tbuckley/cabot-search huggingface dataset:
<i>Notes from the Field:</i> Emergency Department Visits for Unsupervised Pediatric Melatonin Ingestion — United States, 2019–2022
Authors: Devin I. Freeman, Jennifer N. Lind, Nina J. Weidle, Andrew I. Geller, Nimalie D. Stone, Maribeth C. Lovegrove
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

The prevalence of melatonin use by U.S. adults quintupled from 0.4% during 1999-2000 to 2.1% during 2017-2018 (1).This rise coincided with a 530% increase in poison center calls for pediatric melatonin exposures during 2012-2021 and a 420% increase in emergency department (ED) visits for unsupervised melatonin ingestion by infants and young children during 2009-2020 (2,3).CDC analyzed public health surveillance data to describe circumstances involved in these ingestions to help guide development of interventions.* https://health.gov/healthypeople/objectives-and-data/data-sources-andmethods/data-sources/national-electronic-injury-surveillance-systemcooperative-adverse-drug-event-surveillance-project-neiss-cades
Aging-induced tRNAGlu-derived fragment impairs glutamate biosynthesis by targeting mitochondrial translation-dependent cristae organization
Authors: Dingfeng Li, Xinyi Gao, Xiaolin Ma, Ming Wang, Chuandong Cheng, Tian Xue, Feng Gao, Yong Shen, Juan Zhang, Qiang Liu
Journal: Cell Metabolism (2024)
Years of Potential Life Lost and Mean Age of Adults Experiencing Nontraumatic, Out-of-Hospital Cardiac Arrests — Chicago, 2014–2021
Authors: Shaveta Khosla, Marina Del Rios, Pavitra Kotini-Shah, Joseph Weber, Terry Vanden Hoek
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Approximately 1,000 out-of-hospital cardiac arrests (OHCAs) are assessed by emergency medical services in the United States every day, and approximately 90% of patients do not survive, leading to substantial years of potential life lost (YPLL).Chicago emergency medical services data were used to assess changes in mean age and YPLL from nontraumatic OHCA in adults in biennial cycles during 2014-2021.Among 21,070 reported nontraumatic OHCAs during 2014-2021, approximately 60% occurred among men and 57% among non-Hispanic Black or African American (Black) persons.YPLL increased from 52,044 during 2014-2015 to 88,788 during 2020-2021 (p = 0.002) and mean age decreased from 64.7 years during 2014-2015, to 62.7 years during 2020-2021.Decrease in mean age occurred among both men (p<0.001) and women (p = 0.002) and was largest among Black men.Mean age decreased among patients without presumed cardiac etiology from 56.3 to 52.5 years (p<0.001) and among patients with nonshockable rhythm from 65.5 to 62.7 years (p<0.001).Further study is needed to assess whether similar trends are occurring elsewhere, and to understand the mechanisms that underlie these trends in Chicago because these mechanisms could help guide prevention efforts.Increased public awareness of the risk of cardiac arrest and knowledge of how to intervene as a bystander could help decrease associated mortality.
Early Estimate of Nirsevimab Effectiveness for Prevention of Respiratory Syncytial Virus–Associated Hospitalization Among Infants Entering Their First Respiratory Syncytial Virus Season — New Vaccine Surveillance Network, October 2023–February 2024
Authors: Heidi L. Moline, Ayzsa Tannis, Ariana P. Toepfer, John V. Williams, Julie A. Boom, Janet A. Englund, Natasha B. Halasa, Mary Allen Staat, Geoffrey A. Weinberg, Rangaraj Selvarangan, Marian G. Michaels, Leila C. Sahni, Eileen J. Klein, Laura S. Stewart, Elizabeth P. Schlaudecker, Peter G. Szilagyi, Jennifer E. Schuster, Leah Goldstein, Samar Musa, Pedro A. Piedra, Danielle M. Zerr, Kristina A. Betters, Chelsea Rohlfs, Christina Albertin, Dithi Banerjee, Erin R. McKeever, Casey Kalman, Benjamin R. Clopper, Meredith L. McMorrow, Fatimah S. Dawood, Ruth Link-Gelles, Amanda Payne, Ryan Wiegand, Ximena Aguilera Correa, Claudia Guevara Pulido, Hanna Grioni, Bonnie Strelitz, Vasanthi Avadhanula, Flor M. Munoz, Wende Fregoe, Saranya Peri, Anjana Sasidharan, Monika Johnson, Klancie Dauer
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Respiratory syncytial virus (RSV) is the leading cause of hospitalization among infants in the United States. In August 2023, CDC's Advisory Committee on Immunization Practices recommended nirsevimab, a long-acting monoclonal antibody, for infants aged <8 months to protect against RSV-associated lower respiratory tract infection during their first RSV season and for children aged 8-19 months at increased risk for severe RSV disease. In phase 3 clinical trials, nirsevimab efficacy against RSV-associated lower respiratory tract infection with hospitalization was 81% (95% CI = 62%-90%) through 150 days after receipt; post-introduction effectiveness has not been assessed in the United States. In this analysis, the New Vaccine Surveillance Network evaluated nirsevimab effectiveness against RSV-associated hospitalization among infants in their first RSV season during October 1, 2023-February 29, 2024. Among 699 infants hospitalized with acute respiratory illness, 59 (8%) received nirsevimab ≥7 days before symptom onset. Nirsevimab effectiveness was 90% (95% CI = 75%-96%) against RSV-associated hospitalization with a median time from receipt to symptom onset of 45 days (IQR = 19-76 days). The number of infants who received nirsevimab was too low to stratify by duration from receipt; however, nirsevimab effectiveness is expected to decrease with increasing time after receipt because of antibody decay. Although nirsevimab uptake and the interval from receipt of nirsevimab were limited in this analysis, this early estimate supports the current nirsevimab recommendation for the prevention of severe RSV disease in infants. Infants should be protected by maternal RSV vaccination or infant receipt of nirsevimab.
Self-care interventions for women’s health and well-being
Authors: Manjulaa Narasimhan, James R. Hargreaves, Carmen H. Logie, Quarraisha Abdool-Karim, Mandip Aujla, Jonathan Hopkins, Jane Cover, Olive Sentumbwe-Mugisa, Allan Maleche, Kate Gilmore
Journal: Nature Medicine (2024)

