tbuckley/cabot-search huggingface dataset:
Human cytomegalovirus UL18 prevents priming of MHC-E– and MHC-II–restricted CD8 <sup>+</sup> T cells
Authors: Daniel Malouli, Husam Taher, Mandana Mansouri, Ravi F. Iyer, Jason Reed, Courtney Papen, John B. Schell, Teresa Beechwood, Thomas Martinson, David Morrow, Colette M. Hughes, Roxanne M. Gilbride, Kurt Randall, Julia C. Ford, Karina Belica, Sohita Ojha, Jonah B. Sacha, Benjamin N. Bimber, Scott G. Hansen, Louis J. Picker, Klaus Früh
Journal: Science Immunology (2024)

Rhesus cytomegalovirus (RhCMV) vectors elicit major histocompatibility complex (MHC)–E–restricted CD8 + T cells that stringently control simian immunodeficiency virus (SIV) in rhesus macaques. These responses require deletion of eight RhCMV chemokine-like open reading frames (ORFs) that are conserved in human cytomegalovirus (HCMV). To determine whether HCMV encodes additional, nonconserved inhibitors of unconventional T cell priming, we inserted 41 HCMV-specific ORFs into a chemokine-deficient strain (68-1 RhCMV). Monitoring of epitope recognition revealed that HCMV UL18 prevented unconventional T cell priming, resulting in MHC-Ia–targeted responses. UL18 is homologous to MHC-I but does not engage T cell receptors and, instead, binds with high affinity to inhibitory leukocyte immunoglobulin-like receptor–1 (LIR-1). UL18 lacking LIR-1 binding no longer interfered with MHC-E–restricted T cell stimulation by RhCMV-infected cells or the induction of unconventionally restricted T cells. Thus, LIR-1 binding needs to be deleted from UL18 of HCMV/HIV vaccines to allow for the induction of protective MHC-E–restricted T cells.
Contactin-4 suppresses antitumor T cell responses by engaging amyloid precursor protein
Authors: Bu-Nam Jeon, Sujeong Kim, Yunjae Kim, Hyunkyung Yu, Changho Park, Gihyeon Kim, Youngeun Ha, Gyeong-yeon Kim, Hyunuk Kim, Karolina A. Palucka, Charles Lee, Miyoung Cha, Hansoo Park
Journal: Science Immunology (2024)

Immune checkpoint inhibitors have substantial advanced tumor treatment, but their limited benefits and strong responses in only a subset of patients remain challenging. In this study, we explored the immunomodulatory function of contactin-4 (CNTN4). CNTN4 was highly expressed in tumor tissues, and expression impaired the antitumor function of T cells. CNTN4 bound to amyloid precursor protein (APP) on T cells, which attenuated conjugation between cancer cells and T cells, and diminished T cell receptor signaling cascades. We developed an anti-CNTN4 antibody (GENA-104A16) and an anti-APP antibody (5A7) that blocked the binding between CNTN4 and APP. Administration of either GENA-104A16 or 5A7 promoted antitumor T cell responses in a syngeneic mouse model and increased tumor-infiltrating lymphocytes in vivo. Furthermore, elevated CNTN4 levels were associated with poor prognosis and negatively correlated with various cytotoxic immune-related markers. These results suggest that CNTN4-APP is an inhibitory checkpoint in T cells and represents a promising therapeutic strategy for cancer immunotherapy.
Saving the Health Care Safety Net: Progress and Opportunities
Authors: Paula Chatterjee
Journal: Annual Review of Public Health (2024)

The health care safety net provides essential clinical care and social services for low-income, uninsured, and underinsured populations in the United States. Despite these important functions, the health care safety net has experienced recurrent financial instability, growing market pressures, and workforce strain. Payment reform has also introduced unique challenges for safety net providers related to measuring and reaching quality benchmarks. A common theme among these challenges is that many of them result from applying standard health policy approaches to the safety net instead of using safety net–specific approaches. This review describes progress toward strengthening the safety net, key challenges, and opportunities moving forward.
Pandrug-resistant Klebsiella pneumoniae isolated from Ukrainian war victims are hypervirulent
Authors: Oskar Ljungquist, Michal Magda, Christian G. Giske, Chaitanya Tellapragada, Oleksandr Nazarchuk, Dmytro Dmytriiev, Oskar Thofte, Valdemar Öhnström, Erika Matuschek, Anna M. Blom, Kristian Riesbeck
Journal: Journal of Infection (2024)

