tbuckley/cabot-search huggingface dataset:
Sex Disparities After Coronary Artery Bypass Grafting and Hospital Quality
Authors: Catherine M. Wagner, Andrew M. Ibrahim
Journal: JAMA Network Open (2024)

Importance Concern has been raised about persistent sex disparities after coronary artery bypass grafting, with female patients having higher mortality. However, whether these disparities persist across hospitals of different qualities is unknown. Objective To evaluate sex disparities in 30-day mortality after coronary artery bypass grafting across high- and low-quality hospitals. Design, Setting, and Participants This cross-sectional, retrospective cohort study evaluated Medicare beneficiaries undergoing coronary artery bypass grafting between October 1, 2015, and March 31, 2020. Data analysis was performed from July 1, 2023, to December 1, 2023. Exposures The primary exposures were hospital quality and sex. For hospital quality, hospitals were placed into rank order by their overall risk-adjusted mortality rate and divided into quintiles. Main Outcome and Measures Risk-adjusted 30-day mortality using a logistic regression model accounting for patient factors, including sex, age, comorbidities, elective vs unplanned admission, number of bypass grafts, use of arterial graft, and year of surgery. Results A total of 444 855 beneficiaries (mean [SD] age, 71.5 [7.5] years; 120 333 [27.1%] female and 324 522 [72.9%] male) were studied. Compared with male beneficiaries, female beneficiaries were more likely to have an unplanned admission (66 425 [55.2%] vs 157 895 [48.7%], P &amp;amp;lt; .001) and receive care at low-quality (vs high-quality) hospitals (odds ratio, 1.26; 95% CI, 1.23-1.29; P &amp;amp;lt; .001). Overall, risk-adjusted female mortality was 4.24% (95% CI, 4.20%-4.27%), and male mortality was 2.75% (95% CI, 2.75%-2.77%), with an absolute difference of 1.48 (95% CI, 1.45-1.51) percentage points ( P &amp;amp;lt; .001). At the highest-quality hospitals, male mortality was 1.57% (95% CI, 1.56%-1.59%), and female mortality was 2.58% (95% CI, 2.54%-2.62%), with an absolute difference of 1.01 (95% CI, 0.97-1.04) percentage points ( P &amp;amp;lt; .001). At the lowest-quality hospitals, male mortality was 4.94% (95% CI, 4.88%-5.01%), and female mortality was 7.02% (95% CI, 6.90%-7.13%), with an absolute difference of 2.07 (95% CI, 1.95-2.19) percentage points ( P &amp;amp;lt; .001). Female beneficiaries receiving care at low-quality hospitals had a higher mortality than male beneficiaries receiving care at the high-quality hospitals (7.02% vs 1.57%, P &amp;amp;lt; .001). Conclusions and Relevance In this cohort study of Medicare beneficiaries undergoing coronary artery bypass grafting, female beneficiaries were more likely to receive care at low-quality hospitals, where the sex disparity in mortality was double that of high-quality hospitals. Quality improvement targeting low-quality hospitals as well as equitable referral of female beneficiaries to higher-quality hospitals may narrow the sex disparity after coronary artery bypass grafting.
Prediabetes Prevalence by Adverse Social Determinants of Health in Adolescents
Authors: Caleb Harrison, Vaishnavi Peyyety, Adriana Rodriguez Gonzalez, Rutha Chivate, Xu Qin, Margaret F. Zupa, Maya I. Ragavan, Mary Ellen Vajravelu
Journal: JAMA Network Open (2024)

Several clinical practice guidelines advise race- and ethnicity-based screening for youth-onset type 2 diabetes (T2D) due to a higher prevalence among American Indian and Alaska Native, Asian, Black, and Hispanic youths compared with White youths. However, rather than a biological risk, this disparity likely reflects the inequitable distribution of adverse social determinants of health (SDOH), a product of interpersonal and structural racism.
Clinical updates and surveillance recommendations for DNA replication-repair deficiency syndromes in children and young adults
Authors: Anirban Das, Suzanne P. MacFarland, Julia Meade, Jordan R. Hansford, Kami W. Schneider, Roland P. Kuiper, Marjolijn C.J. Jongmans, Harry Lesmana, Kris Ann P. Schultz, Kim E. Nichols, Carol Durno, Kristin Zelley, Christopher C. Porter, Lisa J. States, Shay Ben-Shachar, Sharon A. Savage, Jennifer M. Kalish, Michael F. Walsh, Hamish S. Scott, Sharon E. Plon, Uri Tabori
Journal: Clinical Cancer Research (2024)