The human right to health is universal and non-exclusionary, supporting health in full, and for all. Despite advances in health systems globally, 3.6 billion people lack access to essential health services. Women and girls are disadvantaged when it comes to benefiting from quality health services, owing to social norms, unequal power in relationships, lack of consideration beyond their reproductive roles and poverty. Self-care interventions, including medicines and diagnostics, which offer an additional option to facility-based care, can improve the autonomy and agency of women in managing their own health. However, tackling challenges such as stigma is essential to avoid scenarios in which self-care interventions provide more choice for those who already benefit from access to quality healthcare, and leave behind those with the greatest need. This Perspective explores the opportunities that self-care interventions offer to advance the health and well-being of women with an approach grounded in human rights, gender equality and equity. Self-care interventions have the potential to improve health coverage for women while offering greater agency and autonomy, but only if certain barriers—such as stigma and cost—can be overcome.
Comparison of prior authorization across insurers: cross sectional evidence from Medicare Advantage
Authors: Ravi Gupta, Jay Fein, Joseph P Newhouse, Aaron L Schwartz
Journal: BMJ (2024)

To measure and compare the scope of US insurers' policies for prior authorization (PA), a process by which insurers assess the necessity of planned medical care, and to quantify differences in PA across insurers, physician specialties, and clinical service categories.
Representation of Patients With Chronic Kidney Disease in Clinical Trials of Cardiovascular Disease Medications
Authors: Julia M. T. Colombijn, Demy L. Idema, Sanne van Beem, Anna Marthe Blokland, Kim van der Braak, M. Louis Handoko, Linde F. Huis in ’t Veld, Tabea Kaul, Nurda Kolagasigil-Akdemir, Mike P. T. Kusters, Sabine C. A. Meijvis, Ilse J. Oosting, Rene Spijker, Michiel L. Bots, Lotty Hooft, Marianne C. Verhaar, Robin W. M. Vernooij
Journal: JAMA Network Open (2024)

Patients with chronic kidney disease (CKD) are at high risk for cardiovascular disease, but their systematic underrepresentation in cardiovascular randomized clinical trials (RCTs) limits the generation of appropriate evidence to guide cardiovascular risk management (CVRM).
Advancing Truth in Oncology by Complementing Clinical Trials With Evidence From Clinical Practice
Authors: Elad Sharon
Journal: JAMA Oncology (2024)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Multi-biobank summary data Mendelian randomisation does not support a causal effect of IL-6 signalling on risk of pulmonary arterial hypertension
Authors: Benjamin Woolf, James A. Perry, Charles C. Hong, Martin R. Wilkins, Mark Toshner, Dipender Gill, Stephen Burgess, Christopher J. Rhodes
Journal: European Respiratory Journal (2024)

