tbuckley/cabot-search huggingface dataset:
Tissue-resident T cells in Clinical Response and Immune-related Adverse Events of Immune Checkpoint Blockade
Authors: Ye Zhao, Kai W. Wucherpfennig
Journal: Clinical Cancer Research (2024)

T cell surveillance of tissues is spatially organized: circulating memory T cells perform surveillance of secondary lymphoid organs while tissue-resident memory T cells act as sentinels in barrier tissues. In the context of infection, tissue-resident memory T cells survive long term in barrier tissues and are poised to respond to re-encounter of infectious agents. The activity of such tissue-resident T cells is regulated by the PD-1 and CTLA-4 inhibitory receptors targeted by cancer immunotherapies. This review investigates the hypothesis that T cells with a tissue residency program play an important role in both protective anti-tumor immunity and immune-related adverse events (irAEs) of immune checkpoint blockade (ICB). A series of translational studies have demonstrated that a higher density of tissue-resident T cells within tumors is associated with favorable survival outcomes in a diverse range of cancer types. Tissue-resident T cells have also been implicated in clinical response to immune checkpoint blockade, and dynamic tracking of T cell populations in pre- and on-treatment tumor samples demonstrated that T cells with a tissue residency program responded early to ICB. Investigation of colitis and dermatitis as examples of irAEs demonstrated that tissue-resident memory T cells were reactivated at these epithelial sites, resulting in a highly cytotoxic state and secretion of inflammatory cytokines IFNγ and TNFα. It will therefore be important to consider how a tissue residency program can be enhanced to promote T cell-mediated tumor immunity while preventing the development of irAEs.
FDA Approval Summary: Polatuzumab Vedotin in the First-Line Treatment of Select Large B-cell Lymphomas
Authors: Maryam Sarraf Yazdy, Yvette L. Kasamon, Wenjuan Gu, Lisa R. Rodriguez, Susan Jin, Vishal Bhatnagar, Nicholas C. Richardson, Marc R. Theoret, Richard Pazdur, Nicole J. Gormley
Journal: Clinical Cancer Research (2024)

In April 2023, the U.S. Food and Drug Administration granted regular approval to polatuzumab vedotin-piiq in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (pola+R-CHP) for adult patients who have previously untreated diffuse large B-cell lymphoma, not otherwise specified or high-grade B-cell lymphoma and who have an International Prognostic Index score of 2 or greater. Approval was based on POLARIX, a randomized, double-blinded, placebo-controlled trial evaluating the superiority of substituting vincristine with polatuzumab vedotin in the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen as first-line therapy for patients with large B-cell lymphoma (LBCL). Efficacy was based on investigator-assessed progression-free survival (PFS) in 879 patients who were randomized to receive pola+R-CHP or R-CHOP, followed by two cycles of rituximab alone. PFS was statistically significantly longer with pola+R-CHP with a HR of 0.73 [95% CI: 0.57, 0.95] and log-rank p-value of 0.0177 (two-sided α=0.05). There was no improvement demonstrated in the key secondary endpoints of CR rate at the end of therapy or overall survival (OS). Several issues raised uncertainty about the benefit-risk of polatuzumab vedotin in this curative-intent setting including the modest PFS benefit of pola+R-CHP and lack of OS benefit. The application was therefore presented at an Oncology Drug Advisory Committee. This article summarizes key aspects of the regulatory review, including perspectives on PFS and OS results and other endpoints.
Single-Sample Rule-Out of an Acute Coronary Occlusion With High-Sensitivity Cardiac Troponin—Got the Time?
Authors: Luuk C. Otterspoor, Graham Nichol
Journal: JAMA Network Open (2024)

Mau T. Nguyen, BMedSci(Hons), MBBS; Kristina Lambrakis, BSc; Sam Lehman, MBBS, PhD; Daniel Haustead, MBBS, MRes; Peter J. Psaltis, MBBS, PhD; Derek P. Chew, MBBS, MPH, PhD; Cynthia Papendick, MBBS
On-demand imidazolidinyl urea-based tissue-like, self-healable, and antibacterial hydrogels for infectious wound care
Authors: Qi Wu, Krishanu Ghosal, Nadine Kana'an, Shounak Roy, Nagham Rashed, Ranabir Majumder, Mahitosh Mandal, Liang Gao, Shady Farah
Journal: Bioactive Materials (2024)
TREM2 aggravates sepsis by inhibiting fatty acid oxidation via the SHP1/BTK axis
Authors: Siqi Ming, Xingyu Li, Qiang Xiao, Siying Qu, Qiaohua Wang, Qiongyan Fang, Pingping Liang, Yating Xu, Jingwen Yang, Yongqiang Yang, Xi Huang, Yongjian Wu
Journal: Journal of Clinical Investigation (2024)

