tbuckley/cabot-search huggingface dataset:
Effectiveness of the adapted bivalent mRNA COVID-19 vaccines against hospitalisation in individuals aged ≥ 60 years during the Omicron XBB lineage-predominant period: VEBIS SARI VE network, Europe, February to August, 2023
Authors: Liliana Antunes, Clara Mazagatos, Iván Martínez-Baz, Verónica Gomez, Maria-Louise Borg, Goranka Petrović, Róisín Duffy, François E Dufrasne, Ralf Dürrwald, Mihaela Lazar, Ligita Jancoriene, Beatrix Oroszi, Petr Husa, Jennifer Howard, Aryse Melo, Francisco Pozo, Gloria Pérez-Gimeno, Jesús Castilla, Ausenda Machado, Aušra Džiugytė, Svjetlana Karabuva, Margaret Fitzgerald, Sébastien Fierens, Kristin Tolksdorf, Silvia-Odette Popovici, Auksė Mickienė, Gergő Túri, Lenka Součková, Nathalie Nicolay, Angela MC Rose
Journal: Eurosurveillance (2024)

We conducted a multicentre hospital-based test-negative case–control study to measure the effectiveness of adapted bivalent COVID-19 mRNA vaccines against PCR-confirmed SARS-CoV-2 infection during the Omicron XBB lineage-predominant period in patients aged ≥ 60 years with severe acute respiratory infection from five countries in Europe. Bivalent vaccines provided short-term additional protection compared with those vaccinated &gt; 6 months before the campaign: from 80% (95% CI: 50 to 94) for 14–89 days post-vaccination, 15% (95% CI: −12 to 35) at 90–179 days, and lower to no effect thereafter.
Ontogeny shapes the ability of ETV6::RUNX1 to enhance hematopoietic stem cell self-renewal and disrupt early lymphopoiesis
Authors: Mohamed Eldeeb, Anna Konturek-Ciesla, Qinyu Zhang, Shabnam Kharazi, Johanna Tingvall-Gustafsson, Jonas Ungerbäck, Mikael Sigvardsson, David Bryder
Journal: Leukemia (2024)

The ETV6::RUNX1 (E/R) translocation is the predominant chromosomal aberration in pediatric acute lymphoblastic leukemia (ALL) [1].Despite its good prognosis, current treatments impose longterm side effects and a 20% relapse rate [1, 2], emphasizing the importance of understanding disease mechanisms for improved treatments.E/R leukemogenesis begins in utero upon acquisition of the fusion gene.Despite the high prevalence of this initial event, only a minority acquire secondary mutations and progress to overt disease, with infections possibly playing a role as triggers [1].The period between the initial and secondary events can extend over a decade, emphasizing a remarkable longevity of the preleukemic cells [1].The specific cell of origin for E/R leukemia is debated but likely arises from an undifferentiated hematopoietic stem/ progenitor cell (HSPC) [1,[3][4][5].Here, to gain new insights into the E/R preleukemic state, we generated a transgenic inducible mouse model (iE/R) that enables reversible induction of E/R (Supplementary Fig. S1A).To confirm the model's inducibility and expression levels, we performed quantitative reverse-transcription PCR (qRT-PCR) on RNA extracted from either cultured (Supplementary Fig. S1B) or fresh bone marrow (BM) cells (Supplementary Fig. S1C).This verified E/R expression only upon Dox administration, at levels closely matching those of REH cells, a human cell line for E/R leukemia (Supplementary Fig. S1C).Most E/R-ALL patients present with inactivation of genes critical for normal B-cell development, such as Pax5 and Ebf1 [6].To assess the impact of E/R on B-ALL, we introduced the M2 reverse Tetracycline transactivator (M2-rtTA) and iE/R alleles into Pax5 +/-Ebf1 +/-mice [7].Unfractionated E/R Pax5 +/-Ebf1 +/-BM cells were then transplanted into recipient mice, both with and without Dox treatment.This revealed that E/R expression significantly accelerated B-ALL development (Supplementary Fig. S1D).By transplanting unfractionated wild-type (WT) BM cells into lethally irradiated iE/R mice, we next examined the influence of E/R expressing non-hematological cells on hematopoiesis.This revealed no significant alterations in hematopoietic BM compartments, including on B-cell frequencies (Supplementary Fig. S1E-H), arguing that E/R alters hematopoiesis by mechanisms intrinsic to hematopoiesis.
Improving Health Equity in Rheumatology Through Workforce Diversification and Support for Health Equity Research and Education
Authors: Maria T. Vassileva, Vandana Suresh, Andrew C. Chan, Alisha Valdez Akinsete, Irene Blanco, Ashira Blazer, Lisa Criscione‐Schreiber, Sharon Dowell, Candace H. Feldman, John FitzGerald, Mileka Gilbert, Grant Hughes, M. Elaine Husni, Gail Kerr, Olivia Kwan, Bryanna Mantilla, Susanne Nilson, Alfredo Carlos Rivadeneira, Martha Rodríguez, Benjamin J. Smith, William Daniel Soulsby, Stephen Chee‐Yung Wong, Jinoos Yazdany, Will Ross
Journal: Arthritis & Rheumatology (2024)

