tbuckley/cabot-search huggingface dataset:
Characterisation of Treponema pallidum lineages within the contemporary syphilis outbreak in Australia: a genomic epidemiological analysis
Authors: Mona L Taouk, George Taiaroa, Shivani Pasricha, Sophie Herman, Eric P F Chow, Francesca Azzatto, Bowen Zhang, Cheryll M Sia, Sebastian Duchene, Alvin Lee, Nasra Higgins, Jacqueline Prestedge, Yi Wei Lee, Nicholas R Thomson, Bianca Graves, Ella Meumann, Manoji Gunathilake, Jane S Hocking, Catriona S Bradshaw, Mathew A Beale, Benjamin P Howden, Marcus Y Chen, Christopher K Fairley, Danielle J Ingle, Deborah A Williamson
Journal: The Lancet Microbe (2022)

BackgroundThe incidence of syphilis has increased markedly in the past decade in high-income countries, including Australia. To date, however, genomic studies of Treponema pallidum have focused mainly on the northern hemisphere. Here, we aimed to characterise the lineages of T pallidum driving the current syphilis epidemic in Australia.MethodsIn this genomic epidemiological analysis, using phylogenomic and phylodynamic analyses, we analysed 456 high-quality T pallidum genomes collected from clinical samples in Australia between Oct 19, 2005, and Dec 31, 2020, and contextualised this information with publicly available sequence data. We also performed detailed genomic characterisation of putative antimicrobial resistance determinants, in addition to correlating single-locus typing of the TP0548 allele with the T pallidum phylogeny.FindingsPhylogenomic analyses identified four major sublineages circulating in Australia and globally, two belonging to the SS14 lineage, and two belonging to the Nichols lineage. Australian sublineages were further delineated into twelve subgroups, with five of the six largest subgroups associated with men who have sex with men, and the sixth lineage was predominantly associated with heterosexual people. Most Australian T pallidum genomes (398 [87%] of 456) were genotypically macrolide resistant, and TP0548 typing correlated significantly with T pallidum genomic subgroups.InterpretationThese findings show that the current syphilis epidemic in Australia is driven by multiple lineages of T pallidum, rather than one distinct outbreak. Major subgroups of T pallidum in Australia have emerged within the past 30 years, are closely related to global lineages, and circulate across different sexual networks. In conjunction with improved testing and treatment, these data could better inform the control of syphilis in Australia.FundingNational Health and Medical Research Council, Australian Research Council.
Gut colonisation by extended-spectrum β-lactamase-producing Escherichia coli and its association with the gut microbiome and metabolome in Dutch adults: a matched case-control study
Authors: Quinten R Ducarmon, Romy D Zwittink, Roel P J Willems, Aswin Verhoeven, Sam Nooij, Fiona R M van der Klis, Eelco Franz, Jolanda Kool, Martin Giera, Christina M J E Vandenbroucke-Grauls, Susana Fuentes, Ed J Kuijper
Journal: The Lancet Microbe (2022)

Gut colonisation by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli is a risk factor for developing overt infection. The gut microbiome can provide colonisation resistance against enteropathogens, but it remains unclear whether it confers resistance against ESBL-producing E coli. We aimed to identify a potential role of the microbiome in controlling colonisation by this antibiotic-resistant bacterium.For this matched case-control study, we used faeces from 2751 individuals in a Dutch cross-sectional population study (PIENTER-3) to culture ESBL-producing bacteria. Of these, we selected 49 samples that were positive for an ESBL-producing E coli (ESBL-positive) and negative for several variables known to affect microbiome composition. These samples were matched 1:1 to ESBL-negative samples on the basis of individuals' age, sex, having been abroad or not in the past 6 months, and ethnicity. Shotgun metagenomic sequencing was done and taxonomic species composition and functional annotations (ie, microbial metabolism and carbohydrate-active enzymes) were determined. Targeted quantitative metabolic profiling (proton nuclear magnetic resonance spectroscopy) was done to investigate metabolomic profiles and combinations of univariate (t test and Wilcoxon test), multivariate (principal coordinates analysis, permutational multivariate analysis of variance, and partial least-squares discriminant analysis) and machine-learning approaches (least absolute shrinkage and selection operator and random forests) were used to analyse all the molecular data.No differences in diversity parameters or in relative abundance were observed between ESBL-positive and ESBL-negative groups based on bacterial species-level composition. Machine-learning approaches using microbiota composition did not accurately predict ESBL status (area under the receiver operating characteristic curve [AUROC]=0·41) when using either microbiota composition or any of the functional profiles. The metabolome also did not differ between ESBL groups, as assessed by various methods including random forest (AUROC=0·61).By combining multiomics and machine-learning approaches, we conclude that asymptomatic gut carriage of ESBL-producing E coli is not associated with an altered microbiome composition or function. This finding might suggest that microbiome-mediated colonisation resistance against ESBL-producing E coli is not as relevant as it is against other enteropathogens and antibiotic-resistant bacteria.None.
Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial
Authors: Amalia Gastaldelli, Kenneth Cusi, Laura Fernández Landó, Ross Bray, Bram Brouwers, Ángel Rodríguez
Journal: The Lancet Diabetes & Endocrinology (2022)
The combination of PD-1 blockade with interferon-α has a synergistic effect on hepatocellular carcinoma
Authors: Ying Zhu, Mo Chen, Da Xu, Tian-En Li, Ze Zhang, Jian-Hua Li, Xiang-Yu Wang, Xin Yang, Lu Lu, Hu-Liang Jia, Qiong-Zhu Dong, Lun-Xiu Qin
Journal: Cellular and Molecular Immunology (2022)
Universal lung epithelium DNA methylation markers for detection of lung damage in liquid biopsies
Authors: Judith Magenheim, Ariel Rokach, Ayelet Peretz, Netanel Loyfer, Gordon Cann, Hamed Amini, Patriss Moradi, Sudharani Nagaraju, Wafa Sameer, Assaf Cohen, Ophir Fogel, Rottem Kuint, Avraham Abutbul, Aiman Abu Rmeileh, Mutaz Karameh, Polina Cohen Goichman, Ori Wald, Amit Korach, Daniel Neiman, Ilana Fox-Fisher, Joshua Moss, Daniel Cohen, Sheina Piyanzin, Roni Ben Ami, Ahmad Quteineh, Eliahu Golomb, Ruth Shemer, Benjamin Glaser, Tommy Kaplan, Zvi G. Fridlender, Yuval Dor
Journal: European Respiratory Journal (2022)

Circulating biomarkers for lung damage are lacking. Lung epithelium-specific DNA methylation patterns can potentially report the presence of lung-derived cell-free DNA (cfDNA) in blood, as an indication of lung cell death.We sorted human lung alveolar and bronchial epithelial cells from surgical specimens, and obtained their methylomes using whole-genome bisulfite sequencing. We developed a PCR sequencing assay determining the methylation status of 17 loci with lung-specific methylation patterns, and used it to assess lung-derived cfDNA in the plasma of healthy volunteers and patients with lung disease.Loci that are uniquely unmethylated in alveolar or bronchial epithelial cells are enriched for enhancers controlling lung-specific genes. Methylation markers extracted from these methylomes revealed that normal lung cell turnover probably releases cfDNA into the air spaces, rather than to blood. People with advanced lung cancer show a massive elevation of lung cfDNA concentration in blood. Among individuals undergoing bronchoscopy, lung-derived cfDNA is observed in the plasma of those later diagnosed with lung cancer, and to a lesser extent in those diagnosed with other lung diseases. Lung cfDNA is also elevated in patients with acute exacerbation of COPD compared with patients with stable disease, and is associated with future exacerbation and mortality in these patients.Universal cfDNA methylation markers of normal lung epithelium allow for mutation-independent, sensitive and specific detection of lung-derived cfDNA, reporting on ongoing lung injury. Such markers can find broad utility in the study of normal and pathologic human lung dynamics.
Assessment of Age and Sex Differences in Risk of 1-Year Mortality After Emergency Department Visits Caused by Alcohol Use
Authors: Daniel T. Myran, Emily Rhodes, Haris Imsirovic, Shannon M. Fernando, Manish M. Sood, Peter Tanuseputro
Journal: JAMA Network Open (2022)

This cross-sectional study assesses age and sex differences in risk of 1-year mortality in patients with emergency department visits due to alcohol compared with the general population in Ontario, Canada.
Antibody-mediated delivery of a viral MHC-I epitope into the cytosol of target tumor cells repurposes virus-specific CD8+ T cells for cancer immunotherapy
Authors: Keunok Jung, Min-Jeong Son, Se-Young Lee, Jeong-Ah Kim, Deok-Han Ko, Sojung Yoo, Chul-Ho Kim, Yong-Sung Kim
Journal: Molecular Cancer (2022)

Redirecting pre-existing virus-specific cytotoxic CD8+ T lymphocytes (CTLs) to tumors by simulating a viral infection of the tumor cells has great potential for cancer immunotherapy. However, this strategy is limited by lack of amenable method for viral antigen delivery into the cytosol of target tumors. Here, we addressed the limit by developing a CD8+ T cell epitope-delivering antibody, termed a TEDbody, which was engineered to deliver a viral MHC-I epitope peptide into the cytosol of target tumor cells by fusion with a tumor-specific cytosol-penetrating antibody.To direct human cytomegalovirus (CMV)-specific CTLs against tumors, we designed a series of TEDbodies carrying various CMV pp65 antigen-derived peptides. CMV-specific CTLs from blood of CMV-seropositive healthy donors were expanded for use in in vitro and in vivo experiments. Comprehensive cellular assays were performed to determine the presentation mechanism of TEDbody-mediated CMV peptide-MHC-I complex (CMV-pMHCI) on the surface of target tumor cells and the recognition and lysis by CMV-specific CTLs. In vivo CMV-pMHCI presentation and antitumor efficacy of TEDbody were evaluated in immunodeficient mice bearing human tumors.TEDbody delivered the fused epitope peptides into target tumor cells to be intracellularly processed and surface displayed in the form of CMV-pMHCI, leading to disguise target tumor cells as virally infected cells for recognition and lysis by CMV-specific CTLs. When systemically injected into tumor-bearing immunodeficient mice, TEDbody efficiently marked tumor cells with CMV-pMHCI to augment the proliferation and cytotoxic property of tumor-infiltrated CMV-specific CTLs, resulting in significant inhibition of the in vivo tumor growth by redirecting adoptively transferred CMV-specific CTLs. Further, combination of TEDbody with anti-OX40 agonistic antibody substantially enhanced the in vivo antitumor activity.Our study offers an effective technology for MHC-I antigen cytosolic delivery. TEDbody may thus have utility as a therapeutic cancer vaccine to redirect pre-existing anti-viral CTLs arising from previously exposed viral infections to attack tumors.
In suspected PE, YEARS rule + D-dimer was noninferior to D-dimer alone to rule out PE
Authors: Natasha Goumeniouk, Eddy Lang
Journal: Annals of Internal Medicine (2022)

Source Citation Freund Y, Chauvin A, Jimenez S, et al. Effect of a diagnostic strategy using an elevated and age-adjusted D-dimer threshold on thromboembolic events in emergency department patients with suspected pulmonary embolism: a randomized clinical trial. JAMA. 2021;326:2141-9. 34874418
Physical Activity and Cardiac Function in Long-Term Breast Cancer Survivors
Authors: Willeke R. Naaktgeboren, Wim G. Groen, Judy N. Jacobse, Lars C. Steggink, Annemiek M.E. Walenkamp, Wim H. van Harten, Martijn M. Stuiver, Neil K. Aaronson, Berthe M.P. Aleman, Peter van der Meer, Michael Schaapveld, Gabe S. Sonke, Jourik A. Gietema, Flora E. van Leeuwen, Anne M. May
Journal: JACC CardioOncology (2022)

Higher levels of physical activity are associated with a lower risk of cardiovascular disease in the general population. Whether the same holds for women who underwent treatment for breast cancer is unclear.The aim of this study was to evaluate the association between physical activity in a typical week in the past 12 months and cardiac dysfunction in breast cancer survivors.We used data from a cohort of breast cancer survivors who were treated at ages 40 to 50 years (N = 559). The association between physical activity and global longitudinal strain (GLS) and left ventricular ejection fraction (LVEF) was evaluated using both linear and modified Poisson regression analyses adjusted for relevant confounders.In total, 559 breast cancer survivors were included, with median age of 55.5 years and a median time since treatment of 10.2 years. GLS was less favorable in inactive survivors (-17.1%) than in moderately inactive (-18.4%), moderately active (-18.2%), and active survivors (-18.5%), with an adjusted significant difference for active versus inactive survivors (β = -1.31; 95% CI: -2.55 to -0.06)). Moderately active (n = 57/130) and active survivors (n = 87/124) had significantly lower risks of abnormal GLS (defined as >-18%) compared with inactive survivors (n = 17/26) (RR: 0.65 [95% CI: 0.45-0.94] and RR: 0.61 [95% CI: 0.43-0.87], respectively). LVEF, in normal ranges in all activity categories, was not associated with physical activity.In long-term breast cancer survivors, higher physical activity levels were associated with improved GLS but not LVEF, with the relatively largest benefit for doing any activity versus none. This finding suggests that increasing physical activity may contribute to cardiovascular health benefits, especially in inactive survivors.
Feedback amplification of senolysis using caspase-3-cleavable peptide-doxorubicin conjugate and 2DG
Authors: Jong Cheol Lee, Gui Chul Kim, Na Kyeong Lee, Seong Who Kim, Young Seok Cho, Seung Woo Chung, Yoon Se Lee, Hyo Won Chang, Youngro Byun, Sang Yoon Kim
Journal: Journal of Controlled Release (2022)
Impact of time-to-treatment on survival for advanced non-small cell lung cancer patients in the Netherlands: a nationwide observational cohort study
Authors: Sosse E Klarenbeek, Mieke J Aarts, Michel M van den Heuvel, Mathias Prokop, Marcia Tummers, Olga C J Schuurbiers
Journal: Thorax (2022)

Background The assumption that more rapid treatment improves survival of advanced non-small cell lung cancer (NSCLC) has not yet been proven. We studied the relation between time-to-treatment and survival in advanced stage NSCLC patients in a large multicentric nationwide retrospective cohort. Additionally, we identified factors associated with delay. Method We selected 10 306 patients, diagnosed and treated between 2014 and 2019 for clinical stage III and IV NSCLC, from the Netherlands Cancer Registry that includes nationwide data from 109 Dutch hospitals. Associations between survival and time-to-treatment were tested with Cox proportional hazard regression analyses. Time-to-treatment was adjusted for multiple covariates including diagnostic procedures and type of therapy. Factors associated with delay were identified by multilevel logistic regression. Results Risk of death significantly decreased with longer time-to-treatment for stage III patients receiving only radiotherapy (adjusted HR, aHR &gt;21 days: 0.59 (95% CI 0.48 to 0.73)) or any type of systemic therapy (aHR &gt;49 days: 0.72 (95% CI 0.56 to 0.91)) and stage IV patients receiving chemotherapy and/or immunotherapy (aHR &gt;21 days: 0.81 (95% CI 0.73 to 0.88)). No significant association was found for stage III patients treated with chemoradiotherapy and stage IV patients treated with targeted therapy. More complex diagnostic procedures often delay treatment. Conclusion Although in general it is important to start treatment as early as possible, our study finds no evidence that a more rapid start of treatment improves outcomes in advanced stage NSCLC patients. The benefit of urgent treatment is probably confounded by unmeasured patient and tumour characteristics and, clinical urgency dictating timelines of treatment. Time-to-treatment and its impact should be continuously evaluated as therapeutic strategies continue to evolve and improve.
A network-based approach to identify expression modules underlying rejection in pediatric liver transplantation
Authors: Mylarappa Ningappa, Syed A. Rahman, Brandon W. Higgs, Chethan S. Ashokkumar, Nidhi Sahni, Rakesh Sindhi, Jishnu Das
Journal: Cell Reports Medicine (2022)