Highlights•Thirty-seven Klebsiella pneumoniae isolates from Ukraine were resistant to carbapenems and cephalosporins, including 9 that were also resistant to colistin.•Genome sequencing revealed multiple resistance and virulence genes present in the isolates.•Colistin-resistant isolates were found to carry point mutations in pmrB and phoP genes associated with resistance.•Colistin-resistant isolates had higher serum resistance, were more virulent against Galleria mellonella larvae, and had better survival in mice.•Virulence genes iucA, peg-344, rmpA, rmpC, rmpD were linked to higher virulence.•Hypervirulent, drug-resistant K. pneumoniae from Ukraine pose a significant risk.AbstractObjectivesCarbapenem- and colistin-resistant Klebsiella pneumoniae were isolated from war victims treated in hospitals in Ukraine. The question was whether these pandrug-resistant K. pneumoniae are pathogenic and capable of causing disease in a broader context.MethodsKlebsiella pneumoniae clinical isolates (n = 37) were tested for antibiotic resistance and subjected to whole-genome sequencing (WGS). In addition, their pathogenicity was tested by serum resistance and two separate animal models.ResultsIsolates belonging to the sequence types (ST) 23, 147, 307, 395, and 512 were found to harbor resistance genes against carbapenems and cephalosporins. Nine isolates carried point mutations in pmrB and phoP genes associated with colistin resistance. All bacteria were equipped with multiple virulence genes, and the colistin-resistant isolates each carried 10 different genes. Colistin-resistant K. pneumoniae were more serum-resistant, more virulent against G. mellonella larvae, and displayed an increased survival in mice compared to colistin-susceptible bacteria. The iucA, peg-344, rmpA, rmpC, and rmpD genes were associated with increased virulence in animals.ConclusionsPandrug-resistant K. pneumoniae in Ukraine are hypervirulent and retain their pathogenicity, highlighting the need to prevent disseminated spread.
EULAR recommendations for the treatment of systemic sclerosis: 2023 update
Authors: Francesco Del Galdo, Alain Lescoat, Philip G. Conaghan, Eugenia Bertoldo, Jelena Čolić, Tânia Santiago, Yossra A. Suliman, Marco Matucci-Cerinic, Armando Gabrielli, Oliver Distler, Anna-Maria Hoffmann-Vold, Ivan Castellví, Alexandra Balbir-Gurman, Madelon Vonk, Lidia Ananyeva, Simona Rednic, Anna Tarasova, Pedrag Ostojic, Vladimira Boyadzhieva, Khadija El Aoufy, Sue Farrington, Ilaria Galetti, Christopher P. Denton, Otylia Kowal-Bielecka, Ulf Mueller-Ladner, Yannick Allanore
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Objectives</h3> To update the 2017 European Alliance of Associations for Rheumatology (EULAR) recommendations for treatment of systemic sclerosis (SSc), incorporating new evidence and therapies. <h3>Methods</h3> An international task force was convened in line with EULAR standard operating procedures. A nominal group technique exercise was performed in two rounds to define questions underpinning a subsequent systematic literature review. The evidence derived was discussed and overarching principles, recommendations and future research agenda were iteratively developed with voting rounds. <h3>Results</h3> The task force agreed on 22 recommendations covering 8 clinical/organ domains including Raynaud's phenomenon, digital ulcers, pulmonary arterial hypertension, scleroderma renal crisis, skin fibrosis, interstitial lung disease (ILD), gastrointestinal manifestations and arthritis. Most new recommendations are related to skin fibrosis and ILD. These included novel recommendations for the use of mycophenolate mofetil, nintedanib, rituximab and tocilizumab for the treatment of these crucial disease manifestations. The recommendations also included first-line and second-line interventions, providing increased utility for rheumatology practitioners. Important additions to the future research agenda included consideration of novel interventions for the management of vascular, musculoskeletal and gastrointestinal manifestations and calcinosis, as well as for the local management of digital ulcers. <h3>Conclusion</h3> These updated recommendations include the first set of synthetic and biological targeted therapies recommended for key fibrotic manifestations of SSc as well as first-line combination treatment for newly diagnosed pulmonary artery hypertension and prioritise a new research agenda for the coming years.
#WhatWouldYouDo? A cross-sectional study of sports medicine physicians assessing their competency in managing harassment and abuse in sports
Authors: Margo Mountjoy, Helena Verhelle, Jonathan T Finnoff, Andrew Murray, Amanda Paynter, Fabio Pigozzi, Camille Tooth, Evert Verhagen, Tine Vertommen
Journal: British Journal of Sports Medicine (2024)

