tbuckley/cabot-search huggingface dataset:
A genome-wide association study of severe asthma exacerbations in Latino children and adolescents
Authors: Qi Yan, Erick Forno, Esther Herrera-Luis, Maria Pino-Yanes, Cancan Qi, Raimon Rios, Yueh-Ying Han, Soyeon Kim, Sam Oh, Edna Acosta-Pérez, Rong Zhang, Donglei Hu, Celeste Eng, Scott Huntsman, Lydiana Avila, Nadia Boutaoui, Michelle M. Cloutier, Manuel E. Soto-Quiros, Cheng-Jian Xu, Scott T. Weiss, Jessica Lasky-Su, Megan R. Kiedrowski, Camila Figueiredo, Jennifer Bomberger, Mauricio L. Barreto, Glorisa Canino, Wei Chen, Gerard H. Koppelman, Esteban G. Burchard, Juan C. Celedón
Journal: European Respiratory Journal (2020)

Severe asthma exacerbations are a major cause of school absences and healthcare costs in children, particularly those in high-risk racial/ethnic groups. To identify susceptibility genes for severe asthma exacerbations in Latino children and adolescents, we conducted a meta-analysis of genome-wide association studies (GWAS) in 4010 Latino youth with asthma in four independent cohorts, including 1693 Puerto Ricans, 1019 Costa Ricans, 640 Mexicans, 256 Brazilians and 402 members of other Latino subgroups. We then conducted methylation quantitative trait locus, expression quantitative trait locus and expression quantitative trait methylation analyses to assess whether the top single nucleotide polymorphism (SNP) in the meta-analysis is linked to DNA methylation and gene expression in nasal (airway) epithelium in separate cohorts of Puerto Rican and Dutch children and adolescents. In the meta-analysis of GWAS, an SNP in FLJ22447 (rs2253681) was significantly associated with 1.55 increased odds of severe asthma exacerbation (95% CI 1.34–1.79, p=6.3×10 −9 ). This SNP was significantly associated with DNA methylation of a CpG site (cg25024579) at the FLJ22447 locus, which was in turn associated with increased expression of KCNJ2-AS1 in nasal airway epithelium from Puerto Rican children and adolescents (β=0.10, p=2.18×10 −7 ). SNP rs2253681 was significantly associated with both DNA methylation of a cis-CpG in FLJ22447 and severe asthma exacerbations in Latino youth. This may be partly explained by changes in airway epithelial expression of a gene recently implicated in atopic asthma in Puerto Rican children and adolescents ( KCNJ2-AS1 ).
Evidence Evaluation Process and Management of Potential Conflicts of Interest: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations
Authors: Peter T. Morley, Dianne L. Atkins, Judith C. Finn, Ian Maconochie, Jerry P. Nolan, Yacov Rabi, Eunice M. Singletary, Tzong-Luen Wang, Michelle Welsford, Theresa M. Olasveengen, Richard Aickin, John E. Billi, Robert Greif, Eddy Lang, Mary E. Mancini, William H. Montgomery, Robert W. Neumar, Gavin D. Perkins, Jasmeet Soar, Myra H. Wyckoff, Laurie J. Morrison
Journal: Circulation (2020)
TCT-405 A Novel Machine Learning Algorithm Enhances Prediction of Target Lesion Failure: An Analysis of 4,983 Patients From the XIENCE V USA Database
Authors: Ciaran Byrne, Kusano Hajime, Jin Wang, Richard Rapoza, Jennifer Jones-McMeans, James Hermiller, Krishna Sudhir, Divine Ediebah, Nick West
Journal: Journal of the American College of Cardiology (2021)
TCT CONNECT-441 The Prevalence, Predictors, and Clinical Outcomes of Spontaneous Echocardiographic Contrast or Left Ventricular Thrombus in Patients With HFrEF
Authors: Peiren Shan, Lingfang Yu, Dong Xiao, Ruiyu Shi, Weijian Huang
Journal: Journal of the American College of Cardiology (2020)
TCT CONNECT-24 In-Hospital Outcomes and 30-Day Readmission for Patients Presented With Left Main Coronary Artery ST-Segment Elevation Myocardial Infarction
Authors: Ahmed Elkaryoni, Raed Qarajeh, Adel Muhanna, Ivo Genev, Kirolos Barssoum, Islam Abdelkarim, Anne Arnason, Amir Darki
Journal: Journal of the American College of Cardiology (2020)
Taking science talks online
Authors: Peter Ranscombe
Journal: The Lancet Infectious Diseases (2020)

