tbuckley/cabot-search huggingface dataset:
A Rapid Pharmacogenomic Assay to Detect <i>NAT2</i> Polymorphisms and Guide Isoniazid Dosing for Tuberculosis Treatment
Authors: Renu Verma, Sunita Patil, Nan Zhang, Flora M. F. Moreira, Marize T. Vitorio, Andrea da S. Santos, Ellen Wallace, Devasena Gnanashanmugam, David H. Persing, Rada M. Savic, Julio Croda, Jason R. Andrews
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Standardized dosing of antitubercular drugs contributes to a substantial incidence of toxicities, inadequate treatment response, and relapse, in part due to variable drug concentrations achieved. SNPs in the NAT2 (N-acetyltransferase-2) gene explain the majority of interindividual pharmacokinetic variability of isoniazid (INH). However, an obstacle to implementing pharmacogenomic-guided dosing is the lack of a point-of-care assay. Objectives: To develop and test a NAT2 classification algorithm, validate its performance in predicting isoniazid clearance, and develop a prototype pharmacogenomic assay. Methods: We trained random forest models to predict NAT2 acetylation genotype from unphased SNP data using a global collection of 8,561 phased genomes. We enrolled 48 patients with pulmonary tuberculosis, performed sparse pharmacokinetic sampling, and tested the acetylator prediction algorithm accuracy against estimated INH clearance. We then developed a cartridge-based multiplex quantitative PCR assay on the GeneXpert platform and assessed its analytical sensitivity on whole blood samples from healthy individuals. Measurements and Main Results: With a 5-SNP model trained on two-thirds of the data (n = 5,738), out-of-sample acetylation genotype prediction accuracy on the remaining third (n = 2,823) was 100%. Among the 48 patients with tuberculosis, predicted acetylator types were 27 (56.2%) slow, 16 (33.3%) intermediate, and 5 (10.4%) rapid. INH clearance rates were lowest in predicted slow acetylators (median 14.5 L/h), moderate in intermediate acetylators (median 40.3 L/h), and highest in fast acetylators (median 53.0 L/h). The cartridge-based assay accurately detected all allele patterns directly from 25 μl of whole blood. Conclusions: An automated pharmacogenomic assay on a platform widely used globally for tuberculosis diagnosis could enable personalized dosing of INH.
Myeloid Cell–Derived Oxidized Lipids and Regulation of the Tumor Microenvironment
Authors: Kristin C. Hicks, Yulia Y. Tyurina, Valerian E. Kagan, Dmitry I. Gabrilovich
Journal: Cancer Research (2021)

Abstract Immunosuppressive myeloid cells play a major role in cancer by negatively regulating immune responses, promoting tumor progression, and limiting the efficacy of cancer immunotherapy. Immunosuppression is mediated by various mechanisms dependent upon the type of myeloid cell involved. In recent years, a more universal mechanism of immunosuppressive activity of myeloid cells has emerged: Generation of oxidized lipids. Oxidized lipids accumulate in all types of myeloid cells and are often transferred between cells. In this review, we discuss mechanisms involved in the generation and biological role of myeloid cell–derived oxidized lipids in cancer.
Abstract EP68: Can A Single Model For General Population Predict Cardiovascular Events In Cancer Survivors?
Authors: Hokyou Lee, Hyeok-Hee Lee, Gabin Lee, Danbee Kang, Jin Lee, Jihyun Lim, Juhee Cho, Dong Wook Shin, Jong-Chan Youn, Hyeon Chang Kim
Journal: Circulation (2022)

Introduction: No specific guideline exists for the primary prevention of cardiovascular disease (CVD) in cancer survivors. We hypothesized that CVD risk and its association with risk factors are comparable between cancer survivors and the general population, such that they may share currently available risk scores (e.g., Pooled Cohort Equation; PCE) for initial risk discussion. Methods: We studied 59 445 cancer survivors (≥5 years from diagnosis) and 59 445 age/sex-matched non-cancer controls aged 40-79 years (51.6% female) and free of CVD among participants of 2009 Korean National Health Insurance health screening. We calculated 10-year cumulative incidence of CVD events (composite of myocardial infarction, stroke, or cardiovascular death) and hazard ratios for traditional CVD risk factors in cancer survivors vs. non-cancer controls. We then evaluated discrimination and calibration of a previously-derived, general Korean population-based CVD risk model (having similar predictors as the PCE) applied to cancer survivors. Results: During a median follow-up of 10.3 years, 6,809 CVD events occurred. Multivariable-adjusted 10-year cumulative CVD incidence was 2.8% (2.7-3.0) among cancer survivors and 3.0% (2.0-3.2) among non-cancer controls (Figure A). Associations of traditional risk factors with CVD events were similar between cancer survivors and controls (Figure B). Results were consistent when stratified by sex and age. A CVD risk model, previously derived from the general Korean population similarly as the PCE, showed good discrimination (C-index, 0.747) and calibration (Figure C) when applied to cancer survivors. By cancer subtype, some cancers were associated with higher or lower CVD risk than controls (Figure D). Conclusions: CVD risk and associations with predictors were similar between cancer survivors and non-cancer individuals. Pre-existing models for general population may perform well in overall cancer survivors, although subtype-specific recalibration may be desirable for some cancers.
Abstract 11342: Contemporary in-hospital Outcomes of Chronic Total Occlusion Interventions: Update from the Progress-cto (Prospective Global Registry for the Study of Chronic Total Occlusion Intervention) International Registry
Authors: Spyridon Kostantinis, Khaldoon Alaswad, Dimitrios Karmpaliotis, Oleg Krestyaninov, Dmitrii Khelimskii, James Choi, Farouc A Jaffer, Paul Poommipanit, Judit Karacsonyi, Evangelia Vemmou, Ilias Nikolakopoulos, Sevket Gorgulu, Michael Koutouzis, Ioannis Tsiafoutis, Robert Riley, Basem Elbarouni, Wissam Jaber, Habib Samady, Khalid Tammam, Ahmed M Elguindy, OMER GOKTEKIN, Nidal Abi-Rafeh, Bavana V Rangan, M Nicholas Burke, Emmanouil S Brilakis
Journal: Circulation (2021)

