tbuckley/cabot-search huggingface dataset:
The positive effect of immune checkpoint inhibitor-induced thyroiditis on overall survival accounting for immortal time bias: a retrospective cohort study of 6596 patients
Authors: S. Street, D. Chute, I. Strohbehn, S. Zhao, M. Rengarajan, A. Faje, H. Seethapathy, M. Lee, R. Seethapathy, Z. Drobni, O. Rahma, T.G. Neilan, R.J. Sullivan, A.C. Villani, L. Zubiri, M.J. Mooradian, K.L. Reynolds, M.E. Sise
Journal: Annals of Oncology (2021)
Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease
Authors: Laura Bergamaschi, Federica Mescia, Lorinda Turner, Aimee L. Hanson, Prasanti Kotagiri, Benjamin J. Dunmore, Hélène Ruffieux, Aloka De Sa, Oisín Huhn, Michael D. Morgan, Pehuén Pereyra Gerber, Mark R. Wills, Stephen Baker, Fernando J. Calero-Nieto, Rainer Doffinger, Gordon Dougan, Anne Elmer, Ian G. Goodfellow, Ravindra K. Gupta, Myra Hosmillo, Kelvin Hunter, Nathalie Kingston, Paul J. Lehner, Nicholas J. Matheson, Jeremy K. Nicholson, Anna M. Petrunkina, Sylvia Richardson, Caroline Saunders, James E.D. Thaventhiran, Erik J.M. Toonen, Michael P. Weekes, Berthold Göttgens, Mark Toshner, Christoph Hess, John R. Bradley, Paul A. Lyons, Kenneth G.C. Smith
Journal: Immunity (2021)

The kinetics of the immune changes in COVID-19 across severity groups have not been rigorously assessed. Using immunophenotyping, RNA sequencing, and serum cytokine analysis, we analyzed serial samples from 207 SARS-CoV2-infected individuals with a range of disease severities over 12 weeks from symptom onset. An early robust bystander CD8+ T cell immune response, without systemic inflammation, characterized asymptomatic or mild disease. Hospitalized individuals had delayed bystander responses and systemic inflammation that was already evident near symptom onset, indicating that immunopathology may be inevitable in some individuals. Viral load did not correlate with this early pathological response but did correlate with subsequent disease severity. Immune recovery is complex, with profound persistent cellular abnormalities in severe disease correlating with altered inflammatory responses, with signatures associated with increased oxidative phosphorylation replacing those driven by cytokines tumor necrosis factor (TNF) and interleukin (IL)-6. These late immunometabolic and immune defects may have clinical implications.
Lupus Susceptibility Region Containing <i>CDKN1B</i> rs34330 Mechanistically Influences Expression and Function of Multiple Target Genes, Also Linked to Proliferation and Apoptosis
Authors: Bhupinder Singh, Guru P. Maiti, Xujie Zhou, Mehdi Fazel‐Najafabadi, Sang‐Cheol Bae, Celi Sun, Chikashi Terao, Yukinori Okada, Kek Heng Chua, Yuta Kochi, Joel M. Guthridge, Hong Zhang, Matthew Weirauch, Judith A. James, John B. Harley, Gaurav K. Varshney, Loren L. Looger, Swapan K. Nath
Journal: Arthritis & Rheumatology (2021)