Objectives To assess the clinical competence of sports medicine physicians to recognise and report harassment and abuse in sports, and to identify barriers to reporting and the need for safeguarding education. Methods We implemented a cross-sectional cohort study design recruiting through social media and international sports medicine networks in 2023. The survey captured participant perceptions related to the harmfulness of harassment and abuse. The survey incorporated the reasoned action approach as a theoretical framework to design survey questions to identify attitudes and self-efficacy to detect and report suspicions of harassment and abuse and to identify barriers to reporting. Results Sports medicine physicians (n=406) from 115 countries completed the survey. The situations of harassment and abuse presented in the survey were described by sports medicine physicians as having occurred in the 12 months before participating in the survey. Despite recognising the situations as harmful, sports medicine physicians were somewhat uncomfortable being vigilant for the signs and symptoms and reporting suspicions and disclosures of harassment and abuse (M=2.13, SD=0.67). In addition, just over one-quarter (n = 101, 26.9%) was unaware of where to report harassment and abuse, and over half did not know (n = 114, 28.1%), or were uncertain (n = 95, 23.4%) of who the safeguarding officer was in their sports organisation. Participants identified many barriers to reporting harassment and abuse, including concerns regarding confidentiality, misdiagnosis, fear of reprisals, time constraints and lack of knowledge. Over half felt insufficiently trained (n = 223, 57.6%), and most respondents (n=324, 84.6%) desired more education in the field. Conclusions Educational programmes to better recognise and report harassment and abuse in sports are needed for sports medicine trainees and practising clinicians. An international safeguarding code for sports medicine physicians should be developed.
Precise identification and tracking of HMGCR-reactive CD4+ T cells in the target tissue of patients with anti-HMGCR immune-mediated necrotising myopathy
Authors: Eleni Tiniakou, Alex Girgis, Tiara Siafei, Jemima Albayda, Brittany Adler, Julie J. Paik, Christopher A. Mecoli, Alison Rebman, Mark J. Soloski, Lisa Christopher-Stine, Kellie N. Smith, Antony Rosen, Andrew Lee Mammen, Erika Darrah
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background</h3> Anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR)-positive immune-mediated necrotising myopathy (IMNM) is characterised by the presence of IgG autoantibodies against HMGCR and a strong association with specific HLA-DR alleles. Although these findings implicate HMGCR-specific CD4<sup>+</sup>T-cells in the disease's pathogenesis, no such cells have been described. In this study, we aimed to identify and characterise HMGCR-reactive CD4<sup>+</sup>T-cells and assess their presence in affected muscle tissue from patients with anti-HMGCR+IMNM. <h3>Methods</h3> Peripheral blood mononuclear cells from patients with anti-HMGCR+IMNM (n=10) and dermatomyositis (DM; n=10) were stimulated with HMGCR protein and peptides identified using a natural antigen processing assay (NAPA; n=6). CD4<sup>+</sup>T-cell activation was assessed by CD154 upregulation via flow cytometry. T-cell receptor β(TCR) sequencing was performed on paired HMGCR-reactive T-cells and muscle biopsy tissue (n=5). <h3>Results</h3> CD4<sup>+</sup>T-cell responses to HMGCR protein were higher in patients with anti-HMGCR+IMNM compared with DM (median 0.06 vs 0.00, p=0.0059). These responses were enriched in Th1-Th17 cells, and when present, they positively correlated with anti-HMGCR antibody levels (r<sup>2</sup>=0.89, p=0.0012). NAPA revealed convergent presentation of seven HMGCR core peptides, with substantial overlap in the peptide repertoires between patients. These HMGCR peptides elicited robust CD4<sup>+</sup>T-cell responses, with 9/10 anti-HMGCR+IMNM patients responding to at least one peptide, compared with 1/10 DM (p=0.0003). Analysis of HMGCR-reactive TCRs β yielded antigen-reactive motifs that were enriched in muscle biopsies (projection score 0.03 vs 0.63, p=0.007). <h3>Conclusion</h3> HMGCR-antigen-reactive CD4<sup>+</sup>T-cells are present in the circulation and target tissue of patients with anti-HMGCR+IMNM, suggesting an active role for these cells in the pathogenesis of anti-HMGCR+IMNM.
Neurologic Recovery at Discharge and Long-Term Survival After Cardiac Arrest
Authors: Emelie Dillenbeck, Leif Svensson, Araz Rawshani, Jacob Hollenberg, Mattias Ringh, Andreas Claesson, Akil Awad, Martin Jonsson, Per Nordberg
Journal: JAMA Network Open (2024)

