tbuckley/cabot-search huggingface dataset:
Environmental and Health Care Personnel Sampling and Unobserved <i>Clostridium difficile</i> Transmission in ICU
Authors: Lindsay T. Keegan, Windy Tanner, Brian Orleans, Rachel B. Slayton, John A. Jernigan, L. Clifford McDonald, Judith Noble-Wang, Molly Leecaster, Candace Haroldsen, Karim Khader, Damon J.A. Toth, Tierney O’Sullivan, Matthew H. Samore, William Brazelton, Michael Rubin
Journal: JAMA Network Open (2025)

Importance Clostridioides difficile is among the most prevalent health care–associated pathogens worldwide. Controlling it remains a critical challenge, due in part to spore viability on surfaces. Objective To quantify transmission of C difficile within health care facilities and evaluate the roles of environmental surfaces and health care personnel (HCP) hands in C difficile movement. Design, Setting, and Participants In 2018, a 13-week longitudinal, observational study was conducted in 2 intensive care units (ICUs) in Utah with daily culture-based sampling of patient body sites, room environmental surfaces, HCP hands, and shared environmental surfaces. Both toxigenic and nontoxigenic C difficile strains were selected for whole genome sequencing and included in the analysis. Data were analyzed from September 2021 to September 2024. Main Outcomes and Measures The primary outcome was the identification of transmission clusters based on genomic relatedness between isolates from patients, environmental surfaces, and HCP hands. Clusters were defined as isolates with 2 or fewer single nucleotide variants between them. Results Of the 278 unique ICU admissions, 177 patients consented to body site sampling and were sampled. Along with these, environment surfaces and HCP hands were sampled daily for all occupied rooms, leading to 7000 total samples. Sampling patients, their environment, and HCP hands revealed that nearly 8% of all patients had C difficile linked to other admissions and 57% of transmission clusters bridged nonoverlapping patient-stays. Including environmental surfaces and HCP hands, a 3.6-fold higher C difficile movement was identified than with patient sampling alone, highlighting environmental surfaces as reservoirs. Conclusions and Relevance These results challenge the idea that nosocomial transmission is not a primary source of acquisition and underscore the importance of hand hygiene and environmental decontamination. This study reinforces the need to include environmental surfaces and HCP hands in future work characterizing the burden of nosocomial transmission. Understanding the transmission pathways of C difficile within health care facilities, particularly the roles of environmental surfaces and HCP hands, is critical to improving infection control measures.
Gender Inequity in Institutional Leadership Roles in US Academic Medical Centers
Authors: Morgan S. Levy, Kelby N. Hunt, Kara A. Lindsay, Vikasni Mohan, Alyssa Mercadel, Eileen Malecki, Radhika Desai, Barbara M. Sorondo, Asha Pillai, Marilyn Huang
Journal: JAMA Network Open (2025)

Importance Academic medical centers have focused their efforts on promoting gender equity in recent years, but the positive outcomes associated with those efforts remain to be seen in recruiting and retaining diverse institutional leadership. Objective To evaluate the current state of gender inequity in institutional leadership roles, such as deans, department chairs, and residency and fellowship program directors, at US academic medical centers. Evidence Review A search for articles published from January 1, 2019, to August 5, 2022, on gender inequity in institutional leadership roles at academic medical centers was performed using the PubMed, CINAHL, and ERIC databases. Studies were screened for inclusion by sets of 2 independent reviewers (with disagreements resolved by a third reviewer) and evaluated for risk of bias. The Methodological Expectations of Cochrane Intervention Reviews Standards were followed for conducting the review, and the Preferred Reporting of Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) reporting guideline was followed for reporting results. Findings A total of 8120 articles were retrieved, of which 6368 were screened by title and abstract, 6166 were excluded, and 202 underwent full-text review. Ultimately, 94 studies reported on institutional leadership roles, including deans (5 studies [5.3%]), department chairs (39 studies [41.5%]), division chiefs (25 studies [26.6%]), and program directors (67 studies [71.3%]), with some overlap. A total of 678 participants were deans (564 men [80.5%] and 132 women [19.5%]), 8518 were department chairs (7160 men [84.1%] and 1358 women [15.9%]), 3734 division chiefs (2997 men [80.3%] and 737 women [19.7%]), and 9548 program directors (7455 men [78.1%] and 2093 women [21.9%]). Even in specialties with 50% or more female faculty, none had equal representation of women as department chairs and division chiefs. Gender inequities were particularly pronounced in surgical specialties. Conclusions and Relevance This systematic scoping review suggests that even though emphasis has been placed on addressing gender inequities in academic medicine, considerable disparities remain at the leadership level. While certain positions and specialties have been observed to have more female leaders, niches of academic medicine almost or completely exclude women from their leadership ranks. Importantly, even female-dominated specialties, such as obstetrics and gynecology, have substantial inequity in leadership roles. It is past time for organizational and systems-level changes to ensure equitable gender representation in academic leadership.