Abstract Replication repair deficiency (RRD) is a pan-cancer mechanism characterized by abnormalities in the DNA mismatch repair (MMR) system due to pathogenic variants in the PMS2, MSH6, MSH2, or MLH1 genes, and/or in the polymerase-proofreading genes POLE and POLD1. RRD predisposition syndromes (constitutional MMR deficiency, Lynch, and polymerase proofreading–associated polyposis) share overlapping phenotypic and biological characteristics. Moreover, cancers stemming from germline defects of one mechanism can acquire somatic defects in another, leading to complete RRD. Here we describe the recent advances in the diagnostics, surveillance, and clinical management for children with RRD syndromes. For patients with constitutional MMR deficiency, new data combining clinical insights and cancer genomics have revealed genotype–phenotype associations and helped in the development of novel functional assays, diagnostic guidelines, and surveillance recommendations. Recognition of non-gastrointestinal/genitourinary malignancies, particularly aggressive brain tumors, in select children with Lynch and polymerase proofreading–associated polyposis syndromes harboring an RRD biology have led to new management considerations. Additionally, universal hypermutation and microsatellite instability have allowed immunotherapy to be a paradigm shift in the treatment of RRD cancers independent of their germline etiology. These advances have also stimulated a need for expert recommendations about genetic counseling for these patients and their families. Future collaborative work will focus on newer technologies such as quantitative measurement of circulating tumor DNA and functional genomics to tailor surveillance and clinical care, improving immune surveillance; develop prevention strategies; and deliver these novel discoveries to resource-limited settings to maximize benefits for patients globally.
Pediatric Respiratory Syncytial Virus Hospitalizations, 2017-2023
Authors: Tiffany Fitzpatrick, Sarah A. Buchan, Sanjay Mahant, Longdi Fu, Jeffrey C. Kwong, Therese A. Stukel, Astrid Guttmann
Journal: JAMA Network Open (2024)

Importance Respiratory syncytial virus (RSV) transmission was disrupted worldwide following the COVID-19 pandemic, and further study is required to better understand these changes. Objective To compare observed and expected RSV hospital and intensive care unit (ICU) admission rates and characteristics of admitted children during the 2021-2022 and 2022-2023 seasons. Design, Setting, and Participants A population-based cohort study of all children aged younger than 5 years in Ontario, Canada, July 1, 2017, through March 31, 2023, was conducted. Exposures Individual and neighborhood-level sociodemographic and clinical characteristics were identified from administrative data, including age, palivizumab eligibility, complex medical conditions, rurality, and living in a marginalized neighborhood. Main Outcomes and Measures The main outcome was RSV-associated hospitalization. Secondary outcomes included ICU admissions, mechanical ventilation, extracorporeal membrane oxygenation, and in-hospital death. Poisson generalized estimating equations were used to model weekly age- and sex-specific hospitalization rates and estimate expected rates in the postpandemic era; adjusted rate ratios (RRs) and 95% CIs are reported. Results This cohort study included approximately 700 000 children per study year. Compared with prepandemic years (2017-2018, 2018-2019, and 2019-2020), the 2021-2022 RSV season peaked slightly earlier, but overall admission rates were comparable (289.1 vs 281.4-334.6 per 100 000, or approximately 2000 admissions). The 2022-2023 season peaked a month earlier and resulted in more than twice as many hospitalizations (770.0 per 100 000; n = 4977 admissions). The proportion of children admitted to an ICU in 2022-2023 (13.9%) was slightly higher than prepandemic (9.6%-11.4%); however, the population-based rate was triple the prepandemic levels (106.9 vs 27.6-36.6 per 100 000 children in Ontario). With the exception of palivizumab-eligible children, all sociodemographic and health status characteristics were associated with lower-than-expected RSV hospitalization rates in 2021-2022. In contrast, older age of patients was associated with higher-than-expected rates in 2022-2023 (ie, 24-59 months: RR, 1.90; 95% CI, 1.35-2.66). Conclusions and Relevance There were notable differences in RSV epidemiologic characteristics in Ontario following the COVID-19 pandemic. It is not yet clear whether and how long atypical RSV epidemics may persist. Clinicians and program planners should consider the potential for ongoing impacts to health care capacity and RSV immunization programs.
Real-world Effectiveness of Fecal Microbiota Transplantation for First or Second Clostridioides difficile Infection
Authors: Sara Ellegaard Paaske, Simon Mark Dahl Baumwall, Tone Rubak, Frederik Hyllested Birn, Nina Rågård, Jens Kelsen, Mette Mejlby Hansen, Lise Svenningsen, Anne Lund Krarup, Christa Marie Culmbach Fernis, Anders Neumann, Anders Bergh Lødrup, Henning Glerup, Lars Vinter-Jensen, Morten Helms, Lise Tornvig Erikstrup, Anne Karmisholt Grosen, Susan Mikkelsen, Christian Erikstrup, Jens Frederik Dahlerup, Christian Lodberg Hvas
Journal: Clinical Gastroenterology and Hepatology (2024)

