tbuckley/cabot-search huggingface dataset:
Effects of trientine and penicillamine on intestinal copper uptake: A mechanistic 64Cu PET/CT study in healthy humans
Authors: Frederik Teicher Kirk, Ditte Emilie Munk, Eugene Scott Swenson, Adam Michael Quicquaro, Mikkel Holm Vendelbo, Michael L. Schilsky, Peter Ott, Thomas Damgaard Sandahl
Journal: Hepatology (2023)

Background and Aims: Trientine (TRI) and D-penicillamine (PEN) are used to treat copper overload in Wilson disease. Their main mode of action is thought to be through the facilitation of urinary copper excretion. In a recent study, TRI was noninferior to PEN despite lower 24-hour urinary copper excretion than PEN. We tested whether TRI and/or PEN also inhibit intestinal copper absorption. Approach and Results: Sixteen healthy volunteers were examined with positron emission tomography (PET)/CT 1 and 15 hours after an oral Copper-64 ( 64 Cu) dose. They then received 7 days of either PEN or TRI (trientine tetrahydrochloride), after which the 64 Cu PET/CT scans were repeated. Venous blood samples were also collected. Pretreatment to posttreatment changes of the hepatic 64 Cu uptake reflect the effect of drugs on intestinal absorption. 64 Cu activity was normalized to dose and body weight and expressed as the mean standard uptake value. TRI (n=8) reduced hepatic 64 Cu activity 1 hour after 64 Cu dose from 6.17 (4.73) to 1.47 (2.97) standard uptake value, p &lt;0.02, and after 15 hours from 14.24 (3.09) to 6.19 (3.43), p &lt;0.02, indicating strong inhibition of intestinal 64 Cu absorption. PEN (n=8) slightly reduced hepatic standard uptake value at 15 hours, from 16.30 (5.63) to 12.17 (1.44), p &lt;0.04. Conclusions: In this mechanistic study, we show that TRI inhibits intestinal copper absorption, in addition to its cupriuretic effect. In contrast, PEN has modest effects on the intestinal copper absorption. This may explain why TRI and PEN are equally effective although urinary copper excretion is lower with TRI. The study questions whether the same therapeutic targets for 24-hour urinary excretion apply to both drugs.
Optimizing infection control and antimicrobial stewardship bedside discussion: a scoping review of existing evidence on effective healthcare communication in hospitals
Authors: Candice Bonaconsa, Oluchi Mbamalu, Surya Surendran, Anu George, Marc Mendelson, Esmita Charani
Journal: Clinical Microbiology and Infection (2023)

ObjectivesThe link between healthcare worker (HCW) communication, teamwork and patient safety is well-established. Infection prevention and control (IPC) and antimicrobial stewardship (AMS) require multidisciplinary teamwork and communication. We conducted a scoping review of published evidence on effective mechanisms of HCW team communication in hospitals with the intention of transferring and tailoring learning to IPC and AMS team communication.MethodsPubMed, Scopus, Web of Science, and CINAHL were searched for studies that investigated HCW team communication across in-hospital patient pathways. Studies published between 2000 and 2021 that provided evidence on/or described the effect of communication on team and patient outcomes in hospital were included. Through a process of inductive qualitative content analysis, key themes in the included studies were identified.ResultsOf 537 studies identified, 53 (from high income countries) were included in the data extraction. Fifty one percent (27/53) of studies were conducted in high acuity settings e.g., intensive care units. Standardising or structuring the content and/or process of team communication was the most common goal of interventions (34/53,64%). The key outcome measures were either team communication focused (25/34,74%) or patient and process outcome focused (8/34,24%), such as reduced length of mechanical ventilation days, length of hospital stay, and shorter empiric antibiotic duration. Four studies (4/53,8%) associated improved communication with positive IPC and AMS outcome measures. Mixed method intervention studies primarily facilitated collaborative input from HCWs and applied structures to standardise the content of patient care discussions while observational studies describe component of team communication.ConclusionsA communication strategy that formalises input from multidisciplinary team members can lead to optimised and consistent clinical discussion including in IPC and AMS related care. While we were unable to assess the effectiveness of interventions, the existing evidence suggests that optimising team communication can have a positive effect on infection related patient outcomes.
Letter to the Editor: Diagnostic accuracy of AGILE 3+ score for advanced fibrosis in patients with NAFLD: A systematic review and meta-analysis
Authors: Hui Liu, Han Li, Dong-Xu Wang, Tao Li
Journal: Hepatology (2023)

