tbuckley/cabot-search huggingface dataset:
Major cardiovascular events after COVID-19 in people with HIV
Authors: Raquel Martín-Iguacel, Sergio Moreno-Fornés, Andreu Bruguera, Jordi Aceitón, Daniel Kwakye Nomah, Ana González-Cordón, Pere Domingo, Adrian Curran, Arkaitz Imaz, David Dalmau Juanola, Joaquim Peraire, Beatriz Borjabad, Laia Arbones Fernandez, Isik Somuncu Johansen, José M. Miró, Jordi Casabona, Josep M. Llibre
Journal: Clinical Microbiology and Infection (2024)
Vancomycin relieves tacrolimus-induced hyperglycemia by eliminating gut bacterial beta-glucuronidase enzyme activity
Authors: Peixia Li, Rui Zhang, Jinping Zhou, Pengpeng Guo, Yani Liu, Shaojun Shi
Journal: Gut Microbes (2024)

Up to 40% of transplant recipients treated long-term with tacrolimus (TAC) develop post-transplant diabetes mellitus (PTDM). TAC is an important risk factor for PTDM, but is also essential for immunosuppression after transplantation. Long-term TAC treatment alters the gut microbiome, but the mechanisms of TAC-induced gut microbiota in the pathogenesis of PTDM are poorly characterized. Here, we showed that vancomycin, an inhibitor of bacterial beta-glucuronidase (GUS), prevents TAC-induced glucose disorder and insulin resistance in mice. Metagenomics shows that GUS-producing bacteria are predominant and flourish in the TAC-induced hyperglycemia mouse model, with upregulation of intestinal GUS activity. Targeted metabolomics analysis revealed that in the presence of high GUS activity, the hydrolysis of bile acid (BAs)-glucuronic conjugates is increased and most BAs are overproduced in the serum and liver, which, in turn, activates the ileal farnesoid X receptor (FXR) and suppresses GLP-1 secretion by L-cells. The GUS inhibitor vancomycin significantly eliminated GUS-producing bacteria and inhibited bacterial GUS activity and BAs levels, thereby enhancing L-cell GLP-1 secretion and preventing hyperglycemia. Our results propose a novel clinical strategy for inhibiting the bacterial GUS enzyme to prevent hyperglycemia without requiring withdrawal of TAC treatment. This strategy exerted its effect through the ileal bile acid-FXR-GLP-1 pathway.
Feasibility and Colonoscopy Yield Using the Fecal Immunochemical Test (FIT)-Based Colorectal Cancer Screening in a Latin America Country
Authors: Mauricio Paulin Sorbello, Ulysses Ribeiro Júnior, José Eluf-Neto, Vinicius Pfuetzenreiter, Afonso Henrique da Silva e Sousa Júnior, Fábio Shiguehissa Kawaguti, Diane Dede Cohen, Evandro Sobroza de Mello, Sergio Carlos Nahas, Adriana Vaz Safatle-Ribeiro
Journal: Clinical Gastroenterology and Hepatology (2024)
An enhanced broad-spectrum peptide inhibits Omicron variants in vivo
Authors: Wenwen Bi, Kaiming Tang, Guilin Chen, Yubin Xie, Nicholas F. Polizzi, William F. DeGrado, Shuofeng Yuan, Bobo Dang
Journal: Cell Reports Medicine (2024)