Interleukin-6 (IL-6) has been linked with the pathobiology of pulmonary arterial hypertension (PAH). IL-6 plasma levels are elevated in PAH patients and closely linked to survival (1). Both increased IL-6 activity and gene knockout influence the development of, and resistance to, pulmonary hypertension in animal models (2–4). IL-6 can repress expression of BMPR2, a gene key to PAH risk (5). Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflicts of interests: The authors declare no conflicts of interest.
Endothelial POFUT1 controls injury-induced liver fibrosis by repressing fibrinogen synthesis
Authors: Shan He, Yuru Luo, Wangge Ma, Xiaoke Wang, Chengrong Yan, Wenyang Hao, Yuan Fang, Hongyu Su, Baochang Lai, Junhui Liu, Ying Xiong, Ting Bai, Xiaoyong Ren, Enqi Liu, Hua Han, Yue Wu, Zuyi Yuan, Yidong Wang
Journal: Journal of Hepatology (2024)

Background & AimsNOTCH signaling in liver sinusoidal endothelial cells (LSECs) regulates liver fibrosis, a pathological feature of chronic liver diseases. POFUT1 is an essential regulator of NOTCH signaling. Here, we investigated the role of LSECs-expressed POFUT1 in liver fibrosis.MethodsEndothelial-specific Pofut1 knockout mice were generated and subjected to experimental liver fibrosis by chronic carbon tetrachloride exposure or by common bile duct ligation. Liver samples were assessed by ELISA, histology, electron microscopy, immunostaining and RNA in situ hybridization. LSECs and hepatic stellate cells (HSCs) were isolated for gene expression analysis by RNA-seq, qPCR, and Western blotting. Signaling crosstalk between LSECs and HSCs was investigated by treating HSCs with supernatant from LSECs cultures. Liver single-cell RNA-seq data sets from cirrhotic patients and healthy individuals were analyzed to evaluate the clinical relevance of gene expression changes observed in mouse studies.ResultsPOFUT1 loss promoted injury-induced LSECs capillarization and HSC activation, leading to aggravated liver fibrosis. RNA-seq analysis revealed that POFUT1 deficiency upregulated fibrinogen expression in LSECs. Consistently, fibrinogen was elevated in LSECs of cirrhotic patients. HSCs treated with supernatant from LSECs of Pofut1 null mice showed exacerbated activation compared to treatment with supernatant from control LSECs, and this effect was attenuated by knockdown of fibrinogen or by pharmacological inhibition of fibrinogen receptor signaling, altogether suggesting that LSEC-derived fibrinogen induced the activation of HSCs. Mechanistically, POFUT1 loss augmented fibrinogen expression by enhancing NOTCH/HES1/STAT3 signaling.ConclusionsEndothelial POFUT1 prevents injury-induced liver fibrosis by repressing the expression of fibrinogen which function as a profibrotic paracrine signal to activate HSCs. Therapies targeting the POFUT1/NOTCH/HES1/STAT3/fibrinogen axis offer a promising strategy for the prevention and treatment of fibrotic liver diseases.
DNA topoisomerase II inhibition potentiates osimertinib’s therapeutic efficacy in EGFR-mutant non–small cell lung cancer models
Authors: Zhen Chen, Karin A. Vallega, Dongsheng Wang, Zihan Quan, Songqing Fan, Qiming Wang, Ticiana Leal, Suresh S. Ramalingam, Shi-Yong Sun
Journal: Journal of Clinical Investigation (2024)