Impaired fatty acid oxidation (FAO) and the therapeutic benefits of FAO restoration have been revealed in sepsis. However, the regulatory factors contributing to FAO dysfunction during sepsis remain inadequately clarified. In this study, we identified a subset of lipid-associated macrophages characterized by high expression of trigger receptor expressed on myeloid cells 2 (TREM2) and demonstrated that TREM2 acted as a suppressor of FAO to increase the susceptibility to sepsis. TREM2 expression was markedly up-regulated in sepsis patients and correlated with the severity of sepsis. Knock out of TREM2 in macrophages improved the survival rate and reduced inflammation and organ injuries of sepsis mice. Notably, TREM2-deficient mice exhibited decreased triglyceride accumulation and an enhanced FAO rate. Further observations showed that the blockade of FAO substantially abolished the alleviated symptoms observed in TREM2 knockout mice. Mechanically, we demonstrated that TREM2 interacted with the phosphatase SHP1 to inhibit Bruton tyrosine kinas (BTK)-mediated FAO in sepsis. Our findings expand the understanding of FAO dysfunction in sepsis and reveal TREM2 as a critical regulator of FAO, which may provide a promising target for the clinical treatment of sepsis.
High-Sensitivity Cardiac Troponin T Reporting, Clinical Outcomes, and Health Care Resource Use
Authors: Mau T. Nguyen, Kristina Lambrakis, Sam Lehman, Daniel Haustead, Peter J. Psaltis, Derek P. Chew, Cynthia Papendick
Journal: JAMA Network Open (2024)

Importance Despite being recommended by clinical guidelines, substantial concerns remain regarding the use of high-sensitivity cardiac troponin assays and whether it is associated with increased resource use, myocardial infarction (MI) or myocardial injury diagnoses, and procedural rates. Objective To characterize the association of reporting high-sensitivity cardiac troponin T (hs-cTnT) to the lowest limit of quantification vs conventional troponin reporting with clinical outcomes. Design, Setting, and Participants This cohort study used a historically controlled baseline and follow-up design to compare clinical outcomes after changing hs-cTnT reporting to the lowest limit of quantification. All patients aged 18 years or older presenting to any public emergency department (ED) in the state of South Australia between February 1, 2020, and February 28, 2021, who had an hs-cTnT test in the 6 months before and after the change in troponin reporting practice were included. Outcomes were assessed after adjusting for patient characteristics using inverse probability treatment weighting. The data analysis was performed between May 1, 2022, and July 27, 2023. Exposure hs-cTcnT reporting. Main Outcomes and Measures The main outcomes were frequency of diagnosed MI, coronary angiography, percutaneous coronary intervention, and coronary artery bypass graft (CABG); hospital length of stay; and ED discharge rate as measured using time-to-event Cox regression models. The secondary outcome was the composite 12-month event rate of all-cause mortality, MI, and myocardial injury. Results A total of 40 921 patients were included, of whom 20 206 were included in the unmasked hs-cTnT reporting group (median [IQR] age, 62.0 [46.0-77.0]; 10 120 females [50.1%]) and 20 715 were included in the conventional troponin reporting group (median [IQR] age, 63.0 [47.0-77.0] years; 10 752 males [51.9%]). Unmasked hs-cTnT reporting was associated with higher ED discharge rates (45.2% vs 39.0%; P &amp;amp;lt; .001) and a shorter median hospital length of stay (7.68 [IQR, 4.32-46.80] hours vs 7.92 [IQR, 4.56-49.92] hours; P &amp;amp;lt; .001). There was no difference in diagnosis of MI, coronary angiography, percutaneous coronary intervention, or coronary artery bypass graft. The composite of all-cause mortality, MI, and myocardial injury at 12 months was similar (adjusted hazard ratio, 0.95; 95% CI, 0.90-1.01; P = .09). Conclusions and Relevance This cohort study found that unrestricted reporting of hs-cTnT results to the lowest limit of quantification was not associated with an increase in the diagnosis of MI, invasive coronary procedures, or harm at 12 months but may be associated with improved hospital resource use.
Early Warning Scores With and Without Artificial Intelligence
Authors: Dana P. Edelson, Matthew M. Churpek, Kyle A. Carey, Zhenqiu Lin, Chenxi Huang, Jonathan M. Siner, Jennifer Johnson, Harlan M. Krumholz, Deborah J. Rhodes
Journal: JAMA Network Open (2024)