In a recent genome-wide association study, a significant genetic association between rs34330 of CDKN1B and risk of systemic lupus erythematosus (SLE) in Han Chinese was identified. This study was undertaken to validate the reported association and elucidate the biochemical mechanisms underlying the effect of the variant.We performed an allelic association analysis in patients with SLE, followed by a meta-analysis assessing genome-wide association data across 11 independent cohorts (n = 28,872). In silico bioinformatics analysis and experimental validation in SLE-relevant cell lines were applied to determine the functional consequences of rs34330.We replicated a genetic association between SLE and rs34330 (meta-analysis P = 5.29 × 10-22 , odds ratio 0.84 [95% confidence interval 0.81-0.87]). Follow-up bioinformatics and expression quantitative trait locus analysis suggested that rs34330 is located in active chromatin and potentially regulates several target genes. Using luciferase and chromatin immunoprecipitation-real-time quantitative polymerase chain reaction, we demonstrated substantial allele-specific promoter and enhancer activity, and allele-specific binding of 3 histone marks (H3K27ac, H3K4me3, and H3K4me1), RNA polymerase II (Pol II), CCCTC-binding factor, and a critical immune transcription factor (interferon regulatory factor 1 [IRF-1]). Chromosome conformation capture revealed long-range chromatin interactions between rs34330 and the promoters of neighboring genes APOLD1 and DDX47, and effects on CDKN1B and the other target genes were directly validated by clustered regularly interspaced short palindromic repeat (CRISPR)-based genome editing. Finally, CRISPR/dead CRISPR-associated protein 9-based epigenetic activation/silencing confirmed these results. Gene-edited cell lines also showed higher levels of proliferation and apoptosis.Collectively, these findings suggest a mechanism whereby the rs34330 risk allele (C) influences the presence of histone marks, RNA Pol II, and IRF-1 transcription factor to regulate expression of several target genes linked to proliferation and apoptosis. This process could potentially underlie the association of rs34330 with SLE.
Abstract 023: Effects Of Sodium Reduction And The Dash Diet On Subclinical Cardiac Damage: Results From The Dash-Sodium Trial
Authors: Stephen P Juraschek, Lara Kovell, Lawrence J Appel, Edgar R Miller, Frank M Sacks, Alex R Chang, Robert H Christenson, Heather Rebuck, Kenneth J Mukamal
Journal: Circulation (2021)

Background: We recently documented that the DASH diet has beneficial effects on cardiac biomarkers. The effects of sodium reduction, alone or combined with the DASH diet, are unknown. Objective: To determine the effects of sodium reduction and the DASH diet, alone or combined, on biomarkers of cardiac injury, strain, and inflammation. Methods: DASH-Sodium was a controlled, feeding study in adults with pre- or stage 1 hypertension, who were randomly assigned to the DASH diet or a control diet. On their assigned diet, participants consumed each of three sodium levels for 4 weeks. Body weight was kept constant. The three sodium levels were low (50 mmol/d), medium (100 mmol/d), and high (150 mmol/d). Outcomes were 3 biomarkers representing distinct pathways of cardiac damage: high-sensitivity cardiac troponin I (hs-cTnI, measure of cardiac injury), N-terminal b-type pro natriuretic peptide (NT-proBNP, measure of strain), and high-sensitivity C-reactive protein (hs-CRP, measure of inflammation), collected at baseline and at the end of each feeding period. Results: Of the original 412 participants, mean age was 48 yr; 56% were women, and 56% black. Mean baseline SBP/DBP was 135/86 mm Hg. Lower sodium reduced NT-proBNP independent of diet (overall %-difference of -19%; 95% CI: -24, -14), but not hs-cTnI or hs-CRP ( Figure ). In contrast, DASH (vs control) reduced hs-cTnI by 18% (95% CI: -27, -7) and hs-CRP by 13% (95% CI: -24, -1), but not NT-proBNP. Combining both sodium reduction with DASH reduced hs-cTnI by 20% (95% CI: -31%, -7%), NT-proBNP by 23% (95% CI: -32%, -12%), and hs-CRP by 7% (95% CI: -22%, 9%) compared to the high sodium, control diet. Conclusions: Combining sodium reduction with a DASH dietary pattern represents an efficacious strategy to lower three distinct mechanisms of subclinical cardiac damage: injury, strain, and to a lesser extent inflammation.
Sixty seconds on . . . travel traffic lights
Authors: Gareth Iacobucci
Journal: BMJ (2021)

From some countries, yes. As lockdown restrictions ease, the government has announced a new traffic light system for reopening some international travel to and from England.1

From 17 May, travellers from 12 countries deemed to be of lowest risk—including Australia, Israel, and Portugal—will now be given the green light to return to England without needing to quarantine.