Disclosure form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Haplotype-resolved assembly of a tetraploid potato genome using long reads and low-depth offspring data
Authors: Rebecca Serra Mari, Sven Schrinner, Richard Finkers, Freya Maria Rosemarie Ziegler, Paul Arens, Maximilian H.-W. Schmidt, Björn Usadel, Gunnar W. Klau, Tobias Marschall
Journal: Genome biology (2024)

Abstract Potato is one of the world’s major staple crops, and like many important crop plants, it has a polyploid genome. Polyploid haplotype assembly poses a major computational challenge. We introduce a novel strategy for the assembly of polyploid genomes and present an assembly of the autotetraploid potato cultivar Altus. Our method uses low-depth sequencing data from an offspring population to achieve chromosomal clustering and haplotype phasing on the assembly graph. Our approach generates high-quality assemblies of individual chromosomes with haplotype-specific sequence resolution of whole chromosome arms and can be applied in common breeding scenarios where collections of offspring are available.
Tumor-derived small extracellular vesicles in cancer invasion and metastasis: molecular mechanisms, and clinical significance
Authors: Chi Zhang, Chaoying Qin, Saikat Dewanjee, Hiranmoy Bhattacharya, Pratik Chakraborty, Niraj Kumar Jha, Moumita Gangopadhyay, Saurabh Kumar Jha, Qing Liu
Journal: Molecular Cancer (2024)

Abstract The production and release of tumor-derived small extracellular vesicles (TDSEVs) from cancerous cells play a pivotal role in the propagation of cancer, through genetic and biological communication with healthy cells. TDSEVs are known to orchestrate the invasion-metastasis cascade via diverse pathways. Regulation of early metastasis processes, pre-metastatic niche formation, immune system regulation, angiogenesis initiation, extracellular matrix (ECM) remodeling, immune modulation, and epithelial-mesenchymal transition (EMT) are among the pathways regulated by TDSEVs. MicroRNAs (miRs) carried within TDSEVs play a pivotal role as a double-edged sword and can either promote metastasis or inhibit cancer progression. TDSEVs can serve as excellent markers for early detection of tumors, and tumor metastases. From a therapeutic point of view, the risk of cancer metastasis may be reduced by limiting the production of TDSEVs from tumor cells. On the other hand, TDSEVs represent a promising approach for in vivo delivery of therapeutic cargo to tumor cells. The present review article discusses the recent developments and the current views of TDSEVs in the field of cancer research and clinical applications.
Enriched Single-Nucleus RNA-Sequencing Reveals Unique Attributes of Distal Convoluted Tubule Cells
Authors: Xiao-Tong Su, Jeremiah V. Reyes, Anne E. Lackey, Hasan Demirci, Sebastian Bachmann, Yujiro Maeoka, Ryan J. Cornelius, James A. McCormick, Chao-Ling Yang, Hyun Jun Jung, Paul A. Welling, Jonathan W. Nelson, David H. Ellison
Journal: Journal of the American Society of Nephrology (2024)