To the editor, In recent years, noninvasive diagnostic techniques have been developed to diagnose fibrosis in patients with NAFLD, recently also known as metabolic dysfunction–associated steatotic liver disease (MASLD). The timely meta-analysis conducted by Dalbeni and colleagues revealed that AGILE 3+ accurately diagnoses NAFLD with advanced fibrosis.1 Although these findings are partially compatible with previous individual patient data meta-analysis, this study is currently the most methodological study.2 Some questions are discussed below. The authors need to provide a detailed search strategy for at least 1 database, such as PubMed. The authors did not search for the term "MASLD" because it is a recent nomenclature that was officially announced at the EASL Congress 2023. However, the term "metabolic dysfunction–associated fatty liver disease" has been used for many years and should be searched. In addition, this meta-analysis included a validation set from Sanyal et al's study3 but did not include a validation set from Tang et al4 (validation set consisted of 132 patients). AGILE 3+ and 4 are both novel noninvasive scores that increase accuracy in the identification of advanced fibrosis and cirrhosis in patients with MASLD, respectively (authors mistakenly referred to AGILE 4 as AGILE 4+). Although there was a lack of sufficient data to perform a meta-analysis of AGILE 4 in the past, it now seems achievable. To ascertain that no relevant studies were omitted from this meta-analysis, authors should update their search using the same databases, search terms, and inclusion criteria before submitting.5 Besides these, authors should maintain data uniformity and accuracy. For example, the prevalence of type 2 diabetes mellitus and the total number of participants included in this meta-analysis are inconsistent with the graphical abstract. This meta-analysis of the diagnostic accuracy of the AGILE 3+ score for advanced fibrosis in patients with NAFLD deserves to be updated. Subgroup analysis of diagnostic accuracy of AGILE 3+ score deserves to be investigated. It is necessary to conduct a network meta-analysis comparing different scores for diagnosing F3-F4 fibrosis (like AGILE 3+, fibrosis-4, aspartate aminotransferase to platelet ratio index, non-alcoholic fatty liver disease fibrosis score, and liver stiffness measurement). Results from well-designed prospective cohorts are still needed.
Preconception Phthalate Exposure and Women’s Reproductive Health: Pregnancy, Pregnancy Loss, and Underlying Mechanisms
Authors: Carrie J. Nobles, Pauline Mendola, Keewan Kim, Anna Z. Pollack, Sunni L. Mumford, Neil J. Perkins, Robert M. Silver, Enrique F. Schisterman
Journal: Environmental Health Perspectives (2023)

Phthalates are endocrine-disrupting chemicals linked to adverse pregnancy outcomes. Despite the sensitivity of female reproductive processes to oxidation–reduction reaction stress and endocrine disruption, evidence for the impact of women's phthalate exposure on the ability to establish and maintain pregnancy has been inconclusive.
Exploring Route-Specific Pharmacokinetics of PFAS in Mice by Coupling <i>in Vivo</i> Tests and Physiologically Based Toxicokinetic Models
Authors: Yumin Zhu, Xiaoyu Pan, Yibo Jia, Xin Yang, Xiaohua Song, Jiaqi Ding, Wenjue Zhong, Jianfeng Feng, Lingyan Zhu
Journal: Environmental Health Perspectives (2023)

Oral ingestion, inhalation, and skin contact are important exposure routes for humans to uptake per- and polyfluoroalkyl substances (PFAS). However, nasal and dermal exposure to PFAS remains unclear, and accurately predicting internal body burden of PFAS in humans via multiple exposure pathways is urgently required.
<i>IDH1</i>-Mutant Preleukemic Hematopoietic Stem Cells Can Be Eliminated by Inhibition of Oxidative Phosphorylation
Authors: Niklas Landberg, Thomas Köhnke, Yang Feng, Yusuke Nakauchi, Amy C. Fan, Miles H. Linde, Daiki Karigane, Kelly Lim, Rahul Sinha, Luca Malcovati, Daniel Thomas, Ravindra Majeti
Journal: Blood Cancer Discovery (2023)