Selecting the right immunosuppressant to ensure rejection-free outcomes poses unique challenges in pediatric liver transplant (LT) recipients. A molecular predictor can comprehensively address these challenges. Currently, there are no well-validated blood-based biomarkers for pediatric LT recipients before or after LT. Here, we discover and validate separate pre- and post-LT transcriptomic signatures of rejection. Using an integrative machine learning approach, we combine transcriptomics data with the reference high-quality human protein interactome to identify network module signatures, which underlie rejection. Unlike gene signatures, our approach is inherently multivariate and more robust to replication and captures the structure of the underlying network, encapsulating additive effects. We also identify, in an individual-specific manner, signatures that can be targeted by current anti-rejection drugs and other drugs that can be repurposed. Our approach can enable personalized adjustment of drug regimens for the dominant targetable pathways before and after LT in children.
CPAnet: the challenges of gaining evidence-based knowledge in chronic pulmonary aspergillosis
Authors: Rosanne Sprute, Helmut J.F. Salzer, Danila Seidel
Journal: European Respiratory Journal (2022)

<b>Chronic pulmonary aspergillosis is a destructive fungal disease complicating many respiratory disorders. Evidence is scarce for clinical management decisions. CPAnet aims to improve patient care by collecting data in an international registry.</b>https://bit.ly/3utUFH1
Intensification of Systemic Therapy in Addition to Definitive Local Treatment in Nonmetastatic Unfavourable Prostate Cancer: A Systematic Review and Meta-analysis
Authors: Pawel Rajwa, Benjamin Pradere, Giorgio Gandaglia, Roderick C.N. van den Bergh, Igor Tsaur, Sung Ryul Shim, Takafumi Yanagisawa, Ekaterina Laukhtina, Keiichiro Mori, Hadi Mostafaei, Fahad Quhal, Piotr Bryniarski, Eva Compérat, Guilhem Roubaud, Christophe Massard, Axel S. Merseburger, Michael S. Leapman, Daniel E. Spratt, Fred Saad, Steven Joniau, Anthony V. D'Amico, Alberto Briganti, Shahrokh F. Shariat, Guillaume Ploussard
Journal: European Urology (2022)