Significance Statement High-resolution single-nucleus RNA-sequencing data indicate a clear separation between primary sites of calcium and magnesium handling within distal convoluted tubule (DCT). Both DCT1 and DCT2 express Slc12a3, but these subsegments serve distinctive functions, with more abundant magnesium-handling genes along DCT1 and more calcium-handling genes along DCT2. The data also provide insight into the plasticity of the distal nephron-collecting duct junction, formed from cells of separate embryonic origins. By focusing/changing gradients of gene expression, the DCT can morph into different physiological cell states on demand. Background The distal convoluted tubule (DCT) comprises two subsegments, DCT1 and DCT2, with different functional and molecular characteristics. The functional and molecular distinction between these segments, however, has been controversial. Methods To understand the heterogeneity within the DCT population with better clarity, we enriched for DCT nuclei by using a mouse line combining “Isolation of Nuclei Tagged in specific Cell Types” and sodium chloride cotransporter–driven inducible Cre recombinase. We sorted the fluorescently labeled DCT nuclei using Fluorescence-Activated Nucleus Sorting and performed single-nucleus transcriptomics. Results Among 25,183 DCT cells, 75% were from DCT1 and 25% were from DCT2. In addition, there was a small population (&lt;1%) enriched in proliferation-related genes, such as Top2a , Cenpp , and Mki67 . Although both DCT1 and DCT2 expressed sodium chloride cotransporter, magnesium transport genes were predominantly expressed along DCT1, whereas calcium, electrogenic sodium, and potassium transport genes were more abundant along DCT2. The transition between these two segments was gradual, with a transitional zone in which DCT1 and DCT2 cells were interspersed. The expression of the homeobox genes by DCT cells suggests that they develop along different trajectories. Conclusions Transcriptomic analysis of an enriched rare cell population using a genetically targeted approach clarifies the function and classification of distal cells. The DCT segment is short, can be separated into two subsegments that serve distinct functions, and is speculated to derive from different origins during development.
Infant lung function and early skin barrier impairment in the development of asthma at age 3 years
Authors: Martin Färdig, Angela Hoyer, Catarina Almqvist, Karen Eline S. Bains, Karin C. Lødrup Carlsen, Hrefna Katrín Gudmundsdóttir, Berit Granum, Guttorm Nils Haugen, Gunilla Hedlin, Christine Monceyron Jonassen, Jon R. Konradsen, Anine Lie, Eva Maria Rehbinder, Håvard O. Skjerven, Anne Cathrine Staff, Riyas Vettukattil, Cilla Söderhäll, Björn Nordlund
Journal: Allergy (2024)

Abstract Background Largely unexplored, we investigated if lower lung function, impaired skin barrier function by transepidermal water loss (TEWL), eczema, and filaggrin ( FLG ) mutations in infancy were associated with asthma in early childhood. Methods From the factorially designed randomized controlled intervention study PreventADALL, we evaluated 1337/2394 children from all randomization groups with information on asthma at age 3 years, and at age 3 months either lung function, TEWL, eczema, and/or FLG mutations. Lower lung function was defined as the time to peak tidal expiratory flow to expiratory time ( t PTEF / t E ) &lt;0.25, and skin barrier impairment as a high TEWL &gt;9.50 g/m 2 /h. Eczema was clinically observed, and DNA genotyped for FLG mutations. Asthma was defined as asthma‐like symptoms (≥3 episodes of bronchial obstruction) between age 2–3 years as well as a history of doctor‐diagnosed asthma and/or asthma medication use. Associations were analyzed in logistic regression models, presented with adjusted ORs (aOR) and 95% confidence intervals (CI). Results Lower lung function and skin barrier impairment were associated with asthma in general; aOR (95% CI) 5.4 (2.1, 13.7) and 1.6 (1.1, 2.5), while eczema and FLG mutations were associated with asthma in children with atopic dermatitis or allergic sensitization only. Stratifying for sex, the risk of asthma was only increased in boys with lower lung function; aOR (95% CI) 7.7 (2.5, 23.6), and in girls with FLG mutations; aOR (95% CI) 3.5 (1.5, 8.2). Conclusion Lower lung function and impaired skin barrier function in infancy may increase the risk of asthma at age 3 years.
<scp>T‐cell</scp> prolymphocytic leukemia: Epidemiology and survival trends in the era of novel treatments
Authors: Victoria A. Vardell, Daniel A. Ermann, Lindsey Fitzgerald, Harsh Shah, Boyu Hu, Deborah M. Stephens
Journal: American Journal of Hematology (2024)

Graphical Abstract Survival remains poor for T-cell prolymphocytic leukemia, though treatment in recent years, associated with access to novel therapies, and management at academic medical centers is associated with improved outcomes. There remains a critical need to improve the available treatment options for this population, and access to specialized academic medical centers, comprehensive supportive care, clinical trials, and early palliative care remains essential for T-PLL patients.
DeepVelo: deep learning extends RNA velocity to multi-lineage systems with cell-specific kinetics
Authors: Haotian Cui, Hassaan Maan, Maria C. Vladoiu, Jiao Zhang, Michael D. Taylor, Bo Wang
Journal: Genome biology (2024)