The continual emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) poses a major challenge to vaccines and antiviral therapeutics due to their extensive evasion of immunity. Aiming to develop potent and broad-spectrum anticoronavirus inhibitors, we generated A1-(GGGGS)7-HR2m (A1L35HR2m) by introducing an angiotensin-converting enzyme 2 (ACE2)-derived peptide A1 to the N terminus of the viral HR2-derived peptide HR2m through a long flexible linker, which showed significantly improved antiviral activity. Further cholesterol (Chol) modification at the C terminus of A1L35HR2m greatly enhanced the inhibitory activities against SARS-CoV-2, SARS-CoV-2 VOCs, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) pseudoviruses, with IC50 values ranging from 0.16 to 5.53 nM. A1L35HR2m-Chol also potently inhibits spike-protein-mediated cell-cell fusion and the replication of authentic Omicron BA.2.12.1, BA.5, and EG.5.1. Importantly, A1L35HR2m-Chol distributed widely in respiratory tract tissue and had a long half-life (>10 h) in vivo. Intranasal administration of A1L35HR2m-Chol to K18-hACE2 transgenic mice potently inhibited Omicron BA.5 and EG.5.1 infection both prophylactically and therapeutically.
Development of Chromosome 1q+ Specific Treatment for Highest Risk Pediatric Posterior Fossa Ependymoma
Authors: Andrea M. Griesinger, Annaliese J. Calzadilla, Enrique Grimaldo, Andrew M. Donson, Vladimir Amani, Angela M. Pierce, Jenna Steiner, Soudabeh Kargar, Natalie J. Serkova, Kelsey C. Bertrand, Karen D. Wright, Rajeev Vibhakar, Todd Hankinson, Michael Handler, Holly B. Lindsay, Nicholas K. Foreman, Kathleen Dorris
Journal: Clinical Cancer Research (2024)

Abstract Purpose: There are no effective treatment strategies for children with highest-risk posterior fossa group A ependymoma (PFA). Chromosome 1q gains (1q+) are present in approximately 25% of newly diagnosed PFA tumors, and this number doubles at recurrence. Seventy percent of children with chromosome 1q+ PFA will die because of the tumor, highlighting the urgent need to develop new therapeutic strategies for this population. Experimental Design: In this study, we utilize 1q+ PFA in vitro and in vivo models to test the efficacy of combination radiation and chemotherapy in a preclinical setting. Results: 5-fluorouracil (5FU) enhances radiotherapy in 1q+ PFA cell lines. Specifically, 5FU increases p53 activity mediated by the extra copy of UCK2 located on chromosome 1q in 1q+ PFA. Experimental downregulation of UCK2 resulted in decreased 5FU sensitivity in 1q+ PFA cells. In in vitro studies, a combination of 5FU, retinoid tretinoin (ATRA), and radiation provided the greatest reduction in cellular proliferation and greatest increase in markers of apoptosis in 1q+ PFA cell lines compared with other treatment arms. Similarly, in vivo experiments demonstrated significant enhancement of survival in mice treated with combination radiation and 5FU and ATRA. Conclusions: These results are the first to identify a chromosome 1q+ specific therapy approach in 1q+ PFA. Existing phase I studies have already established single-agent pediatric safety and dosages of 5FU and ATRA, allowing for expedited clinical application as phase II trials for children with high-risk PFA.
Hitchhiking of Cas9 with nucleus-localized proteins impairs its controllability and leads to efficient genome editing of NLS-free Cas9
Authors: Wenfeng Zhang, Haozheng Wang, Zhongtao Luo, Yingzhen Jian, Chenyu Gong, Hui Wang, Xinjian Lin, Meilin Liu, Yangmin Wang, Hongwei Shao
Journal: Molecular Therapy (2024)
DGAT2 inhibition blocks SREBP-1 cleavage and improves hepatic steatosis by increasing phosphatidylethanolamine in the ER
Authors: Shunxing Rong, Mingfeng Xia, Goncalo Vale, Simeng Wang, Chai-Wan Kim, Shili Li, Jeffrey G. McDonald, Arun Radhakrishnan, Jay D. Horton
Journal: Cell Metabolism (2024)

Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step of triglyceride (TG) synthesis. DGAT2 deletion in mice lowers liver TGs, and DGAT2 inhibitors are under investigation for the treatment of fatty liver disease. Here, we show that DGAT2 inhibition also suppressed SREBP-1 cleavage, reduced fatty acid synthesis, and lowered TG accumulation and secretion from liver. DGAT2 inhibition increased phosphatidylethanolamine (PE) levels in the endoplasmic reticulum (ER) and inhibited SREBP-1 cleavage, while DGAT2 overexpression lowered ER PE concentrations and increased SREBP-1 cleavage in vivo. ER enrichment with PE blocked SREBP-1 cleavage independent of Insigs, which are ER proteins that normally retain SREBPs in the ER. Thus, inhibition of DGAT2 shunted diacylglycerol into phospholipid synthesis, increasing the PE content of the ER, resulting in reduced SREBP-1 cleavage and less hepatic steatosis. This study reveals a new mechanism that regulates SREBP-1 activation and lipogenesis that is independent of sterols and SREBP-2 in liver.
Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients With Mild to Moderate COVID-19
Authors: Hiroshi Yotsuyanagi, Norio Ohmagari, Yohei Doi, Masaya Yamato, Nguyen Hoang Bac, Bong Ki Cha, Takumi Imamura, Takuhiro Sonoyama, Genki Ichihashi, Takao Sanaki, Yuko Tsuge, Takeki Uehara, Hiroshi Mukae
Journal: JAMA Network Open (2024)