Importance Brain injury is the leading cause of death following cardiac arrest and is associated with severe neurologic disabilities among survivors, with profound implications for patients and their families, as well as broader societal impacts. How these disabilities affect long-term survival is largely unknown. Objective To investigate whether complete neurologic recovery at hospital discharge after cardiac arrest is associated with better long-term survival compared with moderate or severe neurologic disabilities. Design, Setting, and Participants This cohort study used data from 4 mandatory national registers with structured and predefined data collection and nationwide coverage during a 10-year period in Sweden. Participants included adults who survived in-hospital cardiac arrest (IHCA) or out-of-hospital cardiac arrest (OHCA) beyond 30 days and who underwent predefined neurologic assessment conducted by health care professionals at hospital discharge using the Cerebral Performance Category (CPC) scale between January 2010 and December 2019. Patients were divided into 3 categories: complete recovery (CPC 1), moderate disabilities (CPC 2), and severe disabilities (CPC 3-4). Statistical analyses were performed in December 2023. Exposure CPC score at hospital discharge. Main Outcomes and Measures The primary outcome was long-term survival among patients with CPC 1 compared with those with CPC 2 or CPC 3 or 4. Results A total of 9390 cardiac arrest survivors (median [IQR] age, 69 .0 [58.0-77.0] years; 6544 [69.7%] male) were included. The distribution of functional neurologic outcomes at discharge was 7374 patients (78.5%) with CPC 1, 1358 patients (14.5%) with CPC 2, and 658 patients (7.0%) with CPC 3 or 4. Survival proportions at 5 years were 73.8% (95% CI, 72.5%-75.0%) for patients with CPC 1, compared with 64.7% (95% CI, 62.4%-67.0%) for patients with CPC 2 and 54.2% (95% CI, 50.6%-57.8%) for patients with CPC 3 or 4. Compared with patients with CPC 1, there was significantly higher hazard of death for patients with CPC 2 (adjusted hazard ratio [aHR], 1.57 [95% CI, 1.40-1.75]) or CPC 3 or 4 (aHR, 2.46 [95% CI, 2.13-2.85]). Similar associations were seen in the OHCA and IHCA groups. Conclusions and Relevance In this cohort study of patients with cardiac arrest who survived beyond 30 days, complete neurologic recovery, defined as CPC 1 at discharge, was associated with better long-term survival compared with neurologic disabilities at the same time point.
Health information for all: do large language models bridge or widen the digital divide?
Authors: Arthur Tang, Neo Tung, Huy Quang Nguyen, Kin On Kwok, Stanley Luong, Nhat Bui, Giang Nguyen, Wilson Tam
Journal: BMJ (2024)

Large language models have the potential to enhance equitable access to health information, but their poor performance in some languages could exacerbate the digital divide in healthcare, say <b>Arthur Tang and colleagues</b>
The Effect of Teleprehabilitation on Adverse Events After Elective Cardiac Surgery: A Randomized Controlled Trial
Authors: Bart Scheenstra, Lieke van Susante, Bart C Bongers, Ton Lenssen, Henriette Knols, Sander van Kuijk, Maxime Nieman, Jos Maessen, Arnoud Van't Hof, Peyman Sardari Nia
Journal: Journal of the American College of Cardiology (2024)

Patients scheduled for cardiac surgery and procedures often present with modifiable risk factors for adverse perioperative outcomes. Prehabilitation has shown potential to enhance mental and physical fitness; however, its effect on clinical cardiovascular endpoints in this population has not been studied.
The Intersecting Time, Administrative and Financial Burdens of a Cancer Diagnosis
Authors: Helen M Parsons, Arjun Gupta, Patricia Jewett, Rachel I Vogel
Journal: JNCI Journal of the National Cancer Institute (2024)

Cancer and its care create substantial financial, time, and administrative burdens both for patients and their loved ones. While cancer-related financial burdens have been well documented in the past decade, time and administrative burdens of cancer care have received substantially less attention. We define time burdens as the burden patients and caregivers experience due to the time needed to complete cancer-related treatment and tasks that take away from other life responsibilities. Relatedly, we conceptualize administrative burdens as those burdens patients and caregivers experience due to cancer-related, resource-consuming bureaucratic and logistical tasks. Finally, financial hardship can be conceptualized as problems patients experience related to the cost of medical care. These burdens do not exist in isolation; time, administrative, and financial burdens intersect with and compound each other. Currently, we have limited evidence-based measures on the objective (e.g., scheduling time, transportation, wait time) and subjective (e.g., mental, emotional and physical stress) measures of time and administrative burden. We have even more limited evidence of the risk factors for and outcomes from increased time and administrative burdens, and how they differentially impact populations across social and demographic groups. In this commentary, we present a research agenda to map, measure, evaluate, and mitigate the time, administrative, and financial burdens of cancer and its care.
Grade-stratified meningioma risk among individuals who are Non-Hispanic black and interactions with male sex
Authors: Kyle M Walsh, Mackenzie Price, David R Raleigh, Evan Calabrese, Carol Kruchko, Jill S Barnholtz-Sloan, Quinn T Ostrom
Journal: JNCI Journal of the National Cancer Institute (2024)