Importance Early warning decision support tools to identify clinical deterioration in the hospital are widely used, but there is little information on their comparative performance. Objective To compare 3 proprietary artificial intelligence (AI) early warning scores and 3 publicly available simple aggregated weighted scores. Design, Setting, and Participants This retrospective cohort study was performed at 7 hospitals in the Yale New Haven Health System. All consecutive adult medical-surgical ward hospital encounters between March 9, 2019, and November 9, 2023, were included. Exposures Simultaneous Epic Deterioration Index (EDI), Rothman Index (RI), eCARTv5 (eCART), Modified Early Warning Score (MEWS), National Early Warning Score (NEWS), and NEWS2 scores. Main Outcomes and Measures Clinical deterioration, defined as a transfer from ward to intensive care unit or death within 24 hours of an observation. Results Of the 362 926 patient encounters (median patient age, 64 [IQR, 47-77] years; 200 642 [55.3%] female), 16 693 (4.6%) experienced a clinical deterioration event. eCART had the highest area under the receiver operating characteristic curve at 0.895 (95% CI, 0.891-0.900), followed by NEWS2 at 0.831 (95% CI, 0.826-0.836), NEWS at 0.829 (95% CI, 0.824-0.835), RI at 0.828 (95% CI, 0.823-0.834), EDI at 0.808 (95% CI, 0.802-0.812), and MEWS at 0.757 (95% CI, 0.750-0.764). After matching scores at the moderate-risk sensitivity level for a NEWS score of 5, overall positive predictive values (PPVs) ranged from a low of 6.3% (95% CI, 6.1%-6.4%) for an EDI score of 41 to a high of 17.3% (95% CI, 16.9%-17.8%) for an eCART score of 94. Matching scores at the high-risk specificity of a NEWS score of 7 yielded overall PPVs ranging from a low of 14.5% (95% CI, 14.0%-15.2%) for an EDI score of 54 to a high of 23.3% (95% CI, 22.7%-24.2%) for an eCART score of 97. The moderate-risk thresholds provided a median of at least 20 hours of lead time for all the scores. Median lead time at the high-risk threshold was 11 (IQR, 0-69) hours for eCART, 8 (IQR, 0-63) hours for NEWS, 6 (IQR, 0-62) hours for NEWS2, 5 (IQR, 0-56) hours for MEWS, 1 (IQR, 0-39) hour for EDI, and 0 (IQR, 0-42) hours for RI. Conclusions and Relevance In this cohort study of inpatient encounters, eCART outperformed the other AI and non-AI scores, identifying more deteriorating patients with fewer false alarms and sufficient time to intervene. NEWS, a non-AI, publicly available early warning score, significantly outperformed EDI. Given the wide variation in accuracy, additional transparency and oversight of early warning tools may be warranted.
Temperature, Crime, and Violence: A Systematic Review and Meta-Analysis
Authors: Hayon Michelle Choi, Seulkee Heo, Damien Foo, Yimeng Song, Rory Stewart, Jiyoung Son, Michelle L. Bell
Journal: Environmental Health Perspectives (2024)

Heat is known to affect many health outcomes, but more evidence is needed on the impact of rising temperatures on crime and/or violence.
Tissue‐Compatible and Lubricated Hydrogel Catheter with Promising Activity Against Polymicrobial Infections for Ventilator‐Associated Pneumonia Prevention
Authors: Xiangren Kong, Gang Guo, Burebi Yiming, Jia Yu Hu, Qiang Zheng, Tian Yu Li, Zi Liang Wu, Jin Qian
Journal: Advanced Healthcare Materials (2024)

Endotracheal intubation is a vital means of saving critically ill patients. However, the inserted catheter often causes tissue damage and the formation of tenacious biofilms containing drug-resistant bacteria and fungi, leading to severe ventilator-associated pneumonia (VAP). Currently, the resolution of VAP is usually based on antibiotic treatment and lacks targeted prophylaxis. Here, a quaternary phosphonium salts functionalized hydrogel catheter that enhances tissue compatibility yet inhibits complex and tenacious pathogens in the catheter, thus preventing VAP is reported. By copolymerizing the quaternary phosphonium electrolyte and acrylic acid monomers, the hydrogel catheter demonstrates good shape-supporting ability, and its strength and modulus can be adjusted over a wide range to meet the needs of different ages. Moreover, it possesses good tissue compatibility, antifouling properties, stable lubrication capability, and superior hydrophilicity, which may mitigate tissue damage caused by contact. Importantly, the hydrogel catheter demonstrates potent broad-spectrum intrinsic antimicrobial activity, eradicating nearly 99% of multi-drug resistant bacteria and 80% of fungi. To validate its role in preventing VAP, the real VAP pathogenesis process is mimicked, establishing a polymicrobial infections model considering time effects. The results prove that the hydrogel catheter effectively inhibits the invasion of various drug-resistant pathogens and prevents biofilm formation.
Hospital Strain and Disparities in Sepsis Outcomes
Authors: Sahil Angelo, Sameer S. Kadri
Journal: JAMA Network Open (2024)