Most countries are still amber, and some highest risk countries are red. The advice remains not to …
Core-binding factor leukemia hijacks the T-cell–prone PU.1 antisense promoter
Authors: E. van der Kouwe, G. Heller, A. Czibere, J. A. Pulikkan, C. Agreiter, L. H. Castilla, R. Delwel, A. Di Ruscio, A. K. Ebralidze, M. Forte, F. Grebien, E. Heyes, L. Kazianka, J. Klinger, C. Kornauth, T. Le, K. Lind, I. A. M. Barbosa, T. Pemovska, A. Pichler, A.-S. Schmolke, C. M. Schweicker, H. Sill, W. R. Sperr, A. Spittler, S. Surapally, B. Q. Trinh, P. Valent, K. Vanura, R. S. Welner, J. Zuber, D. G. Tenen, P. B. Staber
Journal: Blood (2021)
Repeated prevalence studies on antibiotic use in Latvia, 2003-2007
Authors: E Dimiņa, M Kūla, U Caune, D Vīgante, M Liepiņš, L Zeidaka, O Ņikitina, D Kūriņa, A Mironovska, U Dumpis
Journal: Eurosurveillance (2009)

Antibiotic resistance and nosocomial infections have recently been recognised as a growing threat in Latvian hospitals. We used a modified point prevalence study design to gain accurate information on the antibiotic prescription pattern and the prevalence of nosocomial infections in different hospital departments. A given department was observed on a given day in a given month (May) five years in a row. All antibiotic treatments, dose and route of administration were recorded, in addition to demographic data. The most commonly used antibiotic groups were first generation cephalosporins (35.6-38.9%), broad-spectrum penicillins (17.5-23.0%), fluoroquinolones (8.4-14.5%) and aminoglycosides (7.7-12.6%). Cefazolin was the most commonly used antibiotic. Antibiotics were predominantly used intravenously. The proportion of oral administration varied from 15.1% to 21.8%. A large proportion (13.3%) of the antibiotics was administered without clear reason. The crude prevalence rate of infection treated with antibiotics was 19.3%. The average prevalence of nosocomial infections was found to be 3.6%. These prevalence studies provided an opportunity to compare hospitals and outline variations and problem areas. They indicated the main problems in antibiotic prescription: large interhospital variations in the choice of an antibiotic for the most common infections, frequent antibiotic use without clear reason, and predominant intravenous administration.
Abstract 15180: Myeloid Differentiation Factor 2 Inhibitor Improves Left Ventricular Function And Heart Rate Variability Via Attenuating Cardiac Mitochondrial Dysfunction In Pre-diabetic Rats
Authors: Natticha Sumneang, Thura Thun Oo, thidarat jaiwongkam, Busarin Arunsak, Nattayaporn Apaijai, Guang Liang, Siriporn Chattipakorn, Nipon CHATTIPAKORN
Journal: Circulation (2020)