When Dr Helen Bridle, an associate professor in the Institute of Biological Chemistry, Biophysics & Bioengineering at Heriot-Watt University, Edinburgh, UK, pitched the idea for her session in the Royal Society of Edinburgh's (RSE's) "Tea & Talk" series, her event was going to follow the tried-and-tested formula for public engagement with science, with a short explanation about her work followed by questions from the audience. Then the COVID-19 pandemic struck, and everything changed. In August, Edinburgh would normally host five arts festivals, together forming the second-largest cultural gathering in the world after the Olympic Games, with more than 4·4 million people watching more than 25 000 artists performing in more than 5000 shows.
Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation
Authors: Brendan Reed, Frances Crawford, Ryan C. Hill, Niyun Jin, Janice White, S. Harsha Krovi, Philippa Marrack, Kirk Hansen, John W. Kappler
Journal: The Journal of Experimental Medicine (2020)

The identification of the peptide epitopes presented by major histocompatibility complex class II (MHCII) molecules that drive the CD4 T cell component of autoimmune diseases has presented a formidable challenge over several decades. In type 1 diabetes (T1D), recent insight into this problem has come from the realization that several of the important epitopes are not directly processed from a protein source, but rather pieced together by fusion of different peptide fragments of secretory granule proteins to create new chimeric epitopes. We have proposed that this fusion is performed by a reverse proteolysis reaction called transpeptidation, occurring during the catabolic turnover of pancreatic proteins when secretory granules fuse with lysosomes (crinophagy). Here, we demonstrate several highly antigenic chimeric epitopes for diabetogenic CD4 T cells that are produced by digestion of the appropriate inactive fragments of the granule proteins with the lysosomal protease cathepsin L (Cat-L). This pathway has implications for how self-tolerance can be broken peripherally in T1D and other autoimmune diseases.
TCT CONNECT-87 Redo Transcatheter Aortic Valve Replacement With the Supra-Annular, Self-Expandable Evolut Platform: Insights From the TVT Registry
Authors: Guilherme Attizzani, Luis Augusto Dallan, Marc Pelletier, G. Deeb, John Forrest, Michael Reardon, Jeffrey Popma
Journal: Journal of the American College of Cardiology (2020)
Blood-based extracellular matrix biomarkers are correlated with clinical outcome after PD-1 inhibition in patients with metastatic melanoma
Authors: Daan P Hurkmans, Christina Jensen, Stijn L W Koolen, Joachim Aerts, Morten Asser Karsdal, Ron H J Mathijssen, Nicholas Willumsen
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Immune checkpoint inhibitors that target the programmed cell death protein 1 (PD-1) receptor induce a response in only a subgroup of patients with metastatic melanoma. Previous research suggests that transforming growth factor beta signaling and a collagen-rich peritumoral stroma (tumor fibrosis), may negatively interfere with the interaction between T cells and tumor cells and thereby contribute to resistance mechanisms by immune-exclusion, while increased tumor infiltration of M1-like macrophages enhances T cell activity. Hence, the current study aimed to assess the relationship between blood-based markers of collagen or vimentin turnover (reflecting M1 macrophage activity) and clinical outcome in patients with metastatic melanoma after PD-1 inhibition. Methods Patients with metastatic melanoma who were treated with anti-PD-1 monotherapy between May 2016 and March 2019 were included in a prospective observational study. N-terminal pro-peptide of type III collagen (PRO-C3) cross-linked N-terminal pro-peptides of type III collagen (PC3X), matrix metalloprotease (MMP)-degraded type III (C3M) and type IV collagen (C4M), granzyme B-degraded type IV collagen and citrullinated and MMP-degraded vimentin (VICM) were measured