tbuckley/cabot-search huggingface dataset:
β3-Adrenoceptor Stimulation on Top of β1-Adrenoceptor Blockade: “Stop or Encore?”**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Jean-Luc Balligand
Journal: Journal of the American College of Cardiology (2009)
A dual antibody test for accurate surveillance of SARS-CoV-2 exposure rates
Authors: Emmanuelle V. LeBlanc, Che C. Colpitts
Journal: Cell Reports Medicine (2021)

Accurate population surveillance of SARS-CoV-2 infection has been hampered by limited testing and inadequate serological assays. In a recent issue of Med, Hippich et al.1 describe a two-step antibody test with 100% specificity, revealing higher-than-reported SARS-CoV-2 exposure rates in children.
Spread of a Variant SARS-CoV-2 in Long-Term Care Facilities in England
Authors: Maria Krutikov, Andrew Hayward, Laura Shallcross
Journal: New England Journal of Medicine (2021)

Rapid Spread of the B.1.1.7 Variant across England Between October and December 2020, a new SARS-CoV-2 variant (B.1.1.7) rapidly spread across England, including in long-term care facilities.
P72.09 Study of Relationship Between Proportion of CTLA-4 Positive Tregs in Tumor Infiltrating Lymphocytes and PD-L1 TPS
Authors: S. Muto, S. Inomata, H. Yamaguchi, H. Mine, H. Takagi, Y. Ozaki, N. Okabe, Y. Matsumura, Y. Shio, H. Suzuki
Journal: Journal of Thoracic Oncology (2021)
Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown, β-Globin Induction and Simultaneous Repression of β-Globin for the Potential Treatment of Sickle Cell Disease
Authors: Olivier Negre, Christian Brendel, Geoffrey B. Parsons, Min Luo, Myriam A Armant, Swaroopa Guda, Lauryn Christiansen, Gretchen Lewis, Gabor Veres, Melissa Bonner, David A. Williams
Journal: Blood (2017)
Vertebral-specific activation of the CX3CL1/ICAM-1 signaling network mediates non-small-cell lung cancer spinal metastasis by engaging tumor cell-vertebral bone marrow endothelial cell interactions
Authors: Ketao Wang, Libo Jiang, Annan Hu, Chi Sun, Lei Zhou, Yiwei Huang, Qing Chen, Jian Dong, Xiaogang Zhou, Feng Zhang
Journal: Theranostics (2021)

Rationale: The spine is one of the most common metastatic sites of non-small cell lung cancer (NSCLC), and NSCLC spinal metastasis results in serious consequences. Metastatic extravasation of disseminated cancer cells including increased invasiveness, adhesion and transendothelial migration is crucial for tumor metastasis. This study aimed to investigate the mechanisms underlying NSCLC spinal metastasis based on the C-X3-C motif chemokine ligand 1- (CX3CL1) and intercellular adhesion molecule-1- (ICAM-1) mediated signaling network. Methods: Immunohistochemistry, western blotting, and reverse transcription-quantitative PCR were conducted to detect the distribution of CX3CL1/ICAM-1 in different organs. Transwell, adhesion, and transendothelial migration assays were performed to evaluate the regulatory effects of CX3CL1/ICAM-1 on NSCLC cell invasion, adhesion, and transendothelial migration in vitro. A spontaneous spinal metastasis mouse model was established via injection of NSCLC cells into the left cardiac ventricle of NOD/SCID mice. The effects of CX3CL1/ICAM-1 on NSCLC spinal metastasis in vivo were validated using bioluminescent, micro-computerized tomography, immunohistochemistry and histological analyses. Results: CX3CL1 expression was specifically higher in vertebral bone compared with limb bones and lung tissue, and was associated with NSCLC spinal metastasis. Mechanically, vertebral bone marrow endothelial cells (VBMECs) enhanced NSCLC cell invasion via CX3CL1 signaling-mediated activation of the PI3K/AKT pathway. Furthermore, we found that VBMECs effectively induced ICAM-1-dependent NSCLC cell adhesion in coordination with platelets through the CX3CL1/ICAM-1/LFA-1 pathway. Meanwhile, CX3CL1 enhanced NSCLC cell transendothelial migration by increasing permeability of VBMECs via ICAM-1-dependent activation of the Src/GEF-H1 pathway. Interestingly, NSCLC cells were indicated to promote CX3CL1 secretion of VBMECs through MAPK14/ADMA17-dependent CX3CL1 release and NF-κB-dependent CX3CL1 synthesis. Based on these findings, we revealed a novel feedback cycle between circulating NSCLC cells and VBMECs mediated by CX3CL1/ICAM-1 signaling. Further disengagement of the CX3CL1/ICAM-1-mediated feedback cycle in vivo significantly restricted metastasis and prolonged mouse survival. Conclusions: Our results indicated a unique feedback cycle between circulating NSCLC cells and VBMECs mediated by CX3CL1/ICAM-1 signaling, which is necessary for NSCLC spinal metastasis. This work provides a new perspective for underlying the mechanisms of NSCLC spinal metastasis and indicates potential novel targets for the prevention of NSCLC spinal metastasis.
P76.05 Radiotherapy with Concurrent Versus Sequential Osimertinib for Advanced Non-Small Cell Lung Cancer: a Multi-Center Toxicity Analysis
Authors: D. Qian, M. Behera, J. Carlisle, T. Owonikoko, C. Steuer, S. Pakkala, A. Kesarwala, B. Fischer-Valuck, J. Bradley, W. Curran, S. Ramalingam, K. Higgins
Journal: Journal of Thoracic Oncology (2021)
Correspondence on ‘Factors associated with progression to inflammatory arthritis in first-degree relatives of individuals with RA following autoantibody positive screening in a non-clinical setting’
Authors: Marc Scherlinger, Thierry Schaeverbeke
Journal: Annals of the Rheumatic Diseases (2021)

<i>HLA class I</i> and <i>KIR</i> sequences were determined for Dogon, Fulani, and Baka populations of western Africa, Mbuti of central Africa, and Datooga, Iraqw, and Hadza of eastern Africa. Study of 162 individuals identified 134 <i>HLA class I</i> alleles (41 <i>HLA-A</i>, 60 <i>HLA-B</i>, and 33 <i>HLA-C</i>). Common to all populations are three <i>HLA-C</i> alleles (<i>C1<sup>+</sup>C*07:01</i>, <i>C1<sup>+</sup>C*07:02</i>, and <i>C2<sup>+</sup>C*06:02</i>) but no <i>HLA-A</i> or <i>-B</i>. Unexpectedly, no novel <i>HLA class I</i> was identified in these previously unstudied and anthropologically distinctive populations. In contrast, of 227 <i>KIR</i> detected, 22 are present in all seven populations and 28 are novel. A high diversity of <i>HLA A-C-B</i> haplotypes was observed. In six populations, most haplotypes are represented just once. But in the Hadza, a majority of haplotypes occur more than once, with 2 having high frequencies and 10 having intermediate frequencies. The centromeric (<i>cen</i>) part of the <i>KIR</i> locus exhibits an even balance between <i>cenA</i> and <i>cenB</i> in all seven populations. The telomeric (<i>tel</i>) part has an even balance of <i>telA</i> to <i>telB</i> in East Africa, but this changes across the continent to where <i>telB</i> is vestigial in West Africa. All four KIR ligands (A3/11, Bw4, C1, and C2) are present in six of the populations. <i>HLA</i> haplotypes of the Iraqw and Hadza encode two KIR ligands, whereas the other populations have an even balance between haplotypes encoding one and two KIR ligands. Individuals in these African populations have a mean of 6.8–8.4 different interactions between KIR and HLA class I, compared with 2.9–6.5 for non-Africans.
Matrix metalloproteinase-1 decorated polymersomes, a surface-active extracellular matrix therapeutic, potentiates collagen degradation and attenuates early liver fibrosis
Authors: Eline Geervliet, Silvia Moreno, Luca Baiamonte, Richell Booijink, Susanne Boye, Peng Wang, Brigitte Voit, Albena Lederer, Dietmar Appelhans, Ruchi Bansal
Journal: Journal of Controlled Release (2021)

Liver fibrosis affects millions of people worldwide and is rising vastly over the past decades. With no viable therapies available, liver transplantation is the only curative treatment for advanced diseased patients. Excessive accumulation of aberrant extracellular matrix (ECM) proteins, mostly collagens, produced by activated hepatic stellate cells (HSCs), is a hallmark of liver fibrosis. Several studies have suggested an inverse correlation between collagen-I degrading matrix metalloproteinase-1 (MMP-1) serum levels and liver fibrosis progression highlighting reduced MMP-1 levels are associated with poor disease prognosis in patients with liver fibrosis. We hypothesized that delivery of MMP-1 might potentiate collagen degradation and attenuate fibrosis development. In this study, we report a novel approach for the delivery of MMP-1 using MMP-1 decorated polymersomes (MMPsomes), as a surface-active vesicle-based ECM therapeutic, for the treatment of liver fibrosis. The storage-stable and enzymatically active MMPsomes were fabricated by a post-loading of Psomes with MMP-1. MMPsomes were extensively characterized for the physicochemical properties, MMP-1 surface localization, stability, enzymatic activity, and biological effects. Dose-dependent effects of MMP-1, and effects of MMPsomes versus MMP-1, empty polymersomes (Psomes) and MMP-1 + Psomes on gene and protein expression of collagen-I, MMP-1/TIMP-1 ratio, migration and cell viability were examined in TGFβ-activated human HSCs. Finally, the therapeutic effects of MMPsomes, compared to MMP-1, were evaluated in vivo in carbon-tetrachloride (CCl4)-induced early liver fibrosis mouse model. MMPsomes exhibited favorable physicochemical properties, MMP-1 surface localization and improved therapeutic efficacy in TGFβ-activated human HSCs in vitro. In CCl4-induced early liver fibrosis mouse model, MMPsomes inhibited intra-hepatic collagen-I (ECM marker, indicating early liver fibrosis) and F4/80 (marker for macrophages, indicating liver inflammation) expression. In conclusion, our results demonstrate an innovative approach of MMP-1 delivery, using surface-decorated MMPsomes, for alleviating liver fibrosis.
Functional and Adaptive Significance of Promoter Mutations That Affect Divergent Myocardial Expressions of <i>TRIM72</i> in Primates
Authors: Yuanqing Feng, Hongzhan Xu, Jinghao Liu, Ning Xie, Lei Gao, Yanyun He, Yuan Yao, Fengxiang Lv, Yan Zhang, Jian Lu, Wei Zhang, Chuan-Yun Li, Xinli Hu, Ziheng Yang, Rui-Ping Xiao
Journal: Molecular Biology and Evolution (2021)

Cis-regulatory elements play important roles in tissue-specific gene expression and in the evolution of various phenotypes, and mutations in promoters and enhancers may be responsible for adaptations of species to environments. TRIM72 is a highly conserved protein that is involved in energy metabolism. Its expression in the heart varies considerably in primates, with high levels of expression in Old World monkeys and near absence in hominids. Here, we combine phylogenetic hypothesis testing and experimentation to demonstrate that mutations in promoter are responsible for the differences among primate species in the heart-specific expression of TRIM72. Maximum likelihood estimates of lineage-specific substitution rates under local-clock models show that relative to the evolutionary rate of introns, the rate of promoter was accelerated by 78% in the common ancestor of Old World monkeys, suggesting a role for positive selection in the evolution of the TRIM72 promoter, possibly driven by selective pressure due to changes in cardiac physiology after species divergence. We demonstrate that mutations in the TRIM72 promoter account for the differential myocardial TRIM72 expression of the human and the rhesus macaque. Furthermore, changes in TRIM72 expression alter the expression of genes involved in oxidative phosphorylation, which in turn affects mitochondrial respiration and cardiac energy capacity. On a broader timescale, phylogenetic regression analyses of data from 29 mammalian species show that mammals with high cardiac expression of TRIM72 have high heart rate, suggesting that the expression changes of TRIM72 may be related to differences in the heart physiology of those species.
The Affordability of Guideline-Directed Medical Therapy
Authors: Alexander T. Sandhu, Paul A. Heidenreich
Journal: Circulation (2021)

BACKGROUNDHeart failure with reduced ejection fraction has seen remarkable advances with multiple medical therapies that reduce mortality.Despite these breakthroughs, guideline-recommended medical therapy (GDMT) is underutilized.The reasons for suboptimal implementation are manifold but surmountable.These include gaps in clinician knowledge, patient reluctance to take chronic medications, clinical inertia, and, increasingly, GDMT affordability.Since generic carvedilol became available in 2007, patients could be treated with generic and relatively affordable formulations of β-blockers, angiotensin-converting enzyme inhibitors, and mineralocorticoid receptor antagonists.However, with the introduction of angiotensin receptor-neprilysin inhibitor and sodium glucose cotransporter 2 inhibitor therapy, optimal medical therapy now requires the use of 2 brand-name medications.An important driver of suboptimal uptake is their cost-both with regard to barriers to insurance approval and high out-of-pocket costs.This not only hinders therapy uptake, contributing to higher morbidity, but also exacerbates existing disparities because low-income patients are especially affected by these costs.In the following sections, we detail concerns regarding GDMT affordability and provide a path forward.
Whole Brain White Matter Tract Deviation and Idiosyncrasy From Normative Development in Autism and ADHD and Unaffected Siblings Link With Dimensions of Psychopathology and Cognition
Authors: Yu-Hung Tung, Hsiang-Yuan Lin, Chang-Le Chen, Chi-Yung Shang, Li-Ying Yang, Yung-Chin Hsu, Wen-Yih Isaac Tseng, Susan Shur-Fen Gau
Journal: American Journal of Psychiatry (2021)

The heterogeneity of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) preclude definitive identification of neurobiomarkers and biological risks. High clinical overlap suggests multifaceted circuit-level alterations across diagnoses, which remains elusive. This study investigated whether individuals with ADHD or ASD and their unaffected siblings constitute a spectrum of neurodevelopmental conditions in terms of white matter etiology.Sex-specific white matter tract normative development was modeled from diffusion MRI of 626 typically developing control subjects (ages 5-40 years; 376 of them male). Individualized metrics estimating white matter tract deviation from the age norm were derived for 279 probands with ADHD, 175 probands with ASD, and their unaffected siblings (ADHD, N=121; ASD, N=72).ASD and ADHD shared diffuse white matter tract deviations in the commissure and association tracts (rho=0.54; p<0.001), while prefrontal corpus callosum deviated more remarkably in ASD (effect size=-0.36; p<0.001). Highly correlated deviance patterns between probands and unaffected siblings were found in both ASD (rho=0.69; p<0.001) and ADHD (rho=0.51; p<0.001), but only unaffected sisters of ASD probands showed a potential endophenotype in long-range association fibers and projection fibers connecting prefrontal regions. ADHD and ASD shared significant white matter tract idiosyncrasy (rho=0.55; p<0.001), particularly in tracts connecting prefrontal regions, not identified in either sibling group. Canonical correlation analysis identified multiple dimensions of psychopathology/cognition across categorical entities; autistic, visual memory, intelligence/planning/inhibition, nonverbal-intelligence/attention, working memory/attention, and set-shifting/response-variability were associated with distinct sets of white matter tract deviations.When conceptualizing neurodevelopmental disorders as white matter tract deviations from normative patterns, ASD and ADHD are more alike than different. The modest white matter tract alterations in siblings suggest potential endophenotypes in these at-risk populations. This study further delineates brain-driven dimensions of psychopathology/cognition, which may help clarify within-diagnosis heterogeneity and high between-diagnosis co-occurrence.
Gut microbiota dysbiosis promotes age-related atrial fibrillation by lipopolysaccharide and glucose-induced activation of NLRP3-inflammasome
Authors: Yun Zhang, Song Zhang, Bolin Li, Yingchun Luo, Yongtai Gong, Xuexin Jin, Jiawei Zhang, Yun Zhou, Xiaozhen Zhuo, Zixi Wang, Xinbo Zhao, Xuejie Han, Yunlong Gao, Hui Yu, Desen Liang, Shiqi Zhao, Danghui Sun, Dingyu Wang, Wei Xu, Guangjin Qu, Wanlan Bo, Dan Li, Yue Wu, Yue Li
Journal: Cardiovascular Research (2021)

Abstract Aims Ageing is the most significant contributor to the increasing prevalence of atrial fibrillation (AF). The gut microbiota dysbiosis is involved in age-related diseases. However, whether the aged-associated dysbiosis contributes to age-related AF is still unknown. Direct demonstration that the aged gut microbiota is sufficient to transmit the enhanced AF susceptibility in a young host via microbiota-intestinal barrier-atria axis has not yet been reported. This study aimed to determine whether gut microbiota dysbiosis affects age-related AF. Methods and results Herein, by using a faecal microbiota transplantation (FMT) rat model, we demonstrated that the high AF susceptibility of aged rats could be transmitted to a young host. Specially, we found the dramatically increased levels of circulating lipopolysaccharide (LPS) and glucose led to the up-regulated expression of NOD-like receptor protein (NLRP)-3 inflammasome, promoting the development of AF, which depended on the enhanced atrial fibrosis in recipient host. Inhibition of inflammasome by a potent and selective inhibitor of the NLRP3 inflammasome, MCC950, resulted in a lower atrial fibrosis and AF susceptibility. Then, we conducted cross-sectional clinical studies to explore the effect of ageing on the altering trends with glucose levels and circulating LPS among clinical individuals in two China hospitals. We found that both of serum LPS and glucose levels were progressively increased in elderly patients as compared with those young. Furthermore, the ageing phenotype of circulating LPS and glucose levels, intestinal structure and atrial NLRP3-inflammasome of rats were also confirmed in clinical AF patients. Finally, aged rats colonized with youthful microbiota restored intestinal structure and atrial NLRP3-inflammasome activity, which suppressed the development of aged-related AF. Conclusions Collectively, these studies described a novel causal role of aberrant gut microbiota in the pathogenesis of age-related AF, which indicates that the microbiota-intestinal barrier-atrial NLRP3 inflammasome axis may be a rational molecular target for the treatment of aged-related arrhythmia disease.
Police in Gosport hospital investigation are looking at 15 000 death certificates
Authors: Clare Dyer
Journal: BMJ (2021)

Police are examining around 15 000 death certificates in an investigation into hospital deaths described as “one of the largest and most complex of its nature in the history of UK policing.”

The police investigation into 700 deaths was launched in 2019 after an independent review panel concluded that at least 456 patients had had their lives shortened in the period from 1987 to 2001 by medically unnecessary doses of opioid painkillers at the War Memorial Hospital in Gosport, Hampshire.12 That inquiry had estimated that at least another 200 patients had their lives shortened, but records …
OA03.04 Efficacy and Safety of the Novel HER3 Directed Antibody Drug Conjugate Patritumab Deruxtecan (HER3-DXd; U3-1402) in EGFR-mutated NSCLC
Authors: H. Yu, C. Baik, K. Gold, H. Hayashi, M. Johnson, M. Koczywas, H. Murakami, M. Nishio, C. Steuer, W. Su, J.C. Yang, S. Karam, Z. Qi, Y. Qiu, S. Chen, C. Yu, P. Janne
Journal: Journal of Thoracic Oncology (2021)
Very long chain fatty acid metabolism is required in acute myeloid leukemia
Authors: Matthew Tcheng, Alessia Roma, Nawaz Ahmed, Richard W. Smith, Preethi Jayanth, Mark D. Minden, Aaron D. Schimmer, David A. Hess, Kristin Hope, Kevin A. Rea, Tariq A. Akhtar, Eric Bohrnsen, Angelo D’Alessandro, Al-Walid Mohsen, Jerry Vockley, Paul A. Spagnuolo
Journal: Blood (2021)
Finerenone and Chronic Kidney Disease Outcomes in Type 2 Diabetes
Authors: Nicola C Edwards, Charles J Ferro, Jonathan N Townend
Journal: New England Journal of Medicine (2021)

teaching and research institutions in France or abroad, or from public or private research centers.L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
P52.10 Profile of Comorbidities and Cancer History in Patients with mNSCLC in the Spanish Population (Thoracic Tumors Registry).
Authors: F. Franco, E. Carcereny, D. Rodríguez-Abreu, R. Lopez Castro, M. Cobo, M. Guirado, B. Massuti, A.L. Ortega Granados, J. Mosquera, O. Juan, A. Blasco, E. Del Barco, R. Bernabé Caro, J. Bosch-Barrera, J.L. Gonzalez-Larriba, M. Sala, J. Trigo Pérez, J. Oramas, A. Estival, M. Provencio
Journal: Journal of Thoracic Oncology (2021)
We need to do better: A systematic review and meta-analysis of diagnostic test accuracy of restless legs syndrome screening instruments
Authors: Stephany Fulda, Richard P. Allen, Christopher J. Earley, Birgit Högl, Diego Garcia-Borreguero, Yuichi Inoue, William Ondo, Arthur S. Walters, Anne-Marie Williams, John W. Winkelman
Journal: Sleep Medicine Reviews (2021)
Abstract 17188: Calcific Degenerative Mitral Disease vs Myxomatous Degeneration: Crystallizing the Differences
Authors: Gerald M Lawrie, Nan R Earle, Elizabeth A Earle
Journal: Circulation (2015)

Introduction: Myxomatous (M) and other non-M, non-ischemic valve pathologies are often all classified as “degenerative mitral valve disease.” We have seen at TEE and surgery a subgroup of older patients with normal or reduced leaflet area, leaflet cholesterol deposition, annular fibrosis and calcification and thickened chordae - at most only two are ruptured. We classify these pts as “calcific degenerative (D).” Hypothesis: Pts with D have different outcomes and require different techniques than pts with M. Methods: Since 1994, D and M have been recorded prospectively and separately; 205 patients had D pathology, 654 had M. Results: D pts were more often female: 63% (130/205) vs. M, 32% (209/654) p&lt;0.0001; older : 69.20±11.34 vs. 60.86±13.42 years, p&lt;0.0001; had a lower preop EF: 55.97±12.82 vs. 61.80±9.10, p&lt;0.0001; smaller preop annular AP diameter: 41.59±5.60 vs. 44.36±4.00, p&lt;0.0001; more concurrent AVRs: 8.8% (18/205) vs. M: 3.5% (23/654) p=0.0038; had fewer posterior chordal replacements: 4.06±1.54 vs. 4.67±1.53, p=0.0016 and smaller ring sizes D: 28.22±3.06 vs. M: 30.72±2.86, p&lt;0.0001. Periop mortality was higher in D: 3.9% (8/205) in D vs 1.2% (8/654) of M pts, p=0.0293. Late 10-yr survival (Kaplan-Meier) was D, 37.94%, and for M, 71.3%, p&lt;0.0001. Late 10-yr freedom from reoperation (Kaplan-Meier) was for D, 95.6% and for M, 93.2%, p=0.375. Late 10-yr freedom from significant mitral regurgitation (MR) (Kaplan-Meier) was for D, 79.9%, and for M, 85.9%, p=0.269. Cox regression for predictors of mortality identified age (relative risk (RR) 1.078, p&lt;0.0001), sex (RR 0.715, p=0.0320) preop EF (RR 0.985, p=0.0220), concomitant CAB (RR 1.614, p=0.0058), posterior leaflet repaired (RR 0.581, p=0.0058) or both posterior and anterior leaflet repaired (RR 0.500, p=0.0150), and leaflet calcification, (RR 1.734, p=0.0440); for predictors of reoperation, age (RR 0.971, p=0.048) and sex (RR 2.914, p=0.040); and for a predictor of late MR, annuloplasty ring size (RR 1.242, p=0.0094). Conclusions: These data confirmed that the D group had distinct clinical and pathological features which can be identified preoperatively and intraoperatively. Leaflet resection is not successful in these patients. Reconstructive techniques are preferred.