Development of effective strategies to manage the inevitable acquired resistance to osimertinib, an approved 3rd generation EGFR inhibitor for the treatment of EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC), is urgently needed. This study reported that the DNA topoisomerase II (Topo II) inhibitors, doxorubicin and etoposide (VP-16) synergistically decreased cell survival with enhanced induction of DNA damage and apoptosis in osimertinib-resistant cells, suppressed the growth of osimertinib-resistant tumors, and delayed the emergence of osimertinib acquired resistance. Mechanistically, osimertinib decreased Topo IIα levels in EGFRm NSCLC cells by facilitating FBXW7-mediated proteasomal degradation, resulting in induction of DNA damage; these effects were lost in osimertinib-resistant cell lines possessing elevated levels of Topo IIα. Topo IIα elevation was also detected in the majority of EGFRm NSCLC tissues relapsed from EGFR-TKI treatment. Enforced expression of an ectopic TOP2A gene in sensitive EGFRm NSCLC cells conferred resistance to osimertinib, whereas knockdown of TOP2A in osimertinib-resistant cell lines restored their response to undergo osimertinib-induced DNA damage and apoptosis. Together, these results reveal an essential role of Topo IIα inhibition in mediating the therapeutic efficacy of osimertinib against EGFRm NSCLC, providing scientific rationale for targeting Topo II to manage acquired resistance to osimertinib.
Targeting CCL2/CCR2 Signaling Overcomes MEK Inhibitor Resistance in Acute Myeloid Leukemia
Authors: Rucha V. Modak, Katia G. de Oliveira Rebola, John McClatchy, Mona Mohammadhosseini, Alisa Damnernsawad, Stephen E. Kurtz, Christopher A. Eide, Guanming Wu, Ted Laderas, Tamilla Nechiporuk, Marina A. Gritsenko, Joshua R. Hansen, Chelsea Hutchinson, Sara J.C. Gosline, Paul Piehowski, Daniel Bottomly, Nicholas Short, Karin Rodland, Shannon K. McWeeney, Jeffrey W. Tyner, Anupriya Agarwal
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Emerging evidence underscores the critical role of extrinsic factors within the microenvironment in protecting leukemia cells from therapeutic interventions, driving disease progression, and promoting drug resistance in acute myeloid leukemia (AML). This finding emphasizes the need for the identification of targeted therapies that inhibit intrinsic and extrinsic signaling to overcome drug resistance in AML. Experimental Design: We performed a comprehensive analysis utilizing a cohort of ∼300 AML patient samples. This analysis encompassed the evaluation of secreted cytokines/growth factors, gene expression, and ex vivo drug sensitivity to small molecules. Our investigation pinpointed a notable association between elevated levels of CCL2 and diminished sensitivity to the MEK inhibitors (MEKi). We validated this association through loss-of-function and pharmacologic inhibition studies. Further, we deployed global phosphoproteomics and CRISPR/Cas9 screening to identify the mechanism of CCR2-mediated MEKi resistance in AML. Results: Our multifaceted analysis unveiled that CCL2 activates multiple prosurvival pathways, including MAPK and cell-cycle regulation in MEKi-resistant cells. Employing combination strategies to simultaneously target these pathways heightened growth inhibition in AML cells. Both genetic and pharmacologic inhibition of CCR2 sensitized AML cells to trametinib, suppressing proliferation while enhancing apoptosis. These findings underscore a new role for CCL2 in MEKi resistance, offering combination therapies as an avenue to circumvent this resistance. Conclusions: Our study demonstrates a compelling rationale for translating CCL2/CCR2 axis inhibitors in combination with MEK pathway-targeting therapies, as a potent strategy for combating drug resistance in AML. This approach has the potential to enhance the efficacy of treatments to improve AML patient outcomes.
GBA1 inactivation in oligodendrocytes affects myelination and induces neurodegenerative hallmarks and lipid dyshomeostasis in mice
Authors: Ilaria Gregorio, Loris Russo, Enrica Torretta, Pietro Barbacini, Gabriella Contarini, Giada Pacinelli, Dario Bizzotto, Manuela Moriggi, Paola Braghetta, Francesco Papaleo, Cecilia Gelfi, Enrico Moro, Matilde Cescon
Journal: Molecular Neurodegeneration (2024)

