a passive mechanical insufflation. Its impact on diaphragm structure and function is unknown. Objectives: To establish an animal model of RT with lung injury receiving lung-protective ventilation and to assess its impact on the structure and function of the diaphragm. Methods: Lung injury was induced by surfactant depletion and high-stress ventilation in 32 ventilated pigs. Animals were allocated to receive passive mechanical ventilation (Vt: 10 ml/kg; respiratory rate [RR]: 30-35 breaths/min; n = 8) or a more lung-protective strategy (Vt: 6-8 ml/kg; n = 24) with adjustments in RR to facilitate the occurrence of RT for 3 hours. Diaphragm function (transdiaphragmatic pressure [Pdi] during phrenic nerve stimulation [force/frequency curve]) and structure (biopsies) were assessed. The impact of RT on diaphragm function was analyzed according to the breathing effort assessed by the pressure-time product. Measurements and Main Results: Compared with passive ventilation, the protective ventilation group with RT received significantly lower Vt (7 vs. 10 ml/kg) and higher RR (45 vs. 31 breaths/min). An entrainment pattern of 1:1 was the most frequently occurring in 83% of the animals. Breathing effort induced by RT was highly variable across animals. RT with the lowest tercile of breathing effort was associated with 23% higher twitch Pdi compared with passive ventilation, whereas RT with high breathing effort was associated with a 10% lower twitch Pdi and a higher proportion of abnormal muscle fibers. Conclusions: In a reproducible animal model of RT with variable levels of breathing effort and entrainment patterns, RT with high effort is associated with impaired diaphragm function, whereas RT with low effort is associated with preserved diaphragm force.
New and Consolidated Therapeutic Options for Pubertal Induction in Hypogonadism: In-depth Review of the Literature
Authors: Silvia Federici, Giovanni Goggi, Richard Quinton, Luca Giovanelli, Luca Persani, Biagio Cangiano, Marco Bonomi
Journal: Endocrine Reviews (2021)

Abstract Delayed puberty (DP) defines a retardation of onset/progression of sexual maturation beyond the expected age from either a lack/delay of the hypothalamo-pituitary-gonadal axis activation or a gonadal failure. DP usually gives rise to concern and uncertainty in patients and their families, potentially affecting their immediate psychosocial well-being and also creating longer term psychosexual sequelae. The most frequent form of DP in younger teenagers is self-limiting and may not need any intervention. Conversely, DP from hypogonadism requires prompt and specific treatment that we summarize in this review. Hormone therapy primarily targets genital maturation, development of secondary sexual characteristics, and the achievement of target height in line with genetic potential, but other key standards of care include body composition and bone mass. Finally, pubertal induction should promote psychosexual development and mitigate both short- and long-term impairments comprising low self-esteem, social withdrawal, depression, and psychosexual difficulties. Different therapeutic options for pubertal induction have been described for both males and females, but we lack the necessary larger randomized trials to define the best approaches for both sexes. We provide an in-depth and updated literature review regarding therapeutic options for inducing puberty in males and females, particularly focusing on recent therapeutic refinements that better encompass the heterogeneity of this population, and underlining key differences in therapeutic timing and goals. We also highlight persistent shortcomings in clinical practice, wherein strategies directed at “the child with delayed puberty of uncertain etiology” risk being misapplied to older adolescents likely to have permanent hypogonadism.
Commentary
Authors: Rogier P. Voermans
Journal: Endoscopy (2021)

Takenaka et al. describe an innovative technique for cannulation of a mobile papilla at the rim of a periampullary diverticulum. Although this is an interesting rescue technique, caution should be exercised. First, contrast injection-based cannulation is needed to show the anatomy of the pancreatic duct. However, wire-assisted cannulation is preferable if possible, because contrast-guided cannulation is associated with a higher risk of post endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis [1]. Second, when cannulation with a guidewire (of one of the ducts) fails in patients with a mobile periampullary diverticula, this is often due to a “hidden” biliary orifice in the diverticulum itself. The technique described will not facilitate cannulation in such a case. Instead, a traction device (such as a clip) can be used to reorientate the papilla towards the duodenal lumen. Lastly, as with many ERCP tricks and devices for cannulation, it is advised to use accessories that the performing endoscopist feels comfortable with. In the case of failure with these accessories, consider referral to an expert colleague or, if you are an expert, try novel techniques such as the one described.
Plasma adiponectin and risk of asthma: observational analysis, genetic Mendelian randomisation and meta-analysis
Authors: Maria Booth Nielsen, Børge G Nordestgaard, Marianne Benn, Yunus Çolak
Journal: Thorax (2021)