Importance Treatment options for COVID-19 are warranted irrespective of the presence of risk factors for severe disease. Objective To assess the efficacy and safety of ensitrelvir in patients with mild to moderate COVID-19. Design, Setting, and Participants This phase 3 part of a phase 2/3, double-blind, placebo-controlled randomized clinical trial was conducted from February 10 to July 10, 2022, with a 28-day follow-up period, at 92 institutions in Japan, Vietnam, and South Korea. Patients (aged 12 to &amp;amp;lt;70 years) with mild to moderate COVID-19 within 120 hours of positive viral test results were studied. Interventions Patients were randomized (1:1:1) to receive 125 mg of once-daily ensitrelvir (375 mg on day 1), 250 mg of once-daily ensitrelvir (750 mg on day 1), or placebo for 5 days. Main Outcomes and Measures The primary end point was the time to resolution of the composite of 5 characteristic symptoms of SARS-CoV-2 Omicron infection, assessed using a Peto-Prentice generalized Wilcoxon test stratified by vaccination history. Virologic efficacy and safety were also assessed. Results A total of 1821 patients were randomized, of whom 1030 (347 in the 125-mg ensitrelvir group, 340 in the 250-mg ensitrelvir group, and 343 in the placebo group) were randomized in less than 72 hours of disease onset (primary analysis population). The mean (SD) age in this population was 35.2 (12.3) years, and 552 (53.6%) were men. A significant difference was observed between the 125-mg ensitrelvir group and the placebo group ( P = .04 with a Peto-Prentice generalized Wilcoxon test). The difference in median time was approximately 1 day between the 125-mg ensitrelvir group and the placebo group (167.9 vs 192.2 hours; difference, −24.3 hours; 95% CI, −78.7 to 11.7 hours). Adverse events were observed in 267 of 604 patients (44.2%) in the 125-mg ensitrelvir group, 321 of 599 patients (53.6%) in the 250-mg ensitrelvir group, and 150 of 605 patients (24.8%) in the placebo group, which included a decrease in high-density lipoprotein level (188 [31.1%] in the 125-mg ensitrelvir group, 231 [38.6%] in the 250-mg ensitrelvir group, and 23 [3.8%] in the placebo group). No treatment-related serious adverse events were reported. Conclusions and Relevance In this randomized clinical trial, 125-mg ensitrelvir treatment reduced the time to resolution of the 5 typical COVID-19 symptoms compared with placebo in patients treated in less than 72 hours of disease onset; the absolute difference in median time to resolution was approximately 1 day. Ensitrelvir demonstrated clinical and antiviral efficacy without new safety concerns. Generalizability to populations outside Asia should be confirmed. Trial Registration Japan Registry of Clinical Trials Identifier: jRCT2031210350
Exploring the more-than-human in trans people’s lives: Connections, sociality, being and animal companionship
Authors: Salem Skelton, Damien W. Riggs
Journal: International Journal of Transgender Health (2024)

Background A growing body of research has explored the benefits of animal companionship to trans people, yet too often this research reinforces human exceptionalism, and fails to explore what it means for trans people to engage in more-than-human relationships. Conversely, trans theorists have increasingly turned to consider what it means for trans people to lay claim to the category 'human', wrapped up as it is in normative claims to gender and sociality.
Merkel cell polyomavirus-specific and CD39+CLA+ CD8 T cells as blood-based predictive biomarkers for PD-1 blockade in Merkel cell carcinoma
Authors: Heeju Ryu, Timothy M. Bi, Thomas H. Pulliam, Korok Sarkar, Candice D. Church, Nandita Kumar, Koshlan Mayer-Blackwell, Saumya Jani, Nirasha Ramchurren, Ulla K. Hansen, Sine R. Hadrup, Steven P. Fling, David M. Koelle, Paul Nghiem, Evan W. Newell
Journal: Cell Reports Medicine (2024)