Background & AimsClostridioides difficile infection (CDI) is associated with high mortality. Fecal microbiota transplantation (FMT) is an established treatment for recurrent CDI, but its use for first or second CDI remains experimental. We aimed to investigate the effectiveness of FMT for first or second CDI in a real-world clinical setting.MethodsThis multi-site Danish cohort study included patients with first or second CDI treated with FMT from June 2019 to February 2023. The primary outcome was cure of C. difficile-associated diarrhea (CDAD) 8 weeks after the last FMT treatment. Secondary outcomes included CDAD cure 1 and 8 weeks after the first FMT treatment and 90-day mortality following positive C. difficile test.ResultsWe included 467 patients, with 187 (40%) having their first CDI. The median patient age was 73 years (interquartile range [IQR], 58–82 years). Notably, 167 (36%) had antibiotic-refractory CDI, 262 (56%) had severe CDI, and 89 (19%) suffered from fulminant CDI. Following the first FMT treatment, cure of CDAD was achieved in 353 patients (76%; 95% confidence interval [CI], 71%–79%) at week 1. At week 8, 255 patients (55%; 95% CI, 50%–59%) maintained sustained effect. In patients without initial effect, repeated FMT treatments led to an overall cure of CDAD in 367 patients (79%; 95% CI, 75%–82%). The 90-day mortality was 10% (95% CI, 8%–14%).ConclusionRepeated FMT treatments demonstrate high effectiveness in managing patients with first or second CDI. Forwarding FMT in CDI treatment guidelines could improve patient survival. ClinicalTrials.gov, Number: NCT03712722Graphical abstract
Pulmonary fibroblast-specific delivery of siRNA exploiting exosomes-based nanoscaffolds for IPF treatment
Authors: Haoyu Lu, Xulu Liu, Mengjun Zhang, Hriday Bera, Wenwen Xu, Huiyang Jiang, Xing Zhao, Lan Wu, Dongmei Cun, Mingshi Yang
Journal: Asian Journal of Pharmaceutical Sciences (2024)