Background Adiponectin, an adipocyte-secreted protein-hormone with inflammatory properties, has a potentially important role in the development and progression of asthma. Unravelling whether adiponectin is a causal risk factor for asthma is an important issue to clarify as adiponectin could be a potential novel drug target for the treatment of asthma. Objective We tested the hypothesis that plasma adiponectin is associated observationally and causally (using genetic variants as instrumental variables) with risk of asthma. Methods In the Copenhagen General Population Study, we did an observational analysis in 28 845 individuals (2278 asthma cases) with plasma adiponectin measurements, and a genetic one-sample Mendelian randomisation analysis in 94 868 individuals (7128 asthma cases) with 4 genetic variants. Furthermore, in the UK Biobank, we did a genetic two-sample Mendelian randomisation analysis in 462 933 individuals (53 598 asthma cases) with 12 genetic variants. Lastly, we meta-analysed the genetic findings. Results While a 1 unit log-transformed higher plasma adiponectin in the Copenhagen General Population Study was associated with an observational OR of 1.65 (95% CI 1.29 to 2.08) for asthma, the corresponding genetic causal OR was 1.03 (95% CI 0.75 to 1.42). The genetic causal OR for asthma in the UK Biobank was 1.00 (95% CI 0.99 to 1.00). Lastly, genetic meta-analysis confirmed lack of association between genetically high plasma adiponectin and causal OR for asthma. Conclusion Observationally, high plasma adiponectin is associated with increased risk of asthma; however, genetic evidence could not support a causal association between plasma adiponectin and asthma.
Primary Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) As First-Line Therapy in Patients with High-Risk Large B-Cell Lymphoma (LBCL)
Authors: Sattva S. Neelapu, Michael Dickinson, Javier Munoz, Matthew L. Ulrickson, Catherine Thieblemont, Olalekan O. Oluwole, Alex F. Herrera, Chaitra S. Ujjani, Yi Lin, Peter A. Riedell, Natasha Kekre, Sven de Vos, Christine Lui, Francesca Milletti, Jinghui Dong, Hairong Xu, Julio C. Chavez
Journal: Blood (2021)
Effect of the Glucagon-Like Peptide-1 Receptor Agonists Semaglutide and Liraglutide on Kidney Outcomes in Patients With Type 2 Diabetes: Pooled Analysis of SUSTAIN 6 and LEADER
Authors: Ahmed M. Shaman, Stephen C. Bain, George L. Bakris, John B. Buse, Thomas Idorn, Kenneth W. Mahaffey, Johannes F.E. Mann, Michael A. Nauck, Søren Rasmussen, Peter Rossing, Benjamin Wolthers, Bernard Zinman, Vlado Perkovic
Journal: Circulation (2021)

We assessed the effect of once-weekly semaglutide and once-daily liraglutide on kidney outcomes in type 2 diabetes.
Correction: Single-cell profiling reveals the trajectories of natural killer cell differentiation in bone marrow and a stress signature induced by acute myeloid leukemia
Authors: Adeline Crinier, Pierre-Yves Dumas, Bertrand Escalière, Christelle Piperoglou, Laurine Gil, Arnaud Villacreces, Frédéric Vély, Zoran Ivanovic, Pierre Milpied, Émilie Narni-Mancinelli, Éric Vivier
Journal: Cellular and Molecular Immunology (2021)
Clinician Trends in Prescribing Direct Oral Anticoagulants for US Medicare Beneficiaries
Authors: Kevin M. Wheelock, Joseph S. Ross, Karthik Murugiah, Zhenqiu Lin, Harlan M. Krumholz, Rohan Khera
Journal: JAMA Network Open (2021)