Merkel cell carcinoma is a skin cancer often driven by Merkel cell polyomavirus (MCPyV) with high rates of response to anti-PD-1 therapy despite low mutational burden. MCPyV-specific CD8 T cells are implicated in anti-PD-1-associated immune responses and provide a means to directly study tumor-specific T cell responses to treatment. Using mass cytometry and combinatorial tetramer staining, we find that baseline frequencies of blood MCPyV-specific cells correlated with response and survival. Frequencies of these cells decrease markedly during response to therapy. Phenotypes of MCPyV-specific CD8 T cells have distinct expression patterns of CD39, cutaneous lymphocyte-associated antigen (CLA), and CD103. Correspondingly, overall bulk CD39+CLA+ CD8 T cell frequencies in blood correlate with MCPyV-specific cell frequencies and similarly predicted favorable clinical outcomes. Conversely, frequencies of CD39+CD103+ CD8 T cells are associated with tumor burden and worse outcomes. These cell subsets can be useful as biomarkers and to isolate blood-derived tumor-specific T cells.
WHO's essential medicines and AWaRe: recommendations on first- and second-choice antibiotics for empiric treatment of clinical infections
Authors: Lorenzo Moja, Veronica Zanichelli, Dominik Mertz, Sumanth Gandra, Bernadette Cappello, Graham S. Cooke, Pem Chuki, Stephan Harbarth, Celine Pulcini, Marc Mendelson, Evelina Tacconelli, Loice Achieng Ombajo, Ronald Chitatanga, Mei Zeng, Monica Imi, Christelle Elias, Per Ashorn, Annamaria Marata, Sarah Paulin, Arno Muller, Awa Aidara-Kane, Teodora Elvira Wi, Wilson Milton Were, Elizabeth Tayler, Albert Figueras, Carmem Pessoa Da Silva, Catharina Van Weezenbeek, Nicola Magrini, Mike Sharland, Benedikt Huttner, Mark Loeb
Journal: Clinical Microbiology and Infection (2024)

The WHO Model List of Essential Medicines (EML) prioritizes medicines that have significant global public health value. The EML can also deliver important messages on appropriate medicine use. Since 2017, in response to the growing challenge of antimicrobial resistance, antibiotics on the EML were reviewed and categorized into three groups: Access, Watch and Reserve, leading to a new categorization called AWaRe. These categories were developed taking into account the impact of different antibiotics and classes on antimicrobial resistance, and the implications for their appropriate use. The 2023 AWaRe classification provides empiric guidance on 41 essential antibiotics for over 30 clinical infections targeting both the primary health care and hospital facility setting. A further 257 antibiotics not included on the EML have been allocated an AWaRe group for stewardship and monitoring purposes. This article describes the development of AWaRe focussing on the clinical evidence base that guided the selection of Access, Watch or Reserve antibiotics as first and second choices for each infection. The overarching objective was to offer a tool for optimising the quality of global antibiotic prescribing and reduce inappropriate use by encouraging the use of Access antibiotics (or no antibiotics) where appropriate. This clinical evidence evaluation and subsequent EML recommendations are the basis for the AWaRe antibiotic book and related smartphone applications. By providing guidance on antibiotic prioritization, AWaRe aims to facilitate the revision of national lists of essential medicines, update of national prescribing guidelines and surveillance of antibiotic use. Adherence to AWaRe would extend the effectiveness of current antibiotics while helping countries to expand access to these life-saving medicines for the benefit of current and future patients, health professionals, and the environment.
Effect of Tai Chi vs Aerobic Exercise on Blood Pressure in Patients With Prehypertension
Authors: Xinye Li, Peifen Chang, Min Wu, Yuchen Jiang, Yonghong Gao, Hengwen Chen, Liyuan Tao, Dawei Wei, Xiaochen Yang, Xingjiang Xiong, Yan Yang, Xiandu Pan, Ran Zhao, Fan Yang, Jiahao Sun, Shengjie Yang, Li Tian, Xiaofang He, Eryu Wang, Yiyuan Yang, Yanwei Xing
Journal: JAMA Network Open (2024)