Idiopathic pulmonary fibrosis (IPF) is a progressive pulmonary disease that leads to interstitial inflammation, lung damage, and eventually life-threatening complications. Among various pathologic factors, Smad4 is a pivotal molecule involved in the progression and exacerbation of IPF. It mediates nuclear transfer of Smad2/Smad3 complexes and initiates the transcription of fibrosis-promoting genes. Thus, the inhibition of Smad4 expression in pulmonary fibroblasts by small interfering RNAs (siRNAs) might be a promising therapeutic strategy for IPF. Herein, we engineered exosome membranes (EM) by cationic lipid (i.e., DOTAP) to load siRNAs against Smad4 (DOTAP/siSmad4@EM), and investigated their specific delivery to pulmonary fibroblasts for treating IPF in a mouse model via pulmonary administration. As reference nanoscaffolds, undecorated DOTAP/siSmad4 complexes (lipoplexes, consisting of cationic lipid DOTAP and siRNAs) and siSmad4-loaded lipid nanoparticles (DOTAP/siSmad4@lipo, consisting of lipoplexes fused with DPPC-Chol liposomes) were also prepared. The results showed that DOTAP/siSmad4@EM exhibited a higher cellular uptake and gene silencing efficacies in mouse pulmonary fibroblasts (viz., MLg2908) as compared to the two reference nanoscaffolds. Furthermore, the outcomes of the in vivo experiments illustrated that DOTAP/siSmad4@EM could significantly down-regulate the Smad4 expression with augmented anti-fibrosis efficiency. Additionally, the DOTAP/siSmad4@EM conferred excellent biocompatibility with low cytokine levels in bronchoalveolar lavage fluid and proinflammatory responses in the pulmonary area. Taken together, the outcomes of our investigation imply that specific inhibition of Smad4 expression in pulmonary fibroblasts by pulmonary administrated DOTAP/siSmad4@EM is a promising therapeutic strategy for IPF, which could safely and effectively deliver siRNA drugs to the targeted site of action.
Act1 drives chemoresistance via regulation of antioxidant RNA metabolism and redox homeostasis
Authors: Lingzi Hong, Tomasz Herjan, Xing Chen, Leah L. Zagore, Katarzyna Bulek, Han Wang, Chi-Fu Jeffrey Yang, Donny D. Licatalosi, Xiaoxia Li, Xiao Li
Journal: The Journal of Experimental Medicine (2024)

The IL-17 receptor adaptor molecule Act1, an RNA-binding protein, plays a critical role in IL-17–mediated cancer progression. Here, we report a novel mechanism of how IL-17/Act1 induces chemoresistance by modulating redox homeostasis through epitranscriptomic regulation of antioxidant RNA metabolism. Transcriptome-wide mapping of direct Act1–RNA interactions revealed that Act1 binds to the 5′UTR of antioxidant mRNAs and Wilms’ tumor 1–associating protein (WTAP), a key regulator in m6A methyltransferase complex. Strikingly, Act1’s binding sites are located in proximity to m6A modification sites, which allows Act1 to promote the recruitment of elF3G for cap-independent translation. Loss of Act1’s RNA binding activity or Wtap knockdown abolished IL-17–induced m6A modification and translation of Wtap and antioxidant mRNAs, indicating a feedforward mechanism of the Act1–WTAP loop. We then developed antisense oligonucleotides (Wtap ASO) that specifically disrupt Act1’s binding to Wtap mRNA, abolishing IL-17/Act1-WTAP-mediated antioxidant protein production during chemotherapy. Wtap ASO substantially increased the antitumor efficacy of cisplatin, demonstrating a potential therapeutic strategy for chemoresistance.
A human STAT3 gain-of-function variant drives local Th17 dysregulation and skin inflammation in mice
Authors: Kelsey A. Toth, Erica G. Schmitt, Ana Kolicheski, Zev J. Greenberg, Elizabeth Levendosky, Nermina Saucier, Kelsey Trammel, Vasileios Oikonomou, Michail S. Lionakis, Eynav Klechevsky, Brian S. Kim, Laura G. Schuettpelz, Naresha Saligrama, Megan A. Cooper
Journal: The Journal of Experimental Medicine (2024)