Contemporary national clinical practice guidelines recommend direct-acting oral anticoagulants (DOACs) as the first-line anticoagulant strategy over warfarin for most indications, especially among older individuals with an elevated bleeding risk.To evaluate anticoagulant prescribing and DOAC uptake by US clinicians in the Medicare population.This retrospective cohort study included all US clinicians with more than 10 Medicare oral anticoagulant prescription claims, who were included in the national Medicare Provider Utilization and Payment Data (2013-2018). Data analyses were conducted between October 2020 and October 2021.DOAC prescription in 2013.Clinicians were categorized based on 2013 prescribing as solely prescribing warfarin, DOAC, or both, and their temporal trajectories of proportionate DOAC use were examined.The analysis included 325 666 unique clinicians with more than 10 oral anticoagulant prescriptions between 2013 and 2018 (26 620 [8.2%] cardiologists, 85 563 [26.3%] internal medicine physicians, 84 369 [25.9%] family medicine physicians, and 81 161 [24.9%] advanced practice clinicians, including nurse practitioners and physician assistants). In 2013, among 91 837 prescribers, 54 501 (59.3%) prescribed only warfarin, 1918 (2.1%) prescribed only a DOAC, and 35 418 (38.6%) prescribed both. During the study period, the number of clinicians prescribing DOACs increased, but 19% continued to prescribe only warfarin in 2018. While 359 cardiologists prescribing anticoagulants (1.6%) were warfarin-only prescribers, 10 414 (20.0%) and 6296 (12.6%) of family and internal medicine physicians also prescribed only warfarin, respectively. Clinicians prescribing only warfarin in 2013 had lower proportionate DOAC use throughout the study compared with 2013 DOAC prescribers, which represents a median (IQR) of 41.9% (20.3%-61.9%) of their anticoagulant prescriptions in 2018 vs 67.0% (49.9%-82.8%) for DOAC prescribers.Despite the increase in DOAC use among Medicare beneficiaries, many clinicians in this study continued to use warfarin as their predominant or only anticoagulant instead of DOACs. There is a need to address barriers to the uptake of these medications to realize their potential benefits for patients.
Corrigendum to ‘TAZ is indispensable for c-MYC-induced hepatocarcinogenesis’ [J Hepatol (2022) 123–134]
Authors: Haichuan Wang, Shanshan Zhang, Yi Zhang, Jiaoyuan Jia, Jingxiao Wang, Xianqiong Liu, Jie Zhang, Xinhua Song, Silvia Ribback, Antonio Cigliano, Matthias Evert, Bingyong Liang, Hong Wu, Diego F. Calvisi, Yong Zeng, Xin Chen
Journal: Journal of Hepatology (2021)
Artemisinin and Procyanidins loaded multifunctional nanocomplexes alleviate atherosclerosis via simultaneously modulating lipid influx and cholesterol efflux
Authors: Hongyan Zhou, Peidong You, Hao Liu, Jialong Fan, Chunyi Tong, Anning Yang, Yideng Jiang, Bin Liu
Journal: Journal of Controlled Release (2021)
Measurable Residual Disease Response and Prognosis in Treatment-Naïve Acute Myeloid Leukemia With Venetoclax and Azacitidine
Authors: Keith W. Pratz, Brian A. Jonas, Vinod Pullarkat, Christian Recher, Andre C. Schuh, Michael J. Thirman, Jacqueline S. Garcia, Courtney D. DiNardo, Vladimir Vorobyev, Nicola S. Fracchiolla, Su-Peng Yeh, Jun Ho Jang, Muhit Ozcan, Kazuhito Yamamoto, Arpad Illes, Ying Zhou, Monique Dail, Brenda Chyla, Jalaja Potluri, Hartmut Döhner
Journal: Journal of Clinical Oncology (2021)

PURPOSE There is limited evidence on the clinical utility of monitoring measurable residual disease (MRD) in patients with acute myeloid leukemia treated with lower-intensity therapy. Herein, we explored the outcomes of patients treated with venetoclax and azacitidine who achieved composite complete remission (CRc; complete remission + complete remission with incomplete hematologic recovery) and MRD &lt; 10 –3 in the VIALE-A trial. METHODS The patients included in this report were treated with venetoclax and azacitidine. Bone marrow aspirate samples for multiparametric flow cytometry assessments were collected for central analysis at baseline, end of cycle 1, and every three cycles thereafter. MRD-negative response was defined as &lt; 1 residual blast per 1,000 leukocytes (&lt; 10 –3 or 0.1%) with an estimated analytic sensitivity of 0.0037%-0.0027%. CRc, duration of remission (DoR), event-free survival (EFS), and overall survival (OS) were assessed. A multivariate Cox regression analysis identified prognostic factors associated with OS. RESULTS One hundred sixty-four of one hundred ninety (86%) patients with CRc were evaluable for MRD. MRD &lt; 10 –3 was achieved by 67 of 164 (41%), and 97 of 164 (59%) had MRD ≥ 10 –3 . The median DoR, EFS, and OS were not reached in patients with CRc and MRD &lt; 10 –3 , and the 12-month estimates for DoR, EFS, and OS in this group were 81.2%, 83.2%, and 94.0%. Among patients with CRc and MRD ≥ 10 –3 , the median DoR, EFS, and OS were 9.7, 10.6, and 18.7 months. Multivariate analysis showed that CRc with MRD &lt; 10 –3 was a strong predictor of OS (adjusted hazard ratio = 0.285; 95% CI, 0.159 to 0.510; P &lt; .001). CONCLUSION Patients who achieved CRc and MRD &lt; 10 –3 with venetoclax and azacitidine had longer DoR, EFS, and OS, than responding patients with MRD ≥ 10 –3 .
Actual knowledge
Authors: Jonathan Phillips, Wesley Buckwalter, Fiery Cushman, Ori Friedman, Alia Martin, John Turri, Laurie Santos, Joshua Knobe
Journal: Behavioral and Brain Sciences (2021)

Abstract This response argues that when you represent others as knowing something, you represent their mind as being related to the actual world. This feature of knowledge explains the limits of knowledge attribution, how knowledge differs from belief, and why knowledge underwrites learning from others. We hope this vision for how knowledge works spurs a new era in theory of mind research.
Hepatology Highlights
Authors: Chaitanya Allamneni, Ravi S. Vora, Adebowale O. Bamidele, Robert E. Schwartz, Davide Povero, David M. Salerno, Robert S. Brown, Rosa Lu Yu, Mati Ullah Dad Ullah, Daryl T.Y. Lau, Wei Zhang, Amani Lee, Enis Kostallari, Nidhi Jalan‐Sakrikar, Shalil Khanal, Enis Kostallari
Journal: Hepatology (2021)