Importance Prehypertension increases the risk of developing hypertension and other cardiovascular diseases. Early and effective intervention for patients with prehypertension is highly important. Objective To assess the efficacy of Tai Chi vs aerobic exercise in patients with prehypertension. Design, Setting, and Participants This prospective, single-blinded randomized clinical trial was conducted between July 25, 2019, and January 24, 2022, at 2 tertiary public hospitals in China. Participants included 342 adults aged 18 to 65 years with prehypertension, defined as systolic blood pressure (SBP) of 120 to 139 mm Hg and/or diastolic BP (DBP) of 80 to 89 mm Hg. Interventions Participants were randomized in a 1:1 ratio to a Tai Chi group (n = 173) or an aerobic exercise group (n = 169). Both groups performed four 60-minute supervised sessions per week for 12 months. Main Outcomes and Measures The primary outcome was SBP at 12 months obtained in the office setting. Secondary outcomes included SBP at 6 months and DBP at 6 and 12 months obtained in the office setting and 24-hour ambulatory BP at 12 months. Results Of the 1189 patients screened, 342 (mean [SD] age, 49.3 [11.9] years; 166 men [48.5%] and 176 women [51.5%]) were randomized to 1 of 2 intervention groups: 173 to Tai Chi and 169 to aerobic exercise. At 12 months, the change in office SBP was significantly different between groups by −2.40 (95% CI, −4.39 to −0.41) mm Hg ( P = .02), with a mean (SD) change of −7.01 (10.12) mm Hg in the Tai Chi group vs −4.61 (8.47) mm Hg in the aerobic exercise group. The analysis of office SBP at 6 months yielded similar results (−2.31 [95% CI, −3.94 to −0.67] mm Hg; P = .006). Additionally, 24-hour ambulatory SBP (−2.16 [95% CI, −3.84 to −0.47] mm Hg; P = .01) and nighttime ambulatory SBP (−4.08 [95% CI, −6.59 to −1.57] mm Hg; P = .002) were significantly reduced in the Tai Chi group compared with the aerobic exercise group. Conclusions and Relevance In this study including patients with prehypertension, a 12-month Tai Chi intervention was more effective than aerobic exercise in reducing SBP. These findings suggest that Tai Chi may help promote the prevention of cardiovascular disease in populations with prehypertension. Trial Registration Chinese Clinical Trial Registry Identifier: ChiCTR1900024368
Advancing Equity at the JAMA Network—Self-Reported Demographics of Editors and Editorial Board Members
Authors: Kirsten Bibbins-Domingo, Annette Flanagin, Caroline Sietmann, Robert O. Bonow, Ann Marie Navar, Kanade Shinkai, Mya L. Roberson, John Z. Ayanian, Ninez Ponce, Sharon K. Inouye, Raegan W. Durant, Melissa A. Simon, Frederick P. Rivara, Monica Vela, S. Andrew Josephson, Ashley Rawls, Mary L. (Nora) Disis, Narjust Florez, Neil M. Bressler, Adrienne W. Scott, Jay F. Piccirillo, Nosayaba Osazuwa-Peters, Dimitri A. Christakis, Andrea F. Duncan, Dost Öngür, Kara S. Bagot, Melina R. Kibbe, Leah Monique Backhus, Preeti N. Malani
Journal: JAMA (2024)

Phil B. Fontanarosa, MD, MBA; Annette Flanagin, RN, MA; John Z. Ayanian, MD, MPP; Robert O. Bonow, MD, MS; Neil M. Bressler, MD; Dimitri Christakis, MD, MPH; Mary L. Disis, MD; S. Andrew Josephson, MD; Melina R. Kibbe, MD; Dost Öngür, MD, PhD; Jay F. Piccirillo, MD; Rita F. Redberg, MD, MPH; Frederick P. Rivara, MD, MPH; Kanade Shinkai, MD, PhD; Clyde W. Yancy, MD, MSc
Heat and Cold Wave–Related Mortality Risk among United States Veterans with Chronic Obstructive Pulmonary Disease: A Case-Crossover Study
Authors: Austin Rau, Gillian A.M. Tarr, Arianne K. Baldomero, Chris H. Wendt, Bruce H. Alexander, Jesse D. Berman
Journal: Environmental Health Perspectives (2024)