Introduction: Systemic inflammation is known as a key mediator of left ventricular (LV) dysfunction in pre-diabetic models including obese-insulin resistance. In obese rats, lipopolysaccharide activates myeloid differentiation factor 2 (MD2)/toll-like receptor 4 complex, leading to systemic inflammation. Previously, MD2 inhibitor L6H21 (20 mg/kg) was shown to effectively reduce systemic inflammation in obese mice. However, its potential benefits on the heart and the underlying mechanisms in pre-diabetic obese-insulin resistant rats are unknown. Hypothesis: L6H21 exerts cardiometabolic protection in pre-diabetic rats by improving LV function and heart rate variability (HRV) via reducing cardiac mitochondrial dysfunction. Methods: Male Wistar rats were fed either a normal diet (n=8) or high-fat diet (HFD, n=40) for 12 weeks. In HFD group, rats were divided into 5 groups (n=8/group): 1) vehicle (1% Na-carboxymethyl cellulose), 2) metformin (300 mg/kg, positive control), 3-5) L6H21 at 10, 20, and 40 mg/kg. After 4 weeks of treatments, LV function and HRV were examined. Heart tissue was assessed for mitochondrial function. Results: Pre-diabetic rats had impaired glucose tolerance, depressed HRV, and decreased LV ejection fraction (LVEF), indicating cardiac autonomic imbalance and LV dysfunction. Cardiac mitochondrial dysfunction was also observed, shown by increased mitochondrial ROS levels, mitochondrial depolarization, and mitochondrial swelling. Although L6H21 at 20 and 40 mg/kg improved insulin sensitivity, cardiac autonomic balance, LV function, and mitochondrial function, L6H21 at 40 mg/kg exerted the highest cardioprotective effects, compared to metformin, in pre-diabetic rats by restoring LV function, HRV, and cardiac mitochondrial function (Fig) . Conclusions: L6H21 exerted cardiometabolic protection in pre-diabetic rats by improving insulin sensitivity and cardiac mitochondrial function, leading to restoring LV function.
Abstract 13091: Pemafibrate Reduced Hepatic Fibrosis and Cardiac Inflammation in Cholesterol-dominant, Atherogenic-Diet Induced Steatohepatitis Model in Mice
Authors: Kotaro Kanno
Journal: Circulation (2020)

Introduction: Pemafibrate reduces serum triglycerides level and has been reported that it also decreased hepatic triglycerides. In recent decades, the number of patients with nonalcoholic fatty liver diseases has increased and it has become a problem that the patients with steatohepatitis would develop cardiovascular diseases. Aim: The aim of this study is to analyze the effect of pemafibrate on hepatic inflammation and cardiac function in a diet-induced steatohepatitis model. Methods: C57Bl/6 wild mice were administered cholesterol-loading atherogenic-diet (Cont group) or the one with pemafibrate 0.1 mg/kg (Pema group) for 3 or 8 weeks, respectively. Serum lipids, hepatic inflammatory cytokines, histology, gene expression, lipid contents, and cardiac magnetic resonance imaging (MRI) were investigated. Left ventricular strain was analyzed by workstation of ENTORRES©. Results: In Pema group, serum HDL-C level was increased, non-HDL-C level was decreased. serum TNFα was decreased (82.0±10.8 v.s. 48.0±2.1, p&lt;0.0001). In liver, gene expression of TNFa, Il1b, Il6, Tgfb, Col1a, Col2a showed marked reduction. In HE staining, destruction of the hepatic lobule structure was improved. F4/80 staining demonstrated marked reduction of macrophage infiltration. In Tunel staining, apoptosis cell was suppressed. Liver lipid extraction study showed total cholesterol and free cholesterol were decreased by 50%. MRI scanning demonstrated that heterogeneous attenuation of longitudinal strain of left ventricular (Figure). Conclusion: Pemafibrate suppresses liver inflammation and inhibit left ventricular dysfunction caused by cholesterol-rich-atherogenic diet.
When Z-POEM comes to the rescue of classical diverticulotomy and vice versa
Authors: Thomas Lambin, Pierre Lafeuille, Jérôme Rivory, Laura Calavas, Thierry Ponchon, Mathieu Pioche
Journal: Endoscopy (2021)