Abstract Existing RNA velocity estimation methods strongly rely on predefined dynamics and cell-agnostic constant transcriptional kinetic rates, assumptions often violated in complex and heterogeneous single-cell RNA sequencing (scRNA-seq) data. Using a graph convolution network, DeepVelo overcomes these limitations by generalizing RNA velocity to cell populations containing time-dependent kinetics and multiple lineages. DeepVelo infers time-varying cellular rates of transcription, splicing, and degradation, recovers each cell’s stage in the differentiation process, and detects functionally relevant driver genes regulating these processes. Application to various developmental and pathogenic processes demonstrates DeepVelo’s capacity to study complex differentiation and lineage decision events in heterogeneous scRNA-seq data.
The Plasma Lipidomic Landscape in Patients with Sepsis due to Community-acquired Pneumonia
Authors: Osoul Chouchane, Alex R. Schuurman, Tom D. Y. Reijnders, Hessel Peters-Sengers, Joe M. Butler, Fabrice Uhel, Marcus J. Schultz, Marc J. Bonten, Olaf L. Cremer, Carolyn S. Calfee, Michael A. Matthay, Raymond J. Langley, Narges Alipanah-Lechner, Stephen F. Kingsmore, Angela Rogers, Michel van Weeghel, Frédéric M. Vaz, Tom van der Poll
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

The plasma lipidome has the potential to reflect many facets of the host status during severe infection. Previous work is limited to specific lipid groups or was focused on lipids as prognosticators.
EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth
Authors: Alexandra Kuhlmann-Hogan, Thekla Cordes, Ziyan Xu, Ramya S. Kuna, Kacie A. Traina, Camila Robles-Oteíza, Deborah Ayeni, Elizabeth M. Kwong, Stellar Levy, Anna-Maria Globig, Matthew M. Nobari, George Z. Cheng, Sandra L. Leibel, Robert J. Homer, Reuben J. Shaw, Christian M. Metallo, Katerina Politi, Susan M. Kaech
Journal: Cancer Discovery (2024)

Abstract The limited efficacy of currently approved immunotherapies in EGFR-driven lung adenocarcinoma (LUAD) underscores the need to better understand alternative mechanisms governing local immunosuppression to fuel novel therapies. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophage (TA-AM) proliferation, which supports tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF–PPARγ signaling and inhibition of airway GM-CSF or PPARγ in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases proinflammatory immune responses. These results reveal new therapeutic combinations for immunotherapy-resistant EGFR-mutant LUADs and demonstrate how cancer cells can metabolically co-opt TA-AMs through GM-CSF–PPARγ signaling to provide nutrients that promote oncogenic signaling and growth. Significance: Alternate strategies harnessing anticancer innate immunity are required for lung cancers with poor response rates to T cell–based immunotherapies. This study identifies a targetable, mutually supportive, metabolic relationship between macrophages and transformed epithelium, which is exploited by tumors to obtain metabolic and immunologic support to sustain proliferation and oncogenic signaling. This article is featured in Selected Articles from This Issue, p. 384
AI’s Threat to the Medical Profession
Authors: Agnes B. Fogo, Andreas Kronbichler, Ingeborg M. Bajema
Journal: JAMA (2024)

This Viewpoint discusses the potential drawbacks of the use of artificial intelligence (AI) in medicine, for example, the loss of certain skills due to the reliance on AI, and how physicians should consider how to take advantage of the potential benefits of AI without losing control over their profession.
Social Risk, Social Need, and Use of the Emergency Department
Authors: Katherine Dickerson Mayes, Rebecca E. Cash, Katherine H. Schiavoni, Christine Vogeli, Anne N. Thorndike, Carlos A. Camargo, Margaret Samuels-Kalow
Journal: JAMA Network Open (2024)

This cohort study examines the association of social risk and social need with emergency department use by patients within a Medicaid accountable care organization who were screened for adverse social determinants of health in primary care.
Timing of Maternal COVID-19 Vaccine and Antibody Concentrations in Infants Born Preterm
Authors: Alisa Kachikis, Mindy Pike, Linda O. Eckert, Emma Roberts, Yael Frank, Amber L. Young, Erin Goecker, Michael G. Gravett, Alexander L. Greninger, Janet A. Englund
Journal: JAMA Network Open (2024)

Importance COVID-19 vaccine–derived antibodies in pregnant people may protect infants from severe infection in the first 6 months of life via transplacental antibody transfer. Few data exist on maternally derived SARS-CoV-2 antibodies in preterm compared with full-term infants in association with vaccination timing. Objective To compare SARS-CoV-2 anti-Spike (anti-S) antibody levels in preterm and full-term infants in the context of vaccine dose timing before delivery. Design, Setting, and Participants This prospective cohort study enrolled pregnant individuals and collected paired maternal and cord blood samples at delivery at the University of Washington between February 1, 2021, and January 31, 2023. Participants who had received at least 2 doses of a messenger RNA COVID-19 vaccine before delivery and did not have a history of prior COVID-19 infection or detectable anti–SARS-CoV-2 nucleocapsid antibodies were included. Exposures Timing of the last vaccine dose and preterm or full-term gestational age at delivery. Main Outcomes and Measures Paired maternal and cord samples were tested for anti-S antibody, and linear regression was used to evaluate associations between preterm delivery and anti-S antibody levels. Covariates included timing of last dose, number of doses, insurance status, and immunosuppressing medications. Results A total of 220 participants (median [IQR] age, 34 [32-37] years; 212 [96.4%] female) with 36 preterm and 184 full-term deliveries were studied. Before delivery, 121 persons received 2 vaccine doses and 99 persons received 3 or more vaccine doses. The geometric mean concentration of maternal anti-S antibodies was 674 (95% CI, 577-787) after 2 doses and 8159 (95% CI, 6636-10 032) after 3 or more doses ( P &amp;amp;lt; .001). The cord anti-S antibody geometric mean concentration was 1000 (95% CI, 874-1144) after 2 doses and 9992 (95% CI, 8381-11 914) after 3 or more doses ( P &amp;amp;lt; .001). After adjustment for vaccine timing and number of doses before delivery, no association was found between preterm delivery and cord anti-S antibody levels (β = 0.44; 95% CI, −0.06 to 0.94). Conclusions and Relevance In this prospective cohort study of pregnant individuals with preterm and full-term deliveries, receipt of 3 or more compared with 2 doses of COVID-19 vaccine before delivery resulted in 10-fold higher cord anti-S antibody levels. Maternal antibody concentration appeared more important than delivery gestational age in determining cord anti-S antibody levels. The number of doses and timing considerations for COVID-19 vaccine in pregnancy should include individuals at risk for preterm delivery.
Dose-Response Associations of Lipid Traits With Coronary Artery Disease and Mortality
Authors: Guoyi Yang, Amy M. Mason, Angela M. Wood, C. Mary Schooling, Stephen Burgess
Journal: JAMA Network Open (2024)

Importance Apolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) are associated with coronary artery disease (CAD). However, trial evidence for the association of intensive LDL-C lowering and TG lowering with mortality is less definitive. Objectives To investigate the associations of apoB, LDL-C, and TG with CAD and mortality, both overall and by sex and age, and to characterize the shapes of these associations. Design, Setting, and Participants This genetic association study used linear and nonlinear mendelian randomization (MR) to analyze a population-based cohort of individuals of European ancestry from the UK Biobank, which recruited participants from 2006 to 2010 with follow-up information updated until September 2021. Data analysis occurred from December 2022 to November 2023. Exposures Genetically predicted apoB, LDL-C, and TG. Main Outcomes and Measures The primary outcomes were CAD, all-cause mortality, and cause-specific mortality. Genetic associations with CAD were calculated using logistic regression, associations with all-cause mortality using Cox proportional hazards regression, and associations with cause-specific mortality using cause-specific Cox proportional hazards regression with censoring for other causes of mortality. Results This study included 347 797 participants (mean [SD] age, 57.2 [8.0] years; 188 330 female [54.1%]). There were 23 818 people who developed CAD and 23 848 people who died. Genetically predicted apoB was positively associated with risk of CAD (odds ratio [OR], 1.65 per SD increase; 95% CI 1.57-1.73), all-cause mortality (hazard ratio [HR], 1.11; 95% CI, 1.06-1.16), and cardiovascular mortality (HR, 1.36; 95% CI, 1.24-1.50), with some evidence for larger associations in male participants than female participants. Findings were similar for LDL-C. Genetically predicted TG was positively associated with CAD (OR, 1.60; 95% CI 1.52-1.69), all-cause mortality (HR, 1.08; 95% CI, 1.03-1.13), and cardiovascular mortality (HR, 1.21; 95% CI, 1.09-1.34); however, sensitivity analyses suggested evidence of pleiotropy. The association of genetically predicted TG with CAD persisted but it was no longer associated with mortality outcomes after controlling for apoB. Nonlinear MR suggested that all these associations were monotonically increasing across the whole observed distribution of each lipid trait, with no diminution at low lipid levels. Such patterns were observed irrespective of sex or age. Conclusions and relevance In this genetic association study, apoB (or, equivalently, LDL-C) was associated with increased CAD risk, all-cause mortality, and cardiovascular mortality, all in a dose-dependent way. TG may increase CAD risk independent of apoB, although the possible presence of pleiotropy is a limitation. These insights highlight the importance of apoB (or, equivalently, LDL-C) lowering for reducing cardiovascular morbidity and mortality across its whole distribution.