with immunoassays in serum before (n=107), and 6 weeks after the first administration of immunotherapy (n=94). The association between biomarker levels and overall survival (OS) or progression-free survival (PFS) was assessed. Results Multivariate Cox regression analysis identified high baseline PRO-C3 (Q4) and PC3X (Q4) as independent variables of worse PFS (PRO-C3: HR=1.81, 95% CI=1.06 to 3.10, p=0.030 and PC3X: HR=1.86, 95% CI=1.09 to 3.18, p=0.023). High baseline PRO-C3 was also independently related to worse OS (HR=2.08, 95% CI=1.06 to 4.09, p=0.035), whereas a high C3M/PRO-C3 ratio was related to improved OS (HR=0.42, 95% CI=0.20 to 0.90, p=0.025). An increase in VICM (p&lt;0.0001; in 56% of the patients) was observed after 6 weeks of treatment, and an increase in VICM was independently associated with improved OS (HR=0.28, 95% CI=0.10 to 0.77, p=0.014). Conclusions Blood-based biomarkers reflecting excessive type III collagen turnover were associated with worse OS and PFS after PD-1 inhibition in metastatic melanoma. Moreover, an increase in VICM levels after 6 weeks of treatment was associated with improved OS. These findings suggest that type III collagen and vimentin turnover contribute to resistance/response mechanisms of PD-1 inhibitors and hold promise of assessing extracellular matrix-derived and stroma-derived components to predict immunotherapy response.
TCT CONNECT-226 In-Hospital Outcomes of CABG Candidates Undergoing PCI During the ICU Restricted COVID-19 Pandemic: The Multi-Center Prospective UK-REVASC Registry
Authors: Thomas Kite, Andrew Ladwiniec, Helen Routledge, Stephen Hoole, Nick Palmer, Mohaned Egred, Divaka Perera, Kyriacos Mouyis, Manas Sinha, Luciano Candilio, Brijesh Anantharam, Aengus Murphy, Farzin Fath-Ordoubadi, Paul Das, Paul Morris, Nick Curzen, Diana Gorog, Angela Hoye, Charley Budgeon, Gregg Stone, Colin Berry, Anthony Gershlick
Journal: Journal of the American College of Cardiology (2020)
Therapy-related B-cell acute lymphoblastic leukemia in adults has unique genetic profile with frequent loss of TP53 and inferior outcome
Authors: Liron Barnea Slonim, Juehua Gao, Madelyn Burkart, Oluwatobi E. Odetola, Masha Kocherginsky, Shira N. Dinner, Xinyan Lu, Firas Wehbe, Lawrence Jennings, Jessica K. Altman, Kamran M. Mirza, Yi-Hua Chen, Madina Sukhanova
Journal: Leukemia (2020)
Immunological considerations for SARS-CoV-2 human challenge studies
Authors: Alexander D. Douglas, Adrian V. S. Hill
Journal: Nature reviews. Immunology (2020)

The ethics and practicalities of controlled human infection with SARS-CoV-2 have been widely discussed. Potential risks are clear. The case in favour hinges upon whether these risks can be mitigated to an acceptable, very low, level and whether the studies will provide substantial benefits that could not readily be obtained by other means. Here, we discuss the immunological considerations relating to each side of this balance. In this Comment article, Sandy Douglas and Adrian Hill discuss the immunological considerations associated with a risk–benefit analysis for controlled human infection models of SARS-CoV-2.
Infographic. Stay physically active during COVID-19 with exercise as medicine
Authors: Isaac J Wedig, Tristan A Duelge, Steven J Elmer
Journal: British Journal of Sports Medicine (2020)

There are over 35 000 000 reported cases of COVID-19 disease and 1 000 000 deaths across more than 200 countries worldwide.1 With cases continuing to rise and a robust vaccine not yet available for safe and widespread delivery, lifestyle adaptations will be needed for the foreseeable future. As we try to contain the spread of the virus, adults are spending more time at home. Recent evidence2 suggests that physical activity levels have decreased by ~30% and sitting time has increased by ~30%. This is a major concern as physical inactivity and sedentary behaviour are risk factors3 for cardiovascular disease, obesity, cancer, diabetes, hypertension, bone and joint disease, depression and premature death.