Hepatocyte Toll‐like receptors contribute to the hepcidin inflammatory response to pathogens and pathogen‐derived ligands
Authors: Katharina Bonitz, Silvia Colucci, Ruiyue Qiu, Sandro Altamura, Richard Sparla, Katja Mudder, Stefan Zimmermann, Matthias W. Hentze, Martina U. Muckenthaler, Oriana Marques
Journal: HemaSphere (2025)

Abstract Iron restriction is a critical pathomechanism underlying the Anemia of Inflammation and an innate immune response limiting the replication of extracellular pathogens. During infections, innate immune cells detect pathogen‐associated molecular patterns (PAMPs) and produce proinflammatory cytokines. Among these, interleukin (IL)‐6 is detected by hepatocytes, where it activates the production of the iron‐regulated hormone hepcidin that inhibits iron export from macrophages. Consequently, macrophages accumulate iron and hypoferremia (low plasma iron) develops. Whether Toll‐like receptors (TLRs) expressed on hepatocytes directly recognize PAMPs and contribute to hepcidin upregulation is still an open question. Stimulation of primary murine hepatocytes with a panel of PAMPs targeting TLRs 1–9 revealed that the TLR5 ligand flagellin and the TLR2:TLR6 ligand FSL1 upregulated hepcidin. Hepcidin was also induced upon treatment with heat‐killed Staphylococcus aureus (HKSA) and Brucella abortus (HKBA). The hepcidin response to flagellin, FSL1, HKSA, and HKBA started at an early time point, was independent of autocrine regulation by IL‐6, and occurred through the TLR‐mitogen‐activated protein kinase (MAPK) axis. By analyzing a macrophage:hepatocyte co‐culture, we additionally show that the hepcidin response was dependent on TLR2:TLR6 expression in hepatocytes and independent of macrophage cytokine secretion. Ex vivo liver perfusion of mice with FSL1 and HKSA further revealed that PAMPs and pathogens can pass the sinusoidal barrier and reach hepatocytes to cause hepcidin upregulation in a TLR2:TLR6‐dependent manner. We conclude that hepatocytes can directly recognize PAMPs and pathogens and promote hepcidin upregulation in a macrophage and cytokine‐independent manner. This positions hepatocytes in the spotlight as potential direct drivers of iron restriction.