If the treatment of Zenkerʼs diverticulum by flexible endoscopy seems to be the preferred option for its efficacy and safety profile [1], the recent arrival of Z-POEM (peroral endoscopic myotomy) technique has blurred the cards a little. Indeed, although the results of the Z-POEM technique seem good [2] [3], no randomized comparative data is available to choose this technique over classical diverticulotomy. The theoretical advantage of classical diverticulotomy is that it cuts the mucosal relief and performs the cricopharyngeal myotomy without having a very clear marker to be certain of the completeness of the myotomy. On the other hand, Z-POEM offers the possibility to cut the muscle completely thanks to better visualization, with almost zero risk of perforation not covered by the tunnel.
Effects of apolipoprotein B on lifespan and risks of major diseases including type 2 diabetes: a mendelian randomisation analysis using outcomes in first-degree relatives
Authors: Tom G Richardson, Qin Wang, Eleanor Sanderson, Anubha Mahajan, Mark I McCarthy, Timothy M Frayling, Mika Ala-Korpela, Allan Sniderman, George Davey Smith, Michael V Holmes
Journal: The Lancet Healthy Longevity (2021)

BackgroundApolipoprotein B (apoB) is emerging as the crucial lipoprotein trait for the role of lipoprotein lipids in the aetiology of coronary heart disease. In this study, we evaluated the effects of genetically predicted apoB on outcomes in first-degree relatives.MethodsData on lipoprotein lipids and disease outcomes in first-degree relatives were obtained from the UK Biobank study. We did a univariable mendelian randomisation analysis using a weighted genetic instrument for apoB. For outcomes with which apoB was associated at a false discovery rate (FDR) of less than 5%, multivariable mendelian randomisation analyses were done, including genetic instruments for LDL cholesterol and triglycerides. Associations between apoB and self-reported outcomes in first-degree relatives were characterised for 12 diseases (including heart disease, stroke, and hypertension) and parental vital status together with age at death. Estimates were inferred causal effects per 1 SD elevated lipoprotein trait (for apoB, 1 SD=0·24 g/L). Replication of estimates for lifespan and type 2 diabetes was done using conventional two-sample mendelian randomisation with summary estimates from genome-wide association study consortia.FindingsIn univariable mendelian randomisation, genetically elevated apoB in participants was identified to lead to a shorter lifespan in parents (fathers: 0·89 years of life lost per 1 SD higher apoB in offspring, 95% CI 0·63–1·16, FDR-adjusted p=4·0 × 10−10; mothers: 0·48 years of life lost per 1 SD higher apoB in offspring, 0·25–0·71, FDR-adjusted p=1·7 × 10−4). The effects were strengthened to around 2 years of life lost in multivariable mendelian randomisation and were replicated in conventional two-sample mendelian randomisation (odds ratio [OR] of surviving to the 90th centile of lifespan: 0·38 per 1 SD higher apoB in offspring, 95% CI 0·22–0·65). Genetically elevated apoB caused higher risks of heart disease in all first-degree relatives and a higher risk of stroke in mothers. Findings in first-degree relatives were replicated in two-sample multivariable mendelian randomisation, which identified apoB to increase (OR 2·32 per 1 SD higher apoB, 95% CI 1·49–3·61) and LDL cholesterol to decrease (0·34 per 1 SD higher LDL cholesterol, 0·21–0·54) the risk of type 2 diabetes.InterpretationHigher apoB shortens lifespan, increases risks of heart disease and stroke, and in multivariable analyses that account for LDL cholesterol, increases risk of diabetes.FundingBritish Heart Foundation, UK Medical Research Council, and UK Research and Innovation.
Med-BERT: pretrained contextualized embeddings on large-scale structured electronic health records for disease prediction
Authors: Laila Rasmy, Yang Xiang, Ziqian Xie, Cui Tao, Degui Zhi
Journal: npj Digital Medicine (2021)

Abstract Deep learning (DL)-based predictive models from electronic health records (EHRs) deliver impressive performance in many clinical tasks. Large training cohorts, however, are often required by these models to achieve high accuracy, hindering the adoption of DL-based models in scenarios with limited training data. Recently, bidirectional encoder representations from transformers (BERT) and related models have achieved tremendous successes in the natural language processing domain. The pretraining of BERT on a very large training corpus generates contextualized embeddings that can boost the performance of models trained on smaller datasets. Inspired by BERT, we propose Med-BERT, which adapts the BERT framework originally developed for the text domain to the structured EHR domain. Med-BERT is a contextualized embedding model pretrained on a structured EHR dataset of 28,490,650 patients. Fine-tuning experiments showed that Med-BERT substantially improves the prediction accuracy, boosting the area under the receiver operating characteristics curve (AUC) by 1.21–6.14% in two disease prediction tasks from two clinical databases. In particular, pretrained Med-BERT obtains promising performances on tasks with small fine-tuning training sets and can boost the AUC by more than 20% or obtain an AUC as high as a model trained on a training set ten times larger, compared with deep learning models without Med-BERT. We believe that Med-BERT will benefit disease prediction studies with small local training datasets, reduce data collection expenses, and accelerate the pace of artificial intelligence aided healthcare.
Abstract 17097: Non-Synonymous Mitochondrial DNA Variants Are Common in Myocardial Tissue of Heart Failure Patients
Authors: Pappu Ananya, Michael Binder, Yang Wanjun, Rebecca McClellan, Brittney Murray, Cynthia James, Andreas S Barth
Journal: Circulation (2020)

Introduction: Mitochondrial heart disease due to pathogenic mitochondrial DNA (mtDNA) mutations can present as hypertrophic or dilated cardiomyopathy, ventricular arrhythmias and conduction disease. It is estimated that the mutation rate of mtDNA is 10 to 20-fold higher than that of nuclear DNA genes due to damage from reactive oxygen species released as byproducts during oxidative phosphorylation. When a new mtDNA mutation arises, it creates an intracellular heteroplasmic mixture of mutant and normal mtDNAs, called heteroplasmy. Heteroplasmy levels can vary in various tissues and examining mtDNA variants in blood may not be representative for the heart. The frequency of pathogenic mtDNA variants in myocardial tissues in unknown. Hypothesis: Human ventricular tissue may contain mtDNA mutations which can lead to alterations in mitochondrial function and increase individual risk for heart failure. Methods: Mitochondrial DNA was isolated from 61 left ventricular myocardial samples obtained from failing human hearts at the time of transplantation. mtDNA was sequenced with 23 primer pairs. In silico prediction of non-conservative missense variants was performed via PolyPhen-2. Heteroplasmy levels of variants predicted to be pathogenic were quantified using allele-specific ARMS-PCR. Results: We identified 21 mtDNA non-synonymous variants predicted to be pathogenic in 17 hearts. Notably, one heart contained four pathogenic mtDNA variants (ATP6: p.M104; ND5: p.P265S; ND4: p.N390S and p.L445F). Heteroplasmy levels exceeded 90% for all four variants in myocardial tissue and were significantly lower in blood. No pathogenic mtDNA variants were identified in 44 hearts. Hearts with mtDNA mutations had higher levels of myocardial GDF-15 (growth differentiation factor-15; 6.2±2.3 vs. 1.3±0.18, p=0.045), an established serum biomarker in various mitochondrial diseases. Conclusions: Non-synonymous mtDNA variants predicted to be pathogenic are common in human left ventricular tissue and may be an important modifier of the heart failure phenotype. Future studies are necessary to correlate myocardial mtDNA mutations with cardiovascular outcomes and to assess whether serum GDF-15 allows identifying patients with myocardial mtDNA mutations.
Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study
Authors: Jamie Lopez Bernal, Nick Andrews, Charlotte Gower, Chris Robertson, Julia Stowe, Elise Tessier, Ruth Simmons, Simon Cottrell, Richard Roberts, Mark O’Doherty, Kevin Brown, Claire Cameron, Diane Stockton, Jim McMenamin, Mary Ramsay
Journal: BMJ (2021)

To estimate the real world effectiveness of the Pfizer-BioNTech BNT162b2 and Oxford-AstraZeneca ChAdOx1-S vaccines against confirmed covid-19 symptoms (including the UK variant of concern B.1.1.7), admissions to hospital, and deaths.