To date, more than 130 authors …
Energy expenditure during cell spreading influences the cellular response to matrix stiffness
Authors: Jing Xie, Min Bao, Xinyu Hu, Werner J.H. Koopman, Wilhelm T.S. Huck
Journal: Biomaterials (2020)

Cells respond to the mechanical properties of the extracellular matrix (ECM) through formation of focal adhesions (FAs), re-organization of the actin cytoskeleton and adjustment of cell contractility. These are energy-demanding processes, but a potential causality between mechanical cues (matrix stiffness) and cellular (energy) metabolism remains largely unexplored. Here, we cultured human mesenchymal stem cells (hMSCs) on stiff (20 kPa) or soft (1 kPa) substrate and demonstrate that cytoskeletal reorganization and FA formation spreading on stiff substrates lead to a drop in intracellular ATP levels, correlating with activation of AMP-activated protein kinase (AMPK). The resulting increase in ATP levels further facilitates cell spreading and reinforces cell tension of the steady state, and coincides with nuclear localization of YAP/TAZ and Runx2. While on soft substrates (1 kPa), lowered ATP levels limit these cellular mechanoresponses. Furthermore, genetic ablation of AMPK lowered cellular ATP levels on stiff substrate and strongly reduced responses to substrate stiffness. Together, these findings reveal a hitherto unidentified relationship between energy expenditure and the cellular mechanoresponse, and point to AMPK as a key mediator of stem cell fate in response to ECM mechanics.
Effective Treatment of Acute Severe Ulcerative Colitis in Pregnancy Is Associated With Good Maternal and Fetal Outcomes
Authors: Jacob E. Ollech, Irit Avni-Biron, Laura Glick, Haider Haider, Sushila R. Dalal, Dejan Micic, Joel Pekow, Henit Yanai, Russel D. Cohen, Iris Dotan, David T. Rubin, Atsushi Sakuraba
Journal: Clinical Gastroenterology and Hepatology (2020)
Infographic. Remote running gait analysis
Authors: Christopher Napier, Tom Goom, Alan Rankin
Journal: British Journal of Sports Medicine (2020)

Physiotherapy has long followed a standard script. The patient is seen in-person at a clinic, a subjective history is taken and the physiotherapist completes a physical examination consisting of strength, range of motion, functional testing, etc to determine the cause of injury and prescribe an appropriate treatment plan. For running injuries, this assessment often includes an analysis—either on a treadmill or overground—of the patient’s running gait. When facilities and equipment are available, this may include three-dimensional (3D) motion capture and force plate analysis, which provides more detailed information about the biomechanics contributing to the presenting injury. Since most clinicians do not have access to this equipment, many use two-dimensional (2D) video analysis in the clinic.

Recent circumstances have pushed many of us to explore remote options using online platforms, such as telehealth. This has forced us to be more creative with how we assess and treat patients and presents an opportunity to evolve our practice. With most runners having access to a high-quality video camera on their phone or tablet, 2D motion capture can be performed remotely. Recent advances and access to wearable technology—inertial measurement units (IMUs), in particular—now allow remote measurement of forces and spatiotemporal data. Remote biomechanical running gait analysis is now a reality (figure 1).



Figure 1 
Infographic: remote …
Albumin internalizes and inhibits endosomal TLR signaling in leukocytes from patients with decompensated cirrhosis
Authors: Mireia Casulleras, Roger Flores-Costa, Marta Duran-Güell, José Alcaraz-Quiles, Silvia Sanz, Esther Titos, Cristina López-Vicario, Javier Fernández, Raquel Horrillo, Montserrat Costa, Pierre de la Grange, Richard Moreau, Vicente Arroyo, Joan Clària
Journal: Science Translational Medicine (2020)

Human serum albumin (HSA) is an emerging treatment for preventing excessive systemic inflammation and organ failure(s) in patients with acutely decompensated (AD) cirrhosis. Here, we investigated the molecular mechanisms underlying the immunomodulatory properties of HSA. Administration of HSA to patients with AD cirrhosis with elevated circulating bacterial DNA rich in unmethylated cytosine-phosphate-guanine dideoxynucleotide motifs (CpG-DNA) was associated with reduced plasma cytokine concentrations. In isolated leukocytes, HSA abolished CpG-DNA-induced cytokine expression and release independently of its oncotic and scavenging properties. Similar anti-inflammatory effects were observed with recombinant human albumin. HSA exerted widespread changes on the immune cell transcriptome, specifically in genes related to cytokines and type I interferon responses. Our data revealed that HSA was taken up by leukocytes and internalized in vesicles positively stained with early endosome antigen 1 and colocalized with CpG-DNA in endosomes, where the latter binds to Toll-like receptor 9 (TLR9), its cognate receptor. Furthermore, HSA also inhibited polyinosinic:polycytidylic acid- and lipopolysaccharide-induced interferon regulatory factor 3 phosphorylation and TIR domain-containing adapter-inducing interferon-β-mediated responses, which are exclusive of endosomal TLR3 and TLR4 signaling, respectively. The immunomodulatory actions of HSA did not compromise leukocyte defensive mechanisms such as phagocytosis, efferocytosis, and intracellular reactive oxygen species production. The in vitro immunomodulatory effects of HSA were confirmed in vivo in analbuminemic humanized neonatal Fc receptor transgenic mice. These findings indicate that HSA internalizes in immune cells and modulates their responses through interaction with endosomal TLR signaling, thus providing a mechanism for the benefits of HSA infusions in patients with cirrhosis.
QT Interval in Patients With COVID-19—Reply
Authors: Christina F. Yen, David J. Shim, Howard S. Gold
Journal: JAMA Cardiology (2020)

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Response to Comment on McIntyre and Moses The Diagnosis and Management of Gestational Diabetes Mellitus in the Context of the COVID-19 Pandemic. Diabetes Care 2020;43:1433–1434
Authors: H. David McIntyre, Robert G. Moses
Journal: Diabetes Care (2020)

We thank Issa et al. (1) for their interest in our commentary (2) and for their data regarding the potential consequences of applying the Royal College of Obstetricians and Gynaecologists (RCOG) modified guidelines for gestational diabetes mellitus (GDM) diagnosis during the coronavirus 2019 (COVID-19) pandemic (3). They note that in their clinical environment the RCOG modifications would miss over half of the women previously diagnosed with GDM under U.K. guidelines and question whether their implementation is appropriate. …
Correlation between in vitro stability and pharmacokinetics of poly(ε-caprolactone)-based micelles loaded with a photosensitizer
Authors: Yanna Liu, Marcel H.A.M. Fens, Robin Bruno Capomaccio, Dora Mehn, Luca Scrivano, Robbert J. Kok, Sabrina Oliveira, Wim E. Hennink, Cornelus F. van Nostrum
Journal: Journal of Controlled Release (2020)