Simulators and training models for diagnostic and therapeutic gastrointestinal endoscopy: European Society of Gastrointestinal Endoscopy (ESGE) Technical and Technology Review
Authors: Ian M. Gralnek, Lorenzo Fuccio, Chiara Coluccio, Jérémie Jacques, Istvan Hritz, Ivo Boskoski, Mohamed Abdelrahim, Vincenzo Bove, João A. Cunha Neves, Pieter J. F. de Jonge, Giuseppe Dell’Anna, Gianluca Esposito, Antonio Facciorusso, Rodica Gincul, Paolo Giuffrida, Rakesh Kalapala, Christina Kapizioni, Gaius Longcroft-Wheaton, Sandra Nagl, Georgios Tziatzios, Theodor Voiosu, Xavier Dray, Bridget Barbieri
Journal: Endoscopy (2025)

Abstract Gastrointestinal (GI) endoscopy comprises both diagnostic and therapeutic procedures involving the luminal GI tract as well as the biliary tree, liver, and pancreas. GI endoscopy is challenging to learn, requiring both cognitive (nontechnical) and technical skills, and requires extensive practice to attain proficiency. Simulation-based training has been shown to assist trainees and young endoscopists in acquiring new skills and accelerating the learning curve. Moreover, simulation-based training creates an ideal environment for trainees to initially learn and practice skills while making mistakes with no risk to patients. This review, divided in two parts, offers a comprehensive summary of the different classes of simulators available for GI endoscopic training. In Part I, only mechanical simulators are reported and described. In Part II, animal simulators (ex vivo/in vivo) and virtual reality models are detailed, together with prototypes that are currently not commercially available.
Effect of gastric bypass versus sleeve gastrectomy on the remission of type 2 diabetes, weight loss, and cardiovascular risk factors at 5 years (Oseberg): secondary outcomes of a single-centre, triple-blind, randomised controlled trial
Authors: Jostein Wågen Hauge, Heidi Borgeraas, Kåre Inge Birkeland, Line Kristin Johnson, Jens Kristoffer Hertel, Milada Hagen, Hanne Løvdal Gulseth, Morten Lindberg, Jolanta Lorentzen, Birgitte Seip, Ronette L Kolotkin, Marius Svanevik, Tone Gretland Valderhaug, Rune Sandbu, Jøran Hjelmesæth, Dag Hofsø
Journal: The Lancet Diabetes & Endocrinology (2025)
Cytochrome P450 <i>2C19</i> Genotypes and Clopidogrel in Patients With Ischemic Stroke
Authors: Yo Han Jung, Tae-Jin Song, Jinkwon Kim, Hee-Kwon Park, Sang Won Han, Young Dae Kim, Jong-Ho Park, Jae-Kwan Cha, Hyun Young Park, Sung-Il Sohn, Sungwook Yu, Jun Hong Lee, Dong Hoon Shin, Eung-Gyu Kim, Hye Sun Lee, Kyung-Yul Lee, Sang-Jun Ahn, Won Chul Shin, Sung-Hun Kim, Yang-Ha Hwang, Sung-Hyuk Heo, Chi-Kyung Kim, Jin-Man Jung, Bon-Koo Yoo, Jong-Yoon Lee, Ki-Chul Park, Beom Joon Kim, Han-Young Jung, Tae-Hwan Park, Jae-Kook Kim, Man-Seok Park, Sung-Hwan Ahn, Kwang-Yeol Park, Ye-Rim Kim, Chul-Ho Kim, Hyung-Young Kim
Journal: JAMA Network Open (2025)

Importance Cytochrome P450 2C19 ( CYP2C19 ) genotypes influence the antiplatelet effectiveness of clopidogrel by affecting its conversion to its active metabolite. However, evidence from prospective trials regarding the effects of CYP2C19 genotypes on the role of clopidogrel preventing cardiovascular events among patients with acute ischemic stroke remains limited. Objective To investigate the association of the CYP2C19 genotypes with the clinical prognosis of patients with acute ischemic stroke treated with clopidogrel. Design, Setting, and Participants A prospective, nonrandomized clinical trial was conducted from September 1, 2019, to January 27, 2023, at 37 clinical sites in South Korea. Patients who received clopidogrel within 72 hours of experiencing an acute ischemic stroke were included. Interventions Patients were classified using CYP2C19 genotyping into carrier and noncarrier of CYP2C19 loss-of-function (LOF) allele. Clopidogrel treatment was maintained throughout the study period. Main Outcomes and Measures The primary outcome was the difference in the risk of cardiovascular events (including ischemic or hemorrhagic stroke, myocardial infarction, or