Chronic obstructive pulmonary disease (COPD) is a heterogeneous pulmonary disease affecting 16 million Americans. Individuals with COPD are susceptible to environmental disturbances including heat and cold waves that can exacerbate disease symptoms.
Cardiovascular magnetic resonance imaging-derived intraventricular pressure gradients in ST-segment elevation myocardial infarction: a long-term follow-up study
Authors: Lara S F Konijnenberg, Casper W H Beijnink, Maarten van Lieshout, Jacqueline L Vos, Laura Rodwell, Vicente Bodi, José T Ortiz-Pérez, Niels van Royen, José Rodriguez Palomares, Robin Nijveldt
Journal:  (2024)

Abstract Aims Recently, novel post-processing tools have become available that measure intraventricular pressure gradients (IVPGs) on routinely obtained long-axis cine cardiac magnetic resonance (CMR) images. IVPGs provide a comprehensive overview of both systolic and diastolic left ventricular (LV) functions. Whether IVPGs are associated with clinical outcome after ST-elevation myocardial infarction (STEMI) is currently unknown. Here, we investigated the association between CMR-derived LV-IVPGs and major adverse cardiovascular events (MACE) in a large reperfused STEMI cohort with long-term outcome. Methods and results In this prospectively enrolled multi-centre cohort study, 307 patients underwent CMR within 14 days after the first STEMI. LV-IVPGs (from apex-to-base) were estimated on the long-axis cine images. During a median follow-up of 9.7 (5.9–12.5) years, MACE (i.e. composite of cardiovascular death and de novo heart failure hospitalisation) occurred in 49 patients (16.0%). These patients had larger infarcts, more often microvascular injury, and impaired LV-IVPGs. In univariable Cox regression, overall LV-IVPG was significantly associated with MACE and remained significantly associated after adjustment for common clinical risk factors (hazard ratio (HR) 0.873, 95% confidence interval (CI) 0.794–0.961, P = 0.005) and myocardial injury parameters (HR 0.906, 95% CI 0.825–0.995, P = 0.038). However, adjusted for LV ejection fraction and LV global longitudinal strain (GLS), overall LV-IVPG does not provide additional prognostic information (HR 0.959, 95% CI 0.866–1.063, P = 0.426). Conclusion Early after STEMI, CMR-derived LV-IVPGs are univariably associated with MACE and this association remains significant after adjustment for common clinical risk factors and measures of infarct severity. However, LV-IVPGs do not add prognostic value to LV ejection fraction and LV GLS.
Ultrasmall Nanoparticles Regulate Immune Microenvironment by Activating IL‐33/ST2 to Alleviate Renal Ischemia‐Reperfusion Injury
Authors: Liyao Xu, Zhaoyu Xing, Jiaxin Yuan, Yaobao Han, Zhilin Jiang, Mengxiao Han, Xianao Hou, Wei Xing, Zhen Li
Journal: Advanced Healthcare Materials (2024)

Renal ischemia-reperfusion injury (IRI) is a common disease with high morbidity and mortality. Renal IRI can cause the disorder of immune microenvironment and reprograming the immune microenvironment to alleviate excessive inflammatory response is crucial for its treatment. Cytokine IL-33 can improve the immune inflammatory microenvironment by modulating both innate and adaptive immune cells, and serve as an important target for modulating immune microenvironment of renal IRI. Herein, we report that bilobetin-functionalized ultrasmall Cu
Effectiveness of integrating a pragmatic pathway for prescribing liraglutide 3.0 mg in weight management services (STRIVE study): a multicentre, open-label, parallel-group, randomized controlled trial
Authors: Dimitris Papamargaritis, Werd Al-Najim, Jonathan Z.M. Lim, James Crane, Danielle H. Bodicoat, Shaun Barber, Michael Lean, Barbara McGowan, Donal O’Shea, David R. Webb, John P.H. Wilding, Carel W. le Roux, Melanie J. Davies
Journal: The Lancet Regional Health - Europe (2024)

An effective prescribing pathway for liraglutide 3 mg, an approved obesity pharmacotherapy, may improve treatment access. This trial compared a targeted prescribing pathway for liraglutide 3 mg with multiple stopping rules in specialist weight management services (SWMS) to standard SWMS care.