Polymeric micelles are extensively investigated as drug delivery systems for hydrophobic drugs including photosensitizers (PSs). In order to benefit from micelles as targeted delivery systems for PS, rather than only solubilizers, the stability and cargo retention of the (PS-loaded) micelles should be properly assessed in biologically relevant media to get insight into the essential parameters predicting their in vivo performance (i.e., pharmacokinetics). In the present study, asymmetric flow field-flow fractionation (AF4) was used to investigate the in vitro stability in human plasma of empty and meta-tetra(hydroxyphenyl)chlorin (mTHPC)-loaded dithiolane-crosslinked micelles based on poly(ɛ-caprolactone)-co-poly(1,2-dithiolane‑carbonate)-b-poly(ethylene glycol) (p(CL-co-DTC)-PEG) and non (covalently)-crosslinked micelles composed of poly(ε-caprolactone)-b-poly(ethylene glycol) (pCL-PEG). AF4 allows separation of the micelles from plasma proteins, which showed that small non (covalently)-crosslinked pCL9-PEG (17 nm) and pCL15-PEG (22 nm) micelles had lower stability in plasma than pCL23-PEG micelles with larger size (43 nm) and higher degree of crystallinity of pCL, and had also lower stability than covalently crosslinked p(CL9-DTC3.9)-PEG and p(CL18-DTC7.5)-PEG micelles with similar small sizes (~20 nm). In addition, PS (re)distribution to specific plasma proteins was observed by AF4, giving strong indications for the (in)stability of PS-loaded micelles in plasma. Nevertheless, fluorescence spectroscopy in human plasma showed that the retention of mTHPC in non (covalently)-crosslinked but semi-crystalline pCL23-PEG micelles (>8 h) was much longer than that in covalently crosslinked p(CL18-DTC7.5)-PEG micelles (~4 h). In line with this, in vivo circulation kinetics showed that pCL23-PEG micelles loaded with mTHPC had significantly longer half-life values (t½-β of micelles and mTHPC was 14 and 18 h, respectively) than covalently crosslinked p(CL18-DTC7.5)-PEG micelles (t½-β of both micelles and mTHPC was ~2 h). As a consequence, long circulating pCL23-PEG micelles resulted in significantly higher tumor accumulation of both the micelles and loaded mTHPC as compared to short circulating p(CL18-DTC7.5)-PEG micelles. These in vivo data were in good agreement with the in vitro stability studies. In conclusion, the present study points out that AF4 and fluorescence spectroscopy are excellent tools to evaluate the (in)stability of nanoparticles in biological media and thus predict the (in)stability of drug loaded nanoparticles after i.v. administration, which is favorable to screen promising delivery systems with reduced experimental time and costs and without excessive use of animals.
TCT CONNECT-73 Weekend Admission for Transcatheter Aortic Valve Replacement Was Associated With Increased In-Hospital Morbidity and All-Cause Mortality
Authors: Louis Vincent, Bertrand Ebner, Jelani Grant, Jennifer Manning, Neal Olarte, Odunayo Olorunfemi, Rosario Colombo, Eduardo De Marchena
Journal: Journal of the American College of Cardiology (2020)
TCT CONNECT-88 Impact of Morbid Obesity And Obesity Phenotype on Outcomes post Transcatheter Aortic Valve Replacement
Authors: Angela McInerney, Gabriela Tirado-Conte, Josep Rodés-Cabau, Francisco Campelo Parada, Jose Tafur Soto, Marco Barbanti, Erika Muñoz-Garcia, Mobeena Arif, Diego Lopez Otero, Stefan Toggweiler, Gabriela Veiga Fernández, Anna Pylko, Teresa Sevilla, Miriam Compagnone, Ander Regueiro, Vicente Serra, Carnero Manuel, Juan Francisco Oteo Dominguez, Fernando Rivero, Henrique Ribeiro, Leonardo Guimarães, Anthony Matta, Natalia Giraldo Echavarria, Roberto Valvo, Federico Moccetti, Antonio J. Muñoz-Garcia, Javier Lopez-Pais, Bruno Garcia-Del-Blanco, Diego Carter Campanha Borges, Eric Dumont, Nieves Gonzalo, Enrico Criscione, Maciej Dabrowski, Fernando Alfonso, Jose Maria De La Torre Hernandez, Asim Cheema, Ignacio Amat-Santos, Francesco Saia, Javier Escaned, Luis Nombela-Franco
Journal: Journal of the American College of Cardiology (2020)