Germline gain-of-function (GOF) variants in STAT3 cause an inborn error of immunity associated with early-onset poly-autoimmunity and immune dysregulation. To study tissue-specific immune dysregulation, we used a mouse model carrying a missense variant (p.G421R) that causes human disease. We observed spontaneous and imiquimod (IMQ)-induced skin inflammation associated with cell-intrinsic local Th17 responses in STAT3 GOF mice. CD4+ T cells were sufficient to drive skin inflammation and showed increased Il22 expression in expanded clones. Certain aspects of disease, including increased epidermal thickness, also required the presence of STAT3 GOF in epithelial cells. Treatment with a JAK inhibitor improved skin disease without affecting local Th17 recruitment and cytokine production. These findings collectively support the involvement of Th17 responses in the development of organ-specific immune dysregulation in STAT3 GOF and suggest that the presence of STAT3 GOF in tissues is important for disease and can be targeted with JAK inhibition.
Boarding Duration in the Emergency Department and Inpatient Delirium and Severe Agitation
Authors: Joshua W. Joseph, Noémie Elhadad, Melissa L.P. Mattison, Lauren M. Nentwich, Sharon A. Levine, Edward R. Marcantonio, Maura Kennedy
Journal: JAMA Network Open (2024)

This cohort study examines the risk factors for developing delirium and/or agitation in patients in the emergency department waiting for an inpatient bed.
Improving Outcomes for Women After Coronary Artery Bypass Grafting
Authors: Jennifer Lawton
Journal: JAMA Network Open (2024)

used claims data from the Medicare Provider Analysis and Review (MEDPAR) file to identify a US-based cohort of Medicare beneficiaries (N = 444 855) undergoing coronary artery bypass grafting (CABG) from 2015 to 2020.In this cohort, female Medicare patients (120 333[27%]) had significantly higher risk-adjusted 30-day mortality (defined as operative mortality by the Society of Thoracic Surgeons [STS] metric as mortality in the same hospitalization or within 30 days) after CABG compared with male patients (4.24% vs 2.75%).Female patients were also more likely to receive care at low-quality hospitals (based on hospital risk-adjusted CABG mortality rate), which came at a huge cost-the risk-adjusted mortality doubled that of high-quality hospitals.Thus, female
Women in STEM becoming independent: The journey to independence is an immensely gratifying odyssey
Authors: Clarissa Campbell, Maja C. Funk, Yuki Hattori, Wei Hu, Jana Jeschke, Colleen M. Lau, Guang Sheng Ling, Siqi Liu, Verónica Lloréns-Rico, Elisa Nemes
Journal: The Journal of Experimental Medicine (2024)

This year at JEM, we are highlighting women in science by sharing their stories and amplifying their voices. In this Viewpoint, we hear from a cross section of women, across multiple research fields, discussing their science and the process of setting up a lab as an independent researcher.
An attenuated lymphocytic choriomeningitis virus vector enhances tumor control in mice partly via IFN-I
Authors: Young Rock Chung, Bakare Awakoaiye, Tanushree Dangi, Nahid Irani, Slim Fourati, Pablo Penaloza-MacMaster
Journal: Journal of Clinical Investigation (2024)

Viral vectors are being used for the treatment of cancer. Yet their efficacy varies among tumors and their use poses challenges in immunosuppressed patients, underscoring the need for alternatives. We report striking antitumoral effects by a nonlytic viral vector based on attenuated lymphocytic choriomeningitis virus (r3LCMV). We show in multiple tumor models that injection of tumor-bearing mice with this vector results in improved tumor control and survival. Importantly, r3LCMV improved tumor control in immunodeficient Rag1–/– mice and MyD88–/– mice, suggesting that multiple pathways contributed to the antitumoral effects. The antitumoral effects of r3LCMV were also observed when this vector was administered several weeks before tumor challenges, suggesting the induction of trained immunity. Single cell RNA-Seq analyses, antibody blockade experiments, and KO models revealed a critical role for host-intrinsic IFN-I in the antitumoral efficacy of r3LCMV vectors. Collectively, these data demonstrate potent antitumoral effects by r3LCMV vectors and unveil multiple mechanisms underlying their antitumoral efficacy.
Kisspeptin signaling in astrocytes modulates the reproductive axis
Authors: Encarnacion Torres, Giuliana Pellegrino, Melissa Granados-Rodríguez, Antonio C. Fuentes-Fayos, Inmaculada Velasco, Adrian Coutteau-Robles, Amandine Legrand, Marya Shanabrough, Cecilia Perdices-Lopez, Silvia Leon, Shel H. Yeo, Stephen M. Manchishi, Maria J. Sánchez-Tapia, Victor M. Navarro, Rafael Pineda, Juan Roa, Frederick Naftolin, Jesús Argente, Raúl M. Luque, Julie A. Chowen, Tamas L. Horvath, Vincent Prevot, Ariane Sharif, William H. Colledge, Manuel Tena-Sempere, Antonio Romero-Ruiz
Journal: Journal of Clinical Investigation (2024)