Laurent G. Glance, MD; Karen E. Joynt Maddox, MD, MPH; Patricia W. Stone, PhD, RN; E. Yoko Furuya, MD, MS; Jingjing Shang, PhD, RN; Mark J. Sorbero, MS; Ashley Chastain, DrPH, MPH; Stewart J. Lustik, MD, MBA; Andrew W. Dick, PhD
Prospective clinical evaluation of deep learning for ultrasonographic screening of abdominal aortic aneurysms
Authors: I-Min Chiu, Tien-Yu Chen, You-Cheng Zheng, Xin-Hong Lin, Fu-Jen Cheng, David Ouyang, Chi-Yung Cheng
Journal: npj Digital Medicine (2024)

Abdominal aortic aneurysm (AAA) often remains undetected until rupture due to limited access to diagnostic ultrasound. This trial evaluated a deep learning (DL) algorithm to guide AAA screening by novice nurses with no prior ultrasonography experience. Ten nurses performed 15 scans each on patients over 65, assisted by a DL object detection algorithm, and compared against physician-performed scans. Ultrasound scan quality, assessed by three blinded expert physicians, was the primary outcome. Among 184 patients, DL-guided novices achieved adequate scan quality in 87.5% of cases, comparable to the 91.3% by physicians (p = 0.310). The DL model predicted AAA with an AUC of 0.975, 100% sensitivity, and 97.8% specificity, with a mean absolute error of 2.8 mm in predicting aortic width compared to physicians. This study demonstrates that DL-guided POCUS has the potential to democratize AAA screening, offering performance comparable to experienced physicians and improving early detection.
Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation
Authors: Nowrin U Chowdhury, Jacqueline-Yvonne Cephus, Emely Henriquez Pilier, Melissa M Wolf, Matthew Z Madden, Shelby N Kuehnle, Kaitlin E McKernan, Erin Q Jennings, Emily N Arner, Darren R Heintzman, Channing Chi, Ayaka Sugiura, Matthew T Stier, Kelsey Voss, Xiang Ye, Kennedi L Scales, Evan S Krystofiak, Vivek D Gandhi, Robert D Guzy, Katherine N Cahill, Anne I Sperling, R Stokes Peebles, Jeffrey C Rathmell, Dawn C Newcomb
Journal: Journal of Clinical Investigation (2024)

Females have an increased prevalence of many Th17 cell-mediated diseases, including asthma. Androgen signaling decreases Th17 cell-mediated airway inflammation, and Th17 cells rely on glutaminolysis. However, it remains unclear whether androgen receptor (AR) signaling modifies glutamine metabolism to suppress Th17 cell-mediated airway inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared to females, and that AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis in mice. Using allergen-induced airway inflammation mouse models, we determined females had a selective reliance upon glutaminolysis for Th17-mediated airway inflammation, and AR signaling attenuated glutamine uptake in CD4+ T cells by reducing expression of glutamine transporters. Minimal reliance on glutamine uptake in male Th17 cells compared to female Th17 cells was also found in circulating T cells from patients with asthma. AR signaling thus attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for Th17 or glutaminolysis targeted therapeutics.
Exercise Limitation in Pulmonary Hypertension – Physiological Insights into the Six-Minute Walk Test
Authors: Nils Kremer, Simon Schaefer, Athiththan Yogeswaran, Zvonimir Rako, Hossein-Ardeschir Ghofrani, Werner Seeger, Baktybek Kojonazarov, Paul M. Heerdt, Ryan J Tedford, Khodr Tello
Journal: American Journal of Respiratory and Critical Care Medicine (2024)
A minimal hybrid sterility genome assembled by chromosome swapping between mouse subspecies (<i>Mus musculus</i>)
Authors: Vladana Fotopulosova, Giordano Tanieli, Karel Fusek, Petr Jansa, Jiri Forejt
Journal: Molecular Biology and Evolution (2024)