Abstract Rare preleukemic hematopoietic stem cells (pHSC) harboring only the initiating mutations can be detected at the time of acute myeloid leukemia (AML) diagnosis. pHSCs are the origin of leukemia and a potential reservoir for relapse. Using primary human samples and gene editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show epigenetic, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSC). We confirm that IDH1-driven clonal hematopoiesis is associated with cytopenia, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation, blocked differentiation, downregulation of MHC class II genes, and reprogramming of oxidative phosphorylation metabolism. Critically, inhibition of oxidative phosphorylation resulted in the complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wild-type HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent the development and relapse of leukemia. Significance: A high burden of pHSCs is associated with worse overall survival in AML. Using single-cell sequencing, metabolic assessment, and gene-edited human models, we find human pHSCs with IDH1 mutations to be metabolically vulnerable and sensitive to eradication by complex I inhibition. See related commentary by Steensma, p. 83. This article is featured in Selected Articles from This Issue, p. 80
Irradiated engineered tumor cell-derived microparticles remodel the tumor immune microenvironment and enhance antitumor immunity
Authors: Yan Hu, Yajie Sun, Zhiyun Liao, Dandan An, Xixi Liu, Xiao Yang, Yu Tian, Suke Deng, Jingshu Meng, Yijun Wang, Jie Li, Yue Deng, Zhiyuan Zhou, Qinyan Chen, Ying Ye, Wenwen Wei, Bian Wu, Jonathan F. Lovell, Honglin Jin, Fang Huang, Chao Wan, Kunyu Yang
Journal: Molecular Therapy (2023)
Benign Breast Disease and Breast Cancer Risk in the Percutaneous Biopsy Era
Authors: Mark E. Sherman, Robert A. Vierkant, Stacey J. Winham, Celine M. Vachon, Jodi M. Carter, Laura Pacheco-Spann, Matthew R. Jensen, Bryan M. McCauley, Tanya L. Hoskin, Lisa Seymour, Denice Gehling, Jessica Fischer, Karthik Ghosh, Derek C. Radisky, Amy C. Degnim
Journal: JAMA Surgery (2023)

Benign breast disease (BBD) comprises approximately 75% of breast biopsy diagnoses. Surgical biopsy specimens diagnosed as nonproliferative (NP), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH) are associated with increasing breast cancer (BC) risk; however, knowledge is limited on risk associated with percutaneously diagnosed BBD.
The Evolving Era of Breast Cancer Risk Assessment in Benign Breast Disease
Authors: Juliet C. Dalton, Akiko Chiba, Jennifer K. Plichta
Journal: JAMA Surgery (2023)

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 Surgery 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 Surgery journal
A Dysfunctional T-cell Gene Signature for Predicting Nonresponse to PD-1 Blockade in Non–small Cell Lung Cancer That Is Suitable for Routine Clinical Diagnostics
Authors: Karlijn Hummelink, Renaud Tissier, Linda J.W. Bosch, Oscar Krijgsman, Michel M. van den Heuvel, Willemijn S.M.E. Theelen, Diane Damotte, François Goldwasser, Karen Leroy, Egbert F. Smit, Gerrit A. Meijer, Daniela S. Thommen, Kim Monkhorst
Journal: Clinical Cancer Research (2023)

Because PD-1 blockade is only effective in a minority of patients with advanced-stage non-small cell lung cancer (NSCLC), biomarkers are needed to guide treatment decisions. Tumor infiltration by PD-1T tumor-infiltrating lymphocytes (TIL), a dysfunctional TIL pool with tumor-reactive capacity, can be detected by digital quantitative IHC and has been established as a novel predictive biomarker in NSCLC. To facilitate translation of this biomarker to the clinic, we aimed to develop a robust RNA signature reflecting a tumor's PD-1T TIL status.
Deep Brain Stimulation Might Improve Cognition Years After TBI
Authors: Emily Harris
Journal: JAMA (2023)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Effect of Ziltivekimab on Determinants of Hemoglobin in Patients with CKD Stage 3–5: An Analysis of a Randomized Trial (RESCUE)
Authors: Pablo E. Pergola, Michael Davidson, Camilla Jensen, Amir A. Mohseni Zonoozi, Dominic S. Raj, Philip Andreas Schytz, Katherine R. Tuttle, Vlado Perkovic
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Systemic inflammation in CKD can lead to anemia. Ziltivekimab, a fully human monoclonal antibody targeting the IL-6 ligand, has been shown to reduce systemic inflammation in patients with CKD. It has also been shown to increase serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to treatment with erythropoiesis-stimulating agents. This exploratory analysis of the RESCUE clinical trial found that among patients with CKD stage 3–5 and systemic inflammation, ziltivekimab treatment significantly increased hemoglobin (Hb) levels after 12 weeks compared with placebo. Ziltivekimab was also associated with significant increases in serum iron levels, total iron-binding capacity, and transferrin saturation. No major safety concerns were reported. Further clinical trials are warranted to study ziltivekimab's potential for anemia management in patients with CKD. Background In the phase 2 RESCUE clinical trial, ziltivekimab, a fully human monoclonal antibody against the IL-6 ligand, significantly reduced the biomarkers of inflammation compared with placebo, in patients with CKD and systemic inflammation (high-sensitivity C-reactive protein ≥2 mg/L). The aim of this subanalysis of RESCUE trial data was to assess the effect of ziltivekimab on Hb and iron homeostasis in this patient population. Methods This was an analysis of exploratory end points from the RESCUE trial (NCT03926117), which included 264 adults with CKD stage 3–5 and high-sensitivity C-reactive protein ≥2 mg/L. Participants received placebo or subcutaneous ziltivekimab (7.5, 15, or 30 mg) (1:1:1:1) once every 4 weeks, up to 24 weeks. End points for this analysis were changes in Hb and biomarkers of iron homeostasis from baseline to week 12. Results The trial was terminated early due to the coronavirus disease 2019 pandemic, and thus, data up to week 12 are presented. Hb levels significantly increased from baseline to week 12 with ziltivekimab 7.5, 15, and 30 mg (treatment differences versus placebo: +0.57 g/dl [95% confidence interval, 0.27 to 0.86], +1.05 g/dl [0.76 to 1.33], and +0.99 g/dl [0.70 to 1.28], respectively, all P &lt; 0.001). Ziltivekimab was associated with significant increases in serum iron levels, total iron-binding capacity, and transferrin saturation from baseline to week 12 ( P &lt; 0.05 versus placebo for all doses and comparisons). Cases of sustained thrombocytopenia, sustained neutropenia, anemia, and iron deficiency anemia were infrequent and similar across all groups. Conclusions Anti-inflammatory therapy with ziltivekimab improved the markers of anemia and iron homeostasis in people with stage 3–5 CKD and systemic inflammation, suggesting a possible role in anemia management.
Multipotent progenitors instruct ontogeny of the superior colliculus
Authors: Giselle Cheung, Florian M. Pauler, Peter Koppensteiner, Thomas Krausgruber, Carmen Streicher, Martin Schrammel, Natalie Gutmann-Özgen, Alexis E. Ivec, Christoph Bock, Ryuichi Shigemoto, Simon Hippenmeyer
Journal: Neuron (2023)

The superior colliculus (SC) in the mammalian midbrain is essential for multisensory integration and is composed of a rich diversity of excitatory and inhibitory neurons and glia. However, the developmental principles directing the generation of SC cell-type diversity are not understood. Here, we pursued systematic cell lineage tracing in silico and in vivo, preserving full spatial information, using genetic mosaic analysis with double markers (MADM)-based clonal analysis with single-cell sequencing (MADM-CloneSeq). The analysis of clonally related cell lineages revealed that radial glial progenitors (RGPs) in SC are exceptionally multipotent. Individual resident RGPs have the capacity to produce all excitatory and inhibitory SC neuron types, even at the stage of terminal division. While individual clonal units show no pre-defined cellular composition, the establishment of appropriate relative proportions of distinct neuronal types occurs in a PTEN-dependent manner. Collectively, our findings provide an inaugural framework at the single-RGP/-cell level of the mammalian SC ontogeny.
Advances in the management of pancreatic cancer
Authors: Marco Del Chiaro, Toshitaka Sugawara, Sana D Karam, Wells A Messersmith
Journal: BMJ (2023)