Abstract Background Mutations in the β-glucocerebrosidase ( GBA1 ) gene do cause the lysosomal storage Gaucher disease (GD) and are among the most frequent genetic risk factors for Parkinson’s disease (PD). So far, studies on both neuronopathic GD and PD primarily focused on neuronal manifestations, besides the evaluation of microglial and astrocyte implication. White matter alterations were described in the central nervous system of paediatric type 1 GD patients and were suggested to sustain or even play a role in the PD process, although the contribution of oligodendrocytes has been so far scarcely investigated. Methods We exploited a system to study the induction of central myelination in vitro, consisting of Oli-neu cells treated with dibutyryl-cAMP, in order to evaluate the expression levels and function of β-glucocerebrosidase during oligodendrocyte differentiation. Conduritol-B-epoxide, a β-glucocerebrosidase irreversible inhibitor was used to dissect the impact of β-glucocerebrosidase inactivation in the process of myelination, lysosomal degradation and α-synuclein accumulation in vitro. Moreover, to study the role of β-glucocerebrosidase in the white matter in vivo, we developed a novel mouse transgenic line in which β-glucocerebrosidase function is abolished in myelinating glia, by crossing the Cnp1-cre mouse line with a line bearing loxP sequences flanking Gba1 exons 9–11, encoding for β-glucocerebrosidase catalytic domain. Immunofluorescence, western blot and lipidomic analyses were performed in brain samples from wild-type and knockout animals in order to assess the impact of genetic inactivation of β-glucocerebrosidase on myelination and on the onset of early neurodegenerative hallmarks, together with differentiation analysis in primary oligodendrocyte cultures. Results Here we show that β-glucocerebrosidase inactivation in oligodendrocytes induces lysosomal dysfunction and inhibits myelination in vitro. Moreover, oligodendrocyte-specific β-glucocerebrosidase loss-of-function was sufficient to induce in vivo demyelination and early neurodegenerative hallmarks, including axonal degeneration, α-synuclein accumulation and astrogliosis, together with brain lipid dyshomeostasis and functional impairment. Conclusions Our study sheds light on the contribution of oligodendrocytes in GBA1-related diseases and supports the need for better characterizing oligodendrocytes as actors playing a role in neurodegenerative diseases, also pointing at them as potential novel targets to set a brake to disease progression.
Neutralizing IgG4 antibodies are a biomarker of sustained efficacy after peanut oral immunotherapy
Authors: Tarun Keswani, Nicole A. LaHood, Orlee Marini-Rapoport, Bijoya Karmakar, Léna Andrieux, Brian Reese, Sunny L. Sneed, Lars C. Pedersen, Geoffrey A. Mueller, Sarita U. Patil
Journal: Journal of Allergy and Clinical Immunology (2024)
Efficacy and Safety of Radiotherapy Plus Relugolix in Men With Localized or Advanced Prostate Cancer
Authors: Daniel E. Spratt, Daniel J. George, Neal D. Shore, Michael S. Cookson, Daniel R. Saltzstein, Ronald Tutrone, Alberto Bossi, Bruce A. Brown, Sophia Lu, Mark Fallick, Sarah Hanson, Bertrand F. Tombal
Journal: JAMA Oncology (2024)

Combination androgen deprivation therapy (ADT) with radiotherapy is commonly used for patients with localized and advanced prostate cancer.
Van Gogh-like 2 is essential for the architectural patterning of the mammalian biliary tree
Authors: Michaela Raab, Ersi Christodoulou, Roopesh Krishnankutty, Andreea Gradinaru, Alexander Daniel Walker, Paula Olaizola, Nicholas Thomas Younger, Anabel Martinez Lyons, Edward Joseph Jarman, Konstantinos Gournopanos, Alexander von Kriegsheim, Scott Hamilton Waddell, Luke Boulter
Journal: Journal of Hepatology (2024)

In the developing liver, bipotent epithelial progenitor cells undergo lineage segregation to form hepatocytes, which constitute the bulk of the liver parenchyma, and biliary epithelial cells (cholangiocytes), which comprise the bile duct (a complex tubular network that is critical for normal liver function). Notch and TGFβ signalling promote the formation of a sheet of biliary epithelial cells, the ductal plate, that organises into discontinuous tubular structures. How these structures elongate and connect to form a continuous duct remains undefined. We aimed to define the mechanisms by which the ductal plate transitions from a simple sheet of epithelial cells into a complex and connected bile duct.
An in vivo screening platform identifies senolytic compounds that target p16INK4a+ fibroblasts in lung fibrosis
Authors: Jin Young Lee, Nabora S. Reyes, Supriya Ravishankar, Minqi Zhou, Maria Krasilnikov, Christian Ringler, Grace Pohan, Chris Wilson, Kenny Kean-Hooi Ang, Paul J. Wolters, Tatsuya Tsukui, Dean Sheppard, Michelle R. Arkin, Tien Peng
Journal: Journal of Clinical Investigation (2024)

The appearance of senescent cells in age-related diseases has spurred the search for compounds that can target senescent cells in tissues ("senolytics"). However, a major caveat with current senolytic screens is the use of cell lines as targets where senescence is induced in vitro, which does not necessarily reflect the identity and function of pathogenic senescent cells in vivo. Here, we developed a new pipeline leveraging a fluorescent murine reporter that allows for isolation and quantification of p16Ink4a+ cells in diseased tissues. By high-throughput screening in vitro, precision cut lung slice (PCLS) screening ex vivo, and phenotypic screening in vivo, we identified a HSP90 inhibitor (XL888) as a potent senolytic in tissue fibrosis. XL888 treatment eliminated pathogenic p16Ink4a+ fibroblasts in a murine model of lung fibrosis and reduced fibrotic burden. Finally, XL888 preferentially targeted p16INK4a-high human lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis (IPF), and reduced p16INK4a+ fibroblasts from IPF PCLS ex vivo. This study provides proof of concept for a platform where p16INK4a+ cells are directly isolated from diseased tissues to identify compounds with in vivo and ex vivo efficacy in mouse and human respectively and provides a senolytic screening platform for other age-related diseases.