Hybrid sterility is a reproductive isolation barrier between diverging taxa securing the early steps of speciation. Hybrid sterility is ubiquitous in the animal and plant kingdoms, but its genetic control is poorly understood. In our previous studies, we have uncovered the sterility of hybrids between musculus and domesticus subspecies of the house mouse, which is controlled by the Prdm9 gene, the X-linked Hstx2 locus, and subspecific heterozygosity for genetic background. To further investigate this form of genic-driven chromosomal sterility, we constructed a simplified hybrid sterility model within the genome of the domesticus subspecies by swapping domesticus autosomes with their homologous partners from the musculus subspecies. We show that the "sterility" allelic combination of Prdm9 and Hstx2 can be activated by a musculus/domesticus heterozygosity of as few as two autosomes, Chromosome 17 (Chr 17) and Chr 18 and is further enhanced when another heterosubspecific autosomal pair is present, whereas it has no effect on meiotic progression in the pure domesticus genome. In addition, we identify a new X-linked hybrid sterility locus, Hstx3, at the centromeric end of Chr X, which modulates the incompatibility between Prdm9 and Hstx2. These results further support our concept of chromosomal hybrid sterility based on evolutionarily accumulated divergence between homologous sequences. Based on these and previous results, we believe that future studies should include more information on the mutual recognition of homologous chromosomes at or before the first meiotic prophase in interspecific hybrids, as this may serve as a general reproductive isolation checkpoint in mice and other species.
RERconverge Expansion: Using Relative Evolutionary Rates to Study Complex Categorical Trait Evolution
Authors: Ruby Redlich, Amanda Kowalczyk, Michael Tene, Heather H Sestili, Kathleen Foley, Elysia Saputra, Nathan Clark, Maria Chikina, Wynn K Meyer, Andreas R Pfenning
Journal: Molecular Biology and Evolution (2024)

Comparative genomics approaches seek to associate molecular evolution with the evolution of phenotypes across a phylogeny. Many of these methods lack the ability to analyze non-ordinal categorical traits with more than two categories. To address this limitation, we introduce an expansion to RERconverge that associates shifts in evolutionary rates with the convergent evolution of categorical traits. The categorical RERconverge expansion includes methods for performing categorical ancestral state reconstruction, statistical tests for associating relative evolutionary rates with categorical variables, and a new method for performing phylogeny-aware permutations, "permulations", on categorical traits. We demonstrate our new method on a three-category diet phenotype, and we compare its performance to binary RERconverge analyses and two existing methods for comparative genomic analyses of categorical traits: phylogenetic simulations and a phylogenetic signal based method. We present an analysis of how the categorical permulations scale with the number of species and the number of categories included in the analysis. Our results show that our new categorical method outperforms phylogenetic simulations at identifying genes and enriched pathways significantly associated with the diet phenotypes and that the categorical ancestral state reconstruction drives an improvement in our ability to capture diet-related enriched pathways compared to binary RERconverge when implemented without user input on phenotype evolution. The categorical expansion to RERconverge will provide a strong foundation for applying the comparative method to categorical traits on larger data sets with more species and more complex trait evolution than have previously been analyzed.
Deep ancestral introgressions between ovine species shape sheep genomes via argali-mediated gene flow
Authors: Feng-Hua Lv, Dong-Feng Wang, Si-Yi Zhao, Xiao-Yang Lv, Wei Sun, Rasmus Nielsen, Meng-Hua Li
Journal: Molecular Biology and Evolution (2024)

Abstract Previous studies revealed extensive genetic introgression between Ovis species, which affects genetic adaptation and morphological traits. However, the exact evolutionary scenarios underlying the hybridization between sheep and allopatric wild relatives remain unknown. To address this problem, we here integrate the reference genomes of several ovine and caprine species: domestic sheep, argali, bighorn sheep, snow sheep, and domestic goats. Additionally, we use 856 whole genomes representing 169 domestic sheep populations and their six wild relatives: Asiatic mouflon, urial, argali, snow sheep, thinhorn sheep, and bighorn sheep. We implement a comprehensive set of analyses to test introgression among these species. We infer that the argali lineage originated ∼3.08 to 3.35 Mya and hybridized with the ancestor of Pachyceriforms (e.g. bighorn sheep and snow sheep) at ∼1.56 Mya. Previous studies showed apparent introgression from North American Pachyceriforms into the Bashibai sheep, a Chinese native sheep breed, despite of their wide geographic separation. We show here that, in fact, the apparent introgression from the Pachyceriforms into Bashibai can be explained by the old introgression from Pachyceriforms into argali and subsequent recent introgression from argali into Bashibai. Our results illustrate the challenges of estimating complex introgression histories and provide an example of how indirect and direct introgression can be distinguished.