Introduction: Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) is an evolving field. Methods: We examined the clinical and angiographic characteristics and procedural outcomes of 8,666 CTO PCIs performed at 36 centers between 2012 and 2021. Results: Mean age was 64±10 years and 82% of the patients were men. The prevalence of prior PCI (62%) and diabetes mellitus (43%) was high. Median ejection fraction was 54% (42%, 60%). Radial access was used in 50%. The most common target vessel was the right coronary artery (52%), followed by the left anterior descending artery (26%). The target CTOs were highly complex with mean J-CTO score of 2.4 ±1.3 and PROGRESS score of (1.3 ±1). Technical and procedural success rates were high (86% and 85% respectively) with a relatively low percentage of in-hospital major adverse cardiac events (Figure 1). The final successful crossing strategy was antegrade wire escalation in 62%, retrograde in 22%, and antegrade dissection re-entry in 16%. Median contrast volume, air kerma radiation dose and procedure time were 220 (155, 300) ml, 2.2 (1.2, 3.8) Gray and 116 (75, 172) minutes, respectively. Conclusions: High success and acceptable complication rates can currently be achieved in CTO PCI among high-volume, experienced centers.
Abstract 10248: Regulation of the Methylation and Expression Levels of the Bmpr2 Gene by Sin3a as a Novel Therapeutic Mechanism in Pulmonary Arterial Hypertension
Authors: Malik Bisserier, Prabhu Mathiyalagan, shihong zhang, Firas Elmastour, Peter Dorfmuller, Marc Humbert, Gregory David, Thomas Weber, Frederic Perros, Yassine Sassi, Susmita Sahoo, Lahouaria Hadri
Journal: Circulation (2021)

Background: Epigenetic mechanisms are critical in the pathogenesis of pulmonary arterial hypertension (PAH). Previous studies have suggested that hypermethylation of the Bone Morphogenetic Protein Receptor Type 2 (BMPR2) promoter is associated with BMPR2 downregulation and progression of PAH. Here, we investigated for the first time the role of Switch-Independent 3a (SIN3a), a transcriptional regulator, in the epigenetic mechanisms underlying hypermethylation of BMPR2 in the pathogenesis of PAH. Methods: We used lung samples from PAH patients and non-PAH controls, preclinical mouse and rat PAH models, and human pulmonary arterial smooth muscle cells (hPASMC). Expression of SIN3a was modulated using a lentiviral vector or a siRNA in vitro and a specific Adeno-Associated Virus serotype 1 (AAV1) or a lentivirus encoding for human SIN3a in vivo . Results: SIN3a is a known transcriptional regulator; however, its role in cardiovascular diseases, especially PAH, is unknown. Interestingly, we detected a dysregulation of SIN3 expression in patients and in rodent models, which is strongly associated with decreased BMPR2 expression. SIN3a is known to regulate epigenetic changes. Therefore, we tested its role in the regulation of BMPR2 and found that BMPR2 is regulated by SIN3a. Interestingly, SIN3a overexpression inhibited hPASMC proliferation and upregulated BMPR2 expression by preventing the methylation of the BMPR2 promoter region. RNA sequencing analysis suggested that SIN3a downregulated the expression of DNA and histone methyltransferases such as DNMT1 and EZH2 while promoting the expression of the DNA demethylase TET1. Mechanistically, SIN3a promoted BMPR2 expression by decreasing CTCF binding to the BMPR2 promoter. Finally, we identified intratracheal delivery of AAV1.hSIN3a to be a beneficial therapeutic approach in PAH- by attenuating pulmonary vascular and RV remodeling, decreasing RVSP and mPAP pressure, and restoring BMPR2 expression in rodent models of PAH. Conclusions: Altogether, our study unveiled the protective/beneficial role of SIN3a in pulmonary hypertension. We also identified a novel and distinct molecular mechanism by which SIN3a regulates BMPR2 in hPASMC.
Effectiveness of Belimumab After Rituximab in Systemic Lupus Erythematosus
Authors: Muhammad Shipa, Andrew Embleton-Thirsk, Mariea Parvaz, Liliana Ribeiro Santos, Patrick Muller, Kashfia Chowdhury, David A. Isenberg, Caroline J. Doré, Caroline Gordon, Michael R. Ehrenstein
Journal: Annals of Internal Medicine (2021)

B-cell depletion with rituximab is commonly used for patients with systemic lupus erythematosus (SLE) that is refractory to conventional therapy, but it yields variable responses. We hypothesized that high B-cell activating factor (BAFF) levels after rituximab can cause disease flares, thereby limiting its effectiveness.To obtain preliminary evidence for efficacy of the anti-BAFF therapeutic belimumab after rituximab in