tbuckley/cabot-search huggingface dataset:
Genetic variation in severe cystic fibrosis liver disease is associated with novel mechanisms for disease pathogenesis
Authors: Jaclyn R. Stonebraker, Rhonda G. Pace, Paul J. Gallins, Hong Dang, Melis A. Aksit, Anna V. Faino, William W. Gordon, Sonya MacParland, Michael J. Bamshad, Ronald L. Gibson, Garry R. Cutting, Peter R. Durie, Fred A. Wright, Yi-Hui Zhou, Scott M. Blackman, Wanda K. O’Neal, Simon C. Ling, Michael R. Knowles
Journal: Hepatology (2024)

It is not known why severe cystic fibrosis (CF) liver disease (CFLD) with portal hypertension occurs in only ~7% of people with CF. We aimed to identify genetic modifiers for severe CFLD to improve understanding of disease mechanisms.
A randomized multicenter trial of a chronic disease management intervention for decompensated cirrhosis. The Australian Liver Failure (ALFIE) trial
Authors: Alan J. Wigg, Sumudu Narayana, Richard J. Woodman, Leon A. Adams, Rachel Wundke, Mohamed A. Chinnaratha, Bin Chen, Gary Jeffrey, Joan-Lee Plummer, Vanessa Sheehan, Edmund Tse, Joanne Morgan, Dep Huynh, Margery Milner, Jeffrey Stewart, Golo Ahlensteil, Asma Baig, Billingsley Kaambwa, Kate Muller, Jeyamani Ramachandran
Journal: Hepatology (2024)

Background and Aims: Improving the care of decompensated cirrhosis is a significant clinical challenge. The primary aim of this trial was to assess the efficacy of a chronic disease management (CDM) model to reduce liver-related emergency admissions (LREA). The secondary aims were to assess model effects on quality-of-care and patient-reported outcomes. Approach and Results: The study design was a 2-year, multicenter, randomized controlled study with 1:1 allocation of a CDM model versus usual care. The study setting involved both tertiary and community care. Participants were randomly allocated following a decompensated cirrhosis admission. The intervention was a multifaceted CDM model coordinated by a liver nurse. A total of 147 participants (intervention=75, control=71) were recruited with a median Model for End-Stage Liver Disease score of 19. For the primary outcome, there was no difference in the overall LREA rate for the intervention group versus the control group (incident rate ratio 0.89; 95% CI: 0.53–1.50, p =0.666) or in actuarial survival (HR=1.14; 95% CI: 0.66–1.96, p =0.646). However, there was a reduced risk of LREA due to encephalopathy in the intervention versus control group (HR=1.87; 95% CI: 1.18–2.96, p =0.007). Significant improvement in quality-of-care measures was seen for the performance of bone density ( p &lt;0.001), vitamin D testing ( p &lt;0.001), and HCC surveillance adherence ( p =0.050). For assessable participants (44/74 intervention, 32/71 controls) significant improvements in patient-reported outcomes at 3 months were seen in self-management ability and quality of life as assessed by visual analog scale ( p =0.044). Conclusions: This CDM intervention did not reduce overall LREA events and may not be effective in decompensated cirrhosis for this end point.
Quality measures in pre-liver transplant care by the Practice Metrics Committee of the American Association for the Study of Liver Diseases
Authors: Mayur Brahmania, Alexander Kuo, Elliot B. Tapper, Michael L. Volk, Jennifer M. Vittorio, Marwan Ghabril, Timothy R. Morgan, Fasiha Kanwal, Neehar D. Parikh, Paul Martin, Shivang Mehta, Gerald Scott Winder, Gene Y. Im, David Goldberg, Jennifer C. Lai, Andres Duarte-Rojo, Angelo H. Paredes, Arpan A. Patel, Amandeep Sahota, Lisa M. McElroy, Charlie Thomas, Anji E. Wall, Maricar Malinis, Saima Aslam, Douglas A. Simonetto, Nneka N. Ufere, Sudha Ramakrishnan, Mary Margaret Flynn, Yasmin Ibrahim, Sumeet K. Asrani, Marina Serper
Journal: Hepatology (2024)