Several recent randomised trials have evaluated the role of combination systemic treatment using androgen deprivation therapy (ADT) plus chemotherapy or an androgen receptor signaling inhibitor (ARSI) in patients with high-risk and/or unfavourable nonmetastatic prostate cancer (nmPC). To assess the outcomes associated with adding combination systemic treatment to primary definitive local therapy in patients with high-risk and/or unfavourable nmPC. We queried the PubMed, Web of Science, and Scopus databases and conference abstracts to identify prospective randomised trials examining the value of adding chemotherapy or an ARSI to ADT and primary local therapy with curative intent for nmPC. The primary endpoints were overall survival (OS), cancer-specific survival (CSS), metastasis-free survival (MFS), and failure-free survival (FFS). Secondary endpoints included adverse events (AEs) and pathologic outcomes. We identified 15 randomised studies, of which nine evaluated chemohormonal and six investigated ARSI-based treatment strategies. In both radical prostatectomy (RP) and radiation therapy (RT) settings, addition of docetaxel to ADT was associated with significantly better CSS (pooled hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.49–0.95; p = 0.025), MFS (pooled HR 0.82, 95% CI 0.71–0.95; p = 0.008), and FFS (pooled HR 0.70, 95% CI 0.62–0.79; p < 0.001); the difference did not meet the conventional level of statistical significance for OS (pooled HR 0.86, 95% CI 0.73–1.01; p = 0.072). For patients treated with RT alone, docetaxel-based combination treatment did not meet the significance threshold set for OS (p = 0.3), CSS (p = 0.072), or MFS (p = 0.079), but the difference for FFS was statistically significant (pooled HR 0.72, 95% CI 0.63–0.84; p < 0.001). On network meta-analyses including RT studies, ARSI + ADT outperformed docetaxel + ADT for survival endpoints and had a more favourable AE profile. Intensification of systemic therapy with docetaxel or an ARSI in addition to ADT improves oncologic endpoints in high-risk and/or unfavourable nmPC treated with local definitive therapy. The highest efficacy was achieved with ARSI + ADT, specifically in patients treated with RT. Our findings highlight that selected patients with high-risk nonmetastatic prostate cancer benefit from intensification of systemic therapy beyond hormonal treatment.
Polysalicylic Acid Polymer Microparticle Decoys Therapeutically Treat Acute Respiratory Distress Syndrome (Adv. Healthcare Mater. 7/2022)
Authors: Emma R. Brannon, William J. Kelley, Michael W. Newstead, Alison L. Banka, Kathryn E. Uhrich, Colleen E. O'Connor, Theodore J. Standiford, Omolola Eniola‐Adefeso
Journal: Advanced Healthcare Materials (2022)

Lung Injury In article number 2101534 by Omolola Eniola-Adefeso and co-workers, acute respiratory distress syndrome (ARDS) is often characterized by the abrupt accumulation of activated neutrophils in the lungs. Particle-based therapeutics can serve as a novel ARDS treatment that diverts rogue neutrophils in the systemic circulation, preventing neutrophil-related organ damage. Furthermore, materials used to fabricate particle-based therapeutics can be optimized to modulate cell phenotypes and, ultimately, the inflammatory response.
Incidence Rates and Clinical Outcomes of SARS-CoV-2 Infection With the Omicron and Delta Variants in Children Younger Than 5 Years in the US
Authors: Lindsey Wang, Nathan A. Berger, David C. Kaelber, Pamela B. Davis, Nora D. Volkow, Rong Xu
Journal: JAMA Pediatrics (2022)

Incidence Rates and Clinical Outcomes of SARS-CoV-2 Infection With the Omicron and Delta Variants in Children Younger Than 5 Years in the US With the Omicron variant (B.1.1.529),SARS-CoV-2 infections and hospitalizations reached record levels. 1 Children younger than 5 years may be especially vulnerable because they are not eligible for COVID-19 vaccination. 2We examined incidence rates and clinical outcomes of Omicron infection before and after Omicron became the predominant variant in the US.Methods | This cohort study (September 1, 2021-January 31, 2022) was approved by the MetroHealth System institutional review board (IRB); the need for informed consent was waived owing to use of deidentified patient data.We used the Tri-NetX Analytics Platform to access aggregated and deidentified electronic health records of 90 million patients from 66 health care organizations.TriNetX built-in analytic functions permit patientlevel analyses while only reporting population-level data.Patients represented 28% of the US population from 50 states covering diverse geographic, age, race, income, and insurance groups. 3Self-identified race and ethnicity were included owing to their association with SARS-CoV-2 infection risk and outcomes. Supplemental contentTable.Characteristics of the Omicron Cohort and the Delta Cohort Before and After Propensity Matching a Characteristic Before matching After matching Cohort, No. (%) SMD Cohort, No. (%)