Meningioma risk factors include older age, female sex, and African-American race. Limited data explore how meningioma risk in African-Americans varies across the lifespan, interacts with sex, and differs by tumor grade.
Risk factors for second primary breast cancer by laterality, age, and race and ethnicity
Authors: Esther M John, Jocelyn Koo, Sue A Ingles, Theresa H Keegan, Scarlett L Gomez, Christopher A Haiman, Allison W Kurian, Marilyn L Kwan, Susan L Neuhausen, Salma Shariff-Marco, Catherine Thomsen, Anna H Wu, Iona Cheng
Journal: JNCI Journal of the National Cancer Institute (2024)

Epidemiologic studies of risk factors for second primary breast cancer (SBC) have been conducted primarily in non-Hispanic White (NHW) women.
Waste clearance shapes aging brain health
Authors: Li-Feng Jiang-Xie, Antoine Drieu, Jonathan Kipnis
Journal: Neuron (2024)

SummaryBrain health is intimately connected to fluid flow dynamics that cleanse the brain of potentially harmful waste material. This system is regulated by vascular dynamics, the maintenance of perivascular spaces, neural activity during sleep, and lymphatic drainage in the meningeal layers. However, aging can impinge on each of these layers of regulation, leading to impaired brain cleansing and the emergence of various age-associated neurological disorders, including Alzheimer's and Parkinson's diseases. Understanding the intricacies of fluid flow regulation in the brain and how this becomes altered with age could reveal new targets and therapeutic strategies to tackle age-associated neurological decline.
Microglia and monocyte-derived macrophages drive progression of pediatric high-grade gliomas and are transcriptionally shaped by histone mutations
Authors: James L. Ross, Montserrat Puigdelloses-Vallcorba, Gonzalo Piñero, Nishant Soni, Wes Thomason, John DeSisto, Angelo Angione, Nadejda M. Tsankova, Maria G. Castro, Matthew Schniederjan, Nitin R. Wadhwani, G. Praveen Raju, Peter Morgenstern, Oren J. Becher, Adam L. Green, Alexander M. Tsankov, Dolores Hambardzumyan
Journal: Immunity (2024)
Prostate cancer microenvironment: multidimensional regulation of immune cells, vascular system, stromal cells, and microbiota
Authors: Lin Chen, Yu-Xin Xu, Yuan-Shuo Wang, Ying-Ying Ren, Xue-Man Dong, Pu Wu, Tian Xie, Qi Zhang, Jian-Liang Zhou
Journal: Molecular Cancer (2024)

Prostate cancer (PCa) is one of the most prevalent malignancies in males worldwide. Increasing research attention has focused on the PCa microenvironment, which plays a crucial role in tumor progression and therapy resistance. This review aims to provide a comprehensive overview of the key components of the PCa microenvironment, including immune cells, vascular systems, stromal cells, and microbiota, and explore their implications for diagnosis and treatment. Keywords such as "prostate cancer", "tumor microenvironment", "immune cells", "vascular system", "stromal cells", and "microbiota" were used for literature retrieval through online databases including PubMed and Web of Science. Studies related to the PCa microenvironment were selected, with a particular focus on those discussing the roles of immune cells, vascular systems, stromal cells, and microbiota in the development, progression, and treatment of PCa. The selection criteria prioritized peer-reviewed articles published in the last five years, aiming to summarize and analyze the latest research advancements and clinical relevance regarding the PCa microenvironment. The PCa microenvironment is highly complex and dynamic, with immune cells contributing to immunosuppressive conditions, stromal cells promoting tumor growth, and microbiota potentially affecting androgen metabolism. Vascular systems support angiogenesis, which fosters tumor expansion. Understanding these components offers insight into the mechanisms driving PCa progression and opens avenues for novel therapeutic strategies targeting the tumor microenvironment. A deeper understanding of the PCa microenvironment is crucial for advancing diagnostic techniques and developing precision therapies. This review highlights the potential of targeting the microenvironment to improve patient outcomes, emphasizing its significance in the broader context of PCa research and treatment innovation.