The liver transplantation (LT) evaluation and waitlisting process is subject to variations in care that can impede quality. The American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) developed quality measures and patient-reported experience measures along the continuum of pre-LT care to reduce care variation and guide patient-centered care. Following a systematic literature review, candidate pre-LT measures were grouped into 4 phases of care: referral, evaluation and waitlisting, waitlist management, and organ acceptance. A modified Delphi panel with content expertise in hepatology, transplant surgery, psychiatry, transplant infectious disease, palliative care, and social work selected the final set. Candidate patient-reported experience measures spanned domains of cognitive health, emotional health, social well-being, and understanding the LT process. Of the 71 candidate measures, 41 were selected: 9 for referral; 20 for evaluation and waitlisting; 7 for waitlist management; and 5 for organ acceptance. A total of 14 were related to structure, 17 were process measures, and 10 were outcome measures that focused on elements not typically measured in routine care. Among the patient-reported experience measures, candidates of LT rated items from understanding the LT process domain as the most important. The proposed pre-LT measures provide a framework for quality improvement and care standardization among candidates of LT. Select measures apply to various stakeholders such as referring practitioners in the community and LT centers. Clinically meaningful measures that are distinct from those used for regulatory transplant reporting may facilitate local quality improvement initiatives to improve access and quality of care.
An Unexpected Seminal Vesicle Pitfall in PSMA PET
Authors: Angela Bronte, Juan J. Rosales, Marcos Torres Roca, Bernardino Miñana, Macarena Rodríguez-Fraile
Journal: Clinical Nuclear Medicine (2024)

Abstract A 76-year-old man undergoing hormone therapy for prostate cancer was referred for 68 Ga-PSMA-11-PET (PSMA PET) due to persistently detectable PSA level. No PSMA-positive tumor lesions were detected, so a delayed phase imaging was performed, which revealed focal PSMA uptake in the right seminal vesicle together with contrast accumulation on excretory phase contrast-enhanced CT. These findings were finally determined to be secondary to urinary reflux as a consequence of a prostatic enucleation he had undergone 5 months earlier following an episode of acute urinary retention.
Letter regarding “Impact of Bevacizumab Being Skipped due to Adverse Events of Special Interest for Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab: An Exploratory Analysis of the Phase III IMbrave150 Study”
Authors: Takeshi Hatanaka, Atsushi Hiraoka, Toshifumi Tada, Satoru Kakizaki
Journal: Liver Cancer (2024)
External Trigger Free Charge Switchable Cationic Ligands in the Design of Safe and Effective Universal Heparin Antidote
Authors: Chanel C. La, Stephanie A. Smith, Manu Thomas Kalathottukaren, Charles A. Haynes, James H. Morrissey, Jayachandran N. Kizhakkedathu
Journal: Advanced Healthcare Materials (2024)

Abstract Thrombosis, the formation of blood clots within a blood vessel, can lead to severe complications including pulmonary embolism, cardiac arrest, and stroke. The most widely administered class of anticoagulants is heparin‐based anticoagulants such as unfractionated heparin, low‐molecular weight heparins (LMWHs), and fondaparinux. Protamine is the only FDA‐approved heparin antidote. Protamine has limited efficacy neutralizing LMWHs and no reversal activity against fondaparinux. The use of protamine can lead to complications, including excessive bleeding, hypotension, and hypersensitivity, and has narrow therapeutic window. In this work, a new concept in the design of a universal heparin antidote: switchable protonation of cationic ligands, is presented. A library of macromolecular polyanion inhibitors (MPIs) is synthesized and screened to identify molecules that can neutralize all heparins with high selectivity and reduced toxicity. MPIs are developed by assembling cationic binding groups possessing switchable protonation states onto a polymer scaffold. By strategically selecting the identity and modulating the density of cationic binding groups on the polymer scaffold, a superior universal heparin reversal agent is developed with improved heparin‐binding activity and increased hemocompatibility profiles leading to minimal effect on hemostasis. The activity of this heparin antidote is demonstrated using in vitro and in vivo studies.
Improved access to the innovative anticancer therapies in resource-limited countries: call for global action
Authors: Yosra Vaez-Gharamaleki, Mohammad-Salar Hosseini
Journal: International Journal of Surgery (2024)

aHematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran bStudent Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran cResearch Center for Evidence-Based Medicine, Iranian EBM Center: A JBI Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran dResearch Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran eClinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding author. Address: Research Center for Evidence-Based Medicine, Tabriz University of Medical Sciences, Golgasht Street, Postal code 51666, Tabriz, EA, Iran. Telephone Number: +984133366581. Fax Number: +984133341994. E-mail address: [email protected], [email protected] (M-S. Hosseini). This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/
A commentary on “C-reactive protein/lymphocyte ratio as a prognostic biomarker in acute pancreatitis: A cross-sectional study assessing disease severity”
Authors: Jing Wang, Yunyang Xu, Ze Xiang, Hua Zhu
Journal: International Journal of Surgery (2024)