Abstract Pancreatic cancer remains among the malignancies with the worst outcomes. Survival has been improving, but at a slower rate than other cancers. Multimodal treatment, including chemotherapy, surgical resection, and radiotherapy, has been under investigation for many years. Because of the anatomical characteristics of the pancreas, more emphasis on treatment selection has been placed on local extension into major vessels. Recently, the development of more effective treatment regimens has opened up new treatment strategies, but urgent research questions have also become apparent. This review outlines the current management of pancreatic cancer, and the recent advances in its treatment. The review discusses future treatment pathways aimed at integrating novel findings of translational and clinical research.
Plasticity of intragraft alloreactive T cell clones in human gut correlates with transplant outcomes
Authors: Jianing Fu, Zicheng Wang, Mercedes Martinez, Aleksandar Obradovic, Wenyu Jiao, Kristjana Frangaj, Rebecca Jones, Xinzheng V. Guo, Ya Zhang, Wan-I Kuo, Huaibin M. Ko, Alina Iuga, Constanza Bay Muntnich, Adriana Prada Rey, Kortney Rogers, Julien Zuber, Wenji Ma, Michelle Miron, Donna L. Farber, Joshua Weiner, Tomoaki Kato, Yufeng Shen, Megan Sykes
Journal: The Journal of Experimental Medicine (2023)

The site of transition between tissue-resident memory (TRM) and circulating phenotypes of T cells is unknown. We integrated clonotype, alloreactivity, and gene expression profiles of graft-repopulating recipient T cells in the intestinal mucosa at the single-cell level after human intestinal transplantation. Host-versus-graft (HvG)–reactive T cells were mainly distributed to TRM, effector T (Teff)/TRM, and T follicular helper compartments. RNA velocity analysis demonstrated a trajectory from TRM to Teff/TRM clusters in association with rejection. By integrating pre- and post-transplantation (Tx) mixed lymphocyte reaction–determined alloreactive repertoires, we observed that pre-existing HvG-reactive T cells that demonstrated tolerance in the circulation were dominated by TRM profiles in quiescent allografts. Putative de novo HvG-reactive clones showed a transcriptional profile skewed to cytotoxic effectors in rejecting grafts. Inferred protein regulon network analysis revealed upstream regulators that accounted for the effector and tolerant T cell states. We demonstrate Teff/TRM interchangeability for individual T cell clones with known (allo)recognition in the human gut, providing novel insight into TRM biology.
Cas9-induced targeted integration of large DNA payloads in primary human T cells via homology-mediated end-joining DNA repair
Authors: Beau R. Webber, Matthew J. Johnson, Joseph G. Skeate, Nicholas J. Slipek, Walker S. Lahr, Anthony P. DeFeo, Lauren J. Mills, Xiaohong Qiu, Blaine Rathmann, Miechaleen D. Diers, Bryce Wick, Tom Henley, Modassir Choudhry, Timothy K. Starr, R. Scott McIvor, Branden S. Moriarity
Journal: Nature Biomedical Engineering (2023)
A chromatin-regulated biphasic circuit coordinates IL-1β-mediated inflammation
Authors: Ezio T. Fok, Simone J. C. F. M. Moorlag, Yutaka Negishi, Laszlo A. Groh, Jéssica Cristina dos Santos, Cathrin Gräwe, Valerie Villacorta Monge, Daphne D. D. Craenmehr, Mellanie van Roosmalen, David Pablo da Cunha Jolvino, Letícia Busato Migliorini, Ary Serpa Neto, Patricia Severino, Michiel Vermeulen, Leo A. B. Joosten, Mihai G. Netea, Stephanie Fanucchi, Musa M. Mhlanga
Journal: Nature Genetics (2023)
Reply to: “5-MTHF enhances the portal pressure reduction achieved with propranolol in patients with cirrhosis: A randomized placebo-controlled trial. Was an accurate statistical analysis performed?”
Authors: Ranka Vukotic, Roberto Di Donato, Jaime Bosch, Pietro Andreone
Journal: Journal of Hepatology (2023)

We thank Dr Fernandez-Garza for his interest in our work and for his comments on the statistical analysis. He underlines that our intention-to-treat analysis (ITT) did not include all planned randomized patients (30 per group) and that we do not explain why.1 We would like to clarify this point.