cardiovascular death) within 6 months after an ischemic stroke between patients who were carriers or noncarriers of the CYP2C19 LOF allele. The primary safety outcomes were the differences in all-cause mortality and the occurrence of major bleeding. Intention-to-treat analysis was performed. Results Overall, 2925 patients were enrolled in the PLATELET trial. The mean (SD) age of the participants was 65.3 (12.4) years, and 1928 (66.3%) were men. Among these patients, 15 were excluded. Of the remaining 2910 patients, 61.3% were classified as poor or intermediate metabolizers and 38.7% as extensive metabolizers. The primary outcome occurred more frequently in carriers of the LOF CYP2C19 allele than in noncarriers (2.7% [49 of 1785] vs 1.6% [18 of 1125]; log-rank P = .048). No significant differences were observed between CYP2C19 LOF allele carriers and noncarriers regarding the occurrence of major bleeding (0.6% [11 of 1785] vs 0.8% [9 of 1125]; P = .56) and all-cause mortality (0.3% [5] vs 0.1% [1]; P = .27). Conclusions and Relevance In this prospective nonrandomized clinical trial, carriers of the CYP2C19 LOF allele genotype exhibited a higher likelihood of experiencing cardiovascular events. Trial Registration ClinicalTrials.gov Identifier: NCT04072705
The weight of air: a Commission on palliative care integration in serious respiratory illness
Authors: William E Rosa, Afsan Bhadelia, Gemma Bowsher, Mark Dransfield, Anand S Iyer, Felicia Marie Knaul, Kathleen Lindell, Matthew Maddocks, Christian Ntizimira, Obianuju Ozoh, Pedro E Pérez-Cruz, Lukas Radbruch, Smriti Rana, Anne-Marie Russell, Mac Skelton, Natasha Smallwood, Samuel Byiringiro, Jeffersson Santos, Donald R Sullivan
Journal: The Lancet Respiratory Medicine (2025)
The promise and compromise of the WHO Pandemic Agreement for spillover prevention and One Health
Authors: Alexandra Finch, Neil M Vora, Latiffah Hassan, Chris Walzer, Raina K Plowright, Robyn Alders, Chyna Yong Suit-B, John H Amuasi, Moses Mulumba, Ted Loch-Temzelides, Sergio Guerrero-Sanchez, Lawrence O Gostin
Journal: The Lancet (2025)
Safety and Efficacy of KN046 in combination with KN026 in Patients with advanced HER2-positive Breast Cancer: a Phase II Trial
Authors: Jieqiong Liu, Chuangui Song, Yaping Yang, Xiangcai Wang, Mingli Ni, Xujuan Wang, Lei Chen, Hongwei Yang, Rusen Zhao, Ting Xu, Lin Shen
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Here we reported the results from a phase II trial assessing the safety and efficacy of KN046 in combination with KN026 in HER2-positive metastatic breast cancer patients, who had progressed after prior anti-HER2 combination therapies. Patients and Methods: Female patients with metastatic HER2-positive breast cancer who were previously treated with at least one line of HER2-targeted combination therapy were enrolled from multiple academic hospitals in China to receive KN046 (iv. 5 mg/kg Q3W) plus KN026 (iv. 30 mg/kg Q3W) until progression, unacceptable toxicities or patient withdrawal. Efficacy was evaluated every 6 weeks per RECIST 1.1. The primary endpoint was objective response rate (ORR). Results: A total of 36 patients with the median age of 53 years were enrolled. 30 of 36 patients (83.3%) received ≥3 lines of HER2-targeted combination therapies in the metastatic setting. Thirty-three patients were evaluable for overall response, and all 36 for safety. The ORR was 47.2% ( 95% CI: 30.4-64.5), with two patient achieving CR. The median PFS was 5.6 (95% CI 4.1-13.8) months. 34 of 36 (94.4%) patients experienced TRAEsof any grade, and 10 of 36 (27.8%) patients had experienced ≥grade 3 TRAEs. The most common TRAEs were infusion-related reaction (36.1%), rash (16.7%), alanine aminotransferase increased (13.9%), diarrhea (13.9%), pruritus (13.9%). No treatment-related deaths were observed. Conclusions: The combination of KN046 and KN026, as a chemo free regimen, demonstrated favorable clinical efficacy with comparative toxicities in pre-treated patients with advanced HER2-positive breast cancer.
DETECTION OF CIRCULATING mRNA VARIANTS IN HEPATOCELLULAR CARCINOMA PATIENTS USING TARGETED RNAseq
Authors: Daniel Zezulinski, Maarouf A Hoteit, David E Kaplan, Angela Simeone, Tingting Zhan, Cataldo Doria, Fowsiyo Y Ahmed, Lewis R Roberts, Timothy M Block, Aejaz Sayeed
Journal: Liver Cancer (2025)

Mutations in circulating nucleic acids can be used as biomarkers for the early detection and management of hepatocellular carcinoma (HCC). However, while circulating tumor DNA and microRNA have been extensively explored, circulating tumor mRNA and circulating mRNA mutants (ctmutRNA), which may provide advantages over other analytes, remain less well described. We previously reported the identification of 288 HCC selective ctmutRNA variants, called "candidates," from a small cohort of HCC patients using total RNAseq. The objective of the current study was to use targeted RNAseq to validate the specificity and sensitivity of these HCC selective variants in an independent cohort of patients with liver cirrhosis (LC). Several methods to isolate small extracellular vesicles and amplify mRNA from the circulation were compared. RNA was isolated, and the primers and probes selective for the 288 regions of interest were used with RNA from HCC (N = 50) and LC and no HCC (N = 35) patients. HCC tumor tissues (N = 11), a normal liver tissue and 3 cell lines were also studied. cDNA synthesis was followed by library construction using QIAseq RNA Fusion XP panel. QC analysis was carried out with an Agilent Bioanalyzer before sequencing on a NextSeq 550 instrument. A GATK HaplotypeCaller was used for variant calling and annotation carried out using snpEff. Among the test panel of 288 ctmutRNA candidates in the original cohort, 75 were detected in the new cohort of plasma samples. Moreover, 388 other variants in proximity to the original lesions were also found in multiple HCC but not LC plasma samples. A subset of 36 HCC selective variants was able to identify all HCC patients. The most common tumor specific variants were Indels and SNPs. Novel mRNA fusion variants, corresponding to SENP7, HYI, SAR1A, RASA2, TUBA transcripts, etc., were identified in HCC and LC patients. Circulating RNA could be a robust analyte for noninvasive early detection of HCC and circulating RNA panels could be powerful tools in the entire spectrum of clinical management.
A Co-Clinical Trial of Exercise Therapy in Breast Cancer Prevention
Authors: Lee W. Jones, Jessica A. Lavery, Brandon L. Tsai, Chaya S. Moskowitz, Catherine P. Lee, Jenna Harrison, Meghan G. Michalski, Kurtis Stoeckel, Courtenay Graham, Neil M. Iyengar, Umeshkumar Bhanot, Irina Linkov, Mala Jain, Maxine S. Jochelson, Mara Monetti, Victoria L. Seewaldt, Melissa L. Pilewskie, Patrick Pribil, Chenghao Zhu, Jaron Arbet, Debra A. Mangino, Paul C. Boutros
Journal: Clinical Cancer Research (2025)

Abstract Purpose. We conducted a mouse–human co-clinical trial to evaluate the biological efficacy of exercise therapy in breast cancer prevention. Materials and methods. In a phase 1 randomized trial, 75 nonexercising women at high-risk of breast cancer were allocated to receive (1:1 ratio): usual care or one of three exercise therapy dose regimens: 75, 150, or 300 minutes/week for 24 consecutive weeks. Biological efficacy was evaluated by changes in breast epithelial cell proliferation (Ki67). Correlative proteomic analysis of paired tissue and plasma samples was also performed. A corresponding preclinical study tested the dose-response of exercise therapy on breast tumor latency. Results. Change in Ki67 was not different between groups (global p-value = 0.2). Among participants with paired Ki67 measures, the mean (s.d) change in Ki67 was: –1.26 (4.32) for 75 minutes/week, –1.74 (5.04) for 150 minutes/week, –0.45 (5.16) for 300 minutes/week, and 3.40 (5.53) for usual care (global p-value = 0.04). Only 150 minutes/week associated with significant reductions in Ki67 compared with usual care (Bonferroni-adjusted p-value 0.03). The “response rate” (reduction in Ki67) was 29% for usual care compared with 52% for 150 minutes/week. Proteomics revealed marked reduction in genes involved in epithelial mesenchymal transition in tissues of responding patients. In the preclinical study, only 150 minutes/week significantly delayed tumor latency compared with control (Benjamini- Hochberg-adjusted p-value 0.02). Conclusion. Exercise therapy is a promising strategy for early interception of breast cancer in high-risk women.
Integrated metabolomics and spatial transcriptomics of cystic pancreatic cancer precursors reveals dysregulated polyamine metabolism as a biomarker of progression
Authors: Ricardo A. León-Letelier, Yihui Chen, Rongzhang Dou, Ehsan Irajizad, Michele T. Yip-Schneider, Ranran Wu, Rahmah Ejaz, Hamid K. Rudsari, Yaxi Li, Rachelle Spencer, Riccardo Ballarò, Jody Vykoukal, Mark Hurd, Jennifer B. Dennison, Kim-Anh Do, Anirban Maitra, Jianjun Zhang, Samir Hanash, C. Max Schmidt, Johannes F. Fahrmann
Journal: Clinical Cancer Research (2025)

Abstract Purpose: We conducted metabolomics and spatial cell transcriptomics of intraductal papillary mucinous neoplasms (IPMN), recognized pancreatic cancer precursors, to identify oncometabolites that inform upon risk of malignancy of IPMN. Experimental Design: Untargeted metabolomic analyses were performed on cystic fluid from 125 patients with low-grade dysplasia (LG) or high-grade (HG) dysplasia with/without concurrent PDAC (IPMN/PDAC). Predictive performance of individual metabolites for identifying HG or PDAC/IPMN was determined and compared to CA19-9 performance. Data were intersected with metabolic profiles of resected IPMN tissues and murine Kras;Gnas IPMN cell lines as well as spatial and single-cell transcriptomics of IPMN. Results: A total of 388 metabolites were quantified in cystic fluid of which 69 were differential (p-value &amp;lt;0.05) between cases (HG IPMN + IPMN/PDAC) and patients with LG IPMN. Spermidine and spermine biosynthesis and catabolism was identified as the top perturbed metabolic pathway (FDR-adjusted p-value&amp;lt; 0.0001). Increases in cystic fluid spermidine, n-acetylputrescine, acetylspermidine, diacetylspermidine, diacetylspermine, and acetylcadaverine were associated elevated risk of harboring HG or IPMN/PDAC. An OR-rule comprising CA19-9, n-acetylputrescine, acetylspermidine, and diacetylspermine achieved 54.8% sensitivity for detecting HG and IPMN\PDAC. CA19-9 alone yielded sensitivity of 11.9% (McNemar Test p-value&amp;lt; 0.001). Polyamines were elevated in IPMN\PDAC tissues compared to LG IPMN tissues; spatial and single-cell transcriptomic data revealed transcript levels of polyamine-metabolizing enzymes to be elevated in neoplastic epithelium and tumor-associated macrophages. Conclusion: Cystic fluid polyamines offer utility for determining risk of malignancy of IPMN that is complementary to CA19-9, and that has potential to aid in clinical management of patients with IPMN.
Trends in Extended-Release and Non–Extended-Release Buprenorphine Dispensing
Authors: Thomas J. Stopka, Netrali Dalvi, Leonard D. Young, Shikhar Shrestha, Danielle DeNufrio Valerio, Alexander Y. Walley
Journal: JAMA Network Open (2025)

This cross-sectional study of buprenorphine prescription data in a US state examines relative changes in prescriptions of extended-release and non–extended-release versions, along with prescription characteristics.