aDepartment of Gastroenterology, Affiliated Hospital 6 of Nantong University, Yancheng Third People's Hospital, Yancheng 224001, Jiangsu, China bAffiliated Yancheng Hospital, School of Medicine, Southeast University, Yancheng 224001, Jiangsu, China cZhejiang University School of Medicine, Hangzhou 310058, China Jing Wang, Yunyang Xu These authors contributed equally to this work. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding author. Address: Department of Gastroenterology, Affiliated Hospital 6 of Nantong University, Yancheng Third People's Hospital, Yancheng 224001, Jiangsu, China. E-mail address: [email protected] (H. Zhu). *Corresponding author. Address: Zhejiang University School of Medicine, Hangzhou 310058, China. E-mail address: [email protected] (Z. Xiang). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/
Derivation and external validation of a simple risk score for predicting severe acute kidney injury after intravenous cisplatin: cohort study
Authors: Shruti Gupta, Ilya G Glezerman, Jamie S Hirsch, Kevin L Chen, Nishant Devaraj, Sophia L Wells, Robert H Seitter, Sarah A Kaunfer, Arunima M Jose, Shreya P Rao, Jessica L Ortega, Olivia Green-Lingren, Robert Hayden, Pavan K Bendapudi, Donald F Chute, Meghan E Sise, Kenar D Jhaveri, Valda D Page, Matthew H Abramson, Shveta S Motwani, Wenxin Xu, Kartik Sehgal, Kerry L Reynolds, Anip Bansal, Ala Abudayyeh, David E Leaf
Journal: BMJ (2024)

To develop and externally validate a prediction model for severe cisplatin associated acute kidney injury (CP-AKI).
Pack-Year Smoking History: An Inadequate and Biased Measure to Determine Lung Cancer Screening Eligibility
Authors: Alexandra L. Potter, Nuo N. Xu, Priyanka Senthil, Deepti Srinivasan, Hang Lee, G. Scott Gazelle, Lydia Chelala, Wei Zheng, Florian J. Fintelmann, Lecia V. Sequist, Jessica Donington, Julie R. Palmer, Chi-Fu Jeffrey Yang
Journal: Journal of Clinical Oncology (2024)

PURPOSE Pack-year smoking history is an imperfect and biased measure of cumulative tobacco exposure. The use of pack-year smoking history to determine lung cancer screening eligibility in the current US Preventive Services Task Force (USPSTF) guideline may unintentionally exclude many high-risk individuals, especially those from racial and ethnic minority groups. It is unclear whether using a smoking duration cutoff instead of a smoking pack-year cutoff would improve the selection of individuals for screening. METHODS We analyzed 49,703 individuals with a smoking history from the Southern Community Cohort Study (SCCS) and 22,126 individuals with a smoking history from the Black Women's Health Study (BWHS) to assess eligibility for screening under the USPSTF guideline versus a proposed guideline that replaces the ≥20-pack-year criterion with a ≥20-year smoking duration criterion. Results Under the USPSTF guideline, only 57.6% of Black patients with lung cancer in the SCCS would have qualified for screening, whereas a significantly higher percentage of White patients with lung cancer (74.0%) would have qualified ( P &lt; .001). Under the proposed guideline, the percentage of Black and White patients with lung cancer who would have qualified for screening increased to 85.3% and 82.0%, respectively, eradicating the disparity in screening eligibility between the groups. In the BWHS, using a 20-year smoking duration cutoff instead of a 20-pack-year cutoff increased the percentage of Black women with lung cancer who would have qualified for screening from 42.5% to 63.8%. Conclusion Use of a 20-year smoking duration cutoff instead of a 20-pack-year cutoff greatly increases the proportion of patients with lung cancer who would qualify for screening and eliminates the racial disparity in screening eligibility between Black versus White individuals; smoking duration has the added benefit of being easier to calculate and being a more precise assessment of smoking exposure compared with pack-year smoking history.
Constructing Linear‐Oriented Pre‐Vascularized Human Spinal Cord Tissues for Spinal Cord Injury Repair
Authors: Caixia Fan, Hui Cai, Lulu Zhang, Xianming Wu, Junyan Yan, Lifang Jin, Baowei Hu, Jiaxiong He, Yanyan Chen, Yannan Zhao, Jianwu Dai
Journal: Advanced Healthcare Materials (2024)