Reproduction is safeguarded by multiple, often cooperative regulatory networks. Kisspeptin signaling, via KISS1R, plays a fundamental role in reproductive control, primarily by regulation of hypothalamic GnRH neurons. We disclose herein a pathway for direct kisspeptin actions in astrocytes that contributes to central reproductive modulation. Protein-protein-interaction and ontology analyses of hypothalamic proteomic profiles after kisspeptin stimulation revealed that glial/astrocyte markers are regulated by kisspeptin in mice. This glial-kisspeptin pathway was validated by the demonstrated expression of Kiss1r in mouse astrocytes in vivo and astrocyte cultures from humans, rats and mice, where kisspeptin activated canonical intracellular signaling-pathways. Cellular co-expression of Kiss1r with the astrocyte markers, GFAP and S100-β, occurred in different brain regions, with higher percentage in Kiss1- and GnRH-enriched areas. Conditional ablation of Kiss1r in GFAP-positive cells, in the G-KiRKO mouse, altered gene expression of key factors in PGE2 synthesis in astrocytes, and perturbed astrocyte-GnRH neuronal appositions, as well as LH responses to kisspeptin and LH pulsatility, as surrogate marker of GnRH secretion. G-KiRKO mice also displayed changes in reproductive responses to metabolic stress induced by high-fat diet, affecting female pubertal onset, estrous cyclicity and LH-secretory profiles. Our data unveil a non-neuronal pathway for kisspeptin actions in astrocytes, which cooperates in fine-tuning the reproductive axis and its responses to metabolic stress.
WED-223 Clinical and biological predictors of liver fat content ≥8% as assessed by MRI-PDFF: combined data from multiple therapeutic trials including more than 10, 000 patients
Authors: Mazen Noureddin, Sophie Jeannin, Naim Alkhouri, Vlad Ratziu, Jörn M. Schattenberg, Michael Charlton, Julie Dubourg, Stephen A. Harrison
Journal: Journal of Hepatology (2024)
SAT-465 Increasing awareness among primary care physicians about MASLD reduced unnecessary referral rates and an increased cardiovascular evaluation
Authors: Eileen Yoon, Jihyun An, Ha Il Kim, Joo Hyun Sohn, Bo-Kyeong Kang, Eun Chul Jang, Huiyul Park, Hye-Lin Kim, Sang Bong Ahn, Joo Hyun Oh, Hyunwoo Oh, Hyo Young Lee, Dae Won Jun
Journal: Journal of Hepatology (2024)
THU-336 Combination of fatty acid synthase (FASN) inhibitor and thyroid hormone receptor beta (THRb) agonist resmetirom shows synergistic improvement of NAFLD activity score (NAS) within 6-weeks in diet-induced obese mice with biopsy-confirmed MASH
Authors: Wen-Wei Tsai, Malte H. Nielsen, Michael Feigh, Eduardo Martins, George Kemble, Marie O’ Farrell
Journal: Journal of Hepatology (2024)
SAT-212 Real-world use of Glucagon-like peptide 1 receptor agonists in patients with MASLD: a cross-sectional analysis from TARGETNASH
Authors: A. Sidney Barritt, Andrea Mospan, Heather Morris, Anthony Perez, Rohit Loomba, Michael Fried, Arun J. Sanyal, Philip N. Newsome
Journal: Journal of Hepatology (2024)
WED-481 Elimination days-Howgood clinical practice can contribute to the elimination of hepatitis C
Authors: Pedro Lages Martins, Mário Jorge Silva, João Silva, Daniela Rabaça, Cláudia Pereira, Filipe Mendes, Margarida Alves, Paulo Caldeira, Rita Corte-Real, Filipe Calinas
Journal: Journal of Hepatology (2024)