Repairing spinal cord injury (SCI) is a global medical challenge lacking effective clinical treatment. Developing human-engineered spinal cord tissues that can replenish lost cells and restore a regenerative microenvironment offers promising potential for SCI therapy. However, creating vascularized human spinal cord-like tissues (VSCT) that mimic the diverse cell types and longitudinal parallel structural features of spinal cord tissues remains a significant hurdle. In the present study, VSCTs are engineered using embryonic human spinal cord-derived neural and endothelial cells on linear-ordered collagen scaffolds (LOCS). Studies have shown that astrocytes and endothelial cells align along the scaffolds in VSCT, supporting axon extension from various human neurons myelinated by oligodendrocytes. After transplantation into SCI rats, VSCT survives at the injury sites and promotes endogenous neural regeneration and vascularization, ultimately reducing scarring and enhancing behavioral functional recovery. It suggests that pre-vascularization of engineered spinal cord tissues is beneficial for SCI treatment and highlights the important role of exogenous endothelial cells in tissue engineering.
Lessons From Insulin: Policy Prescriptions for Affordable Diabetes and Obesity Medications
Authors: Kathryn E. Nagel, Reshma Ramachandran, Kasia J. Lipska
Journal: Diabetes Care (2024)

Escalating insulin prices have prompted public scrutiny of the practices of drug manufacturers, pharmacy benefit managers, health insurers, and pharmacies involved in production and distribution of medications. As a result, a series of policies have been proposed or enacted to improve insulin affordability and foster greater equity in access. These policies have implications for other diabetes and obesity therapeutics. Recent legislation, at both the state and federal level, has capped insulin out-of-pocket payments for some patients. Other legislation has targeted drug manufacturers directly in requiring rebates on drugs with price increases beyond inflation rates, an approach that may restrain price hikes for existing medications. In addition, government negotiation of drug pricing, a contentious issue, has gained traction, with the Inflation Reduction Act of 2022 permitting limited negotiation for certain high expenditure drugs without generic or biosimilar competition, including some insulin products and other diabetes medications. However, concerns persist that this may inadvertently encourage higher launch prices for new medications. Addressing barriers to competition has also been a priority such as through increased enforcement against anticompetitive practices (e.g., “product hopping”) and reduced regulatory requirements for biosimilar development and market entry. A novel approach involves public production, exemplified by California’s CalRx program, which aims to provide biosimilar insulins at significantly reduced prices. Achieving affordable and equitable access to insulin and other diabetes and obesity medications requires a multifaceted approach, involving state and federal intervention, ongoing policy evaluation and refinement, and critical examination of corporate influences in health care.
The gut microbiota posttranslationally modifies IgA1 in autoimmune glomerulonephritis
Authors: Patrick J. Gleeson, Nicolas Benech, Jonathan Chemouny, Eleftheria Metallinou, Laureline Berthelot, Jennifer da Silva, Julie Bex-Coudrat, Erwan Boedec, Fanny Canesi, Carine Bounaix, Willy Morelle, Maryse Moya-Nilges, John Kenny, Liam O’Mahony, Loredana Saveanu, Bertrand Arnulf, Aurélie Sannier, Eric Daugas, François Vrtovsnik, Patricia Lepage, Harry Sokol, Renato C. Monteiro
Journal: Science Translational Medicine (2024)

Mechanisms underlying the disruption of self-tolerance in acquired autoimmunity remain unclear. Immunoglobulin A (IgA) nephropathy is an acquired autoimmune disease where deglycosylated IgA1 (IgA subclass 1) auto-antigens are recognized by IgG auto-antibodies, forming immune complexes that are deposited in the kidneys, leading to glomerulonephritis. In the intestinal microbiota of patients with IgA nephropathy, there was increased relative abundance of mucin-degrading bacteria, including Akkermansia muciniphila . IgA1 was deglycosylated by A. muciniphila both in vitro and in the intestinal lumen of mice. This generated neo-epitopes that were recognized by autoreactive IgG from the sera of patients with IgA nephropathy. Mice expressing human IgA1 and the human Fc α receptor I (α1 KI -CD89 tg ) that underwent intestinal colonization by A. muciniphila developed an aggravated IgA nephropathy phenotype. After deglycosylation of IgA1 by A. muciniphila in the mouse gut lumen, IgA1 crossed the intestinal epithelium into the circulation by retrotranscytosis and became deposited in the glomeruli of mouse kidneys. Human α-defensins—a risk locus for IgA nephropathy—inhibited growth of A. muciniphila in vitro. A negative correlation observed between stool concentration of α-defensin 6 and quantity of A. muciniphila in the guts of control participants was lost in patients with IgA nephropathy. This study demonstrates that gut microbiota dysbiosis contributes to generation of auto-antigens in patients with IgA nephropathy and in a mouse model of this disease.
Comparison of the immunogenicity and protective efficacy of ACAM2000, MVA, and vectored subunit vaccines for Mpox in rhesus macaques
Authors: Catherine Jacob-Dolan, Darren Ty, David Hope, Katherine McMahan, Jinyan Liu, Olivia C. Powers, Catherine A. Cotter, Michela Sciacca, Cindy Wu, Erica Borducchi, Emily Bouffard, Hannah Richter, Jason Velasco, Elyse Teow, Mona Boursiquot, Anthony Cook, Karen Feliciano, Jake Yalley-Ogunro, Michael S. Seaman, Laurent Pessiant, Mark G. Lewis, Hanne Andersen, Bernard Moss, Dan H. Barouch
Journal: Science Translational Medicine (2024)

The 2022-2023 mpox outbreak triggered vaccination efforts using smallpox vaccines that were approved for mpox, including modified vaccinia Ankara (MVA; JYNNEOS), which is a safer alternative to live replicating vaccinia virus (ACAM2000). Here, we compare the immunogenicity and protective efficacy of JYNNEOS by the subcutaneous or intradermal routes, ACAM2000 by the percutaneous route, and subunit Ad35 vector-based L1R/B5R or L1R/B5R/A27L/A33R vaccines by the intramuscular route in rhesus macaques. All vaccines provided robust protection against high-dose intravenous mpox virus challenge with the current outbreak strain, with ACAM2000 providing near complete protection and JYNNEOS and Ad35 vaccines providing robust but incomplete protection. Protection correlated with neutralizing antibody responses as well as L1R/M1R- and B5R/B6R-specific binding antibody responses, although additional immune responses likely also contributed to protection. This study demonstrates the protective efficacy of multiple vaccine platforms against mpox virus challenge, including both current clinical vaccines and vectored subunit vaccines.
Attenuation of fibroblast activation and fibrosis by adropin in systemic sclerosis
Authors: Minrui Liang, Nicholas Dickel, Andrea-Hermina Györfi, Bilgesu SafakTümerdem, Yi-Nan Li, Aleix Rius Rigau, Chunguang Liang, Xuezhi Hong, Lichong Shen, Alexandru-Emil Matei, Thuong Trinh-Minh, Cuong Tran-Manh, Xiang Zhou, Ariella Zehender, Alexander Kreuter, Hejian Zou, Georg Schett, Meik Kunz, Jörg H. W. Distler
Journal: Science Translational Medicine (2024)

Fibrotic diseases impose a major socioeconomic challenge on modern societies and have limited treatment options. Adropin, a peptide hormone encoded by the energy homeostasis–associated ( ENHO ) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and in vivo experiments to characterize adropin as a potential regulator involved in fibroblast activation and tissue fibrosis in systemic sclerosis (SSc). We demonstrated consistent down-regulation of adropin/ ENHO in skin across multiple cohorts of patients with SSc. The prototypical profibrotic cytokine TGFβ reduced adropin/ ENHO expression in a JNK-dependent manner. Restoration of adropin signaling by therapeutic application of bioactive adropin 34–76 peptides in turn inhibited TGFβ-induced fibroblast activation and fibrotic tissue remodeling in primary human dermal fibroblasts, three-dimensional full-thickness skin equivalents, mouse models of bleomycin-induced pulmonary fibrosis and sclerodermatous chronic graft-versus-host-disease (sclGvHD), and precision-cut human skin slices. Knockdown of GPR19 , an adropin receptor, abrogated the antifibrotic effects of adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of adropin 34–76 were functionally linked to deactivation of GLI1-dependent profibrotic transcriptional networks, which was experimentally confirmed in vitro, in vivo, and ex vivo using cultured human dermal fibroblasts, a sclGvHD mouse model, and precision-cut human skin slices. ChIP-seq confirmed adropin 34–76 -induced changes in TGFβ/GLI1 signaling. Our study characterizes the TGFβ-induced down-regulation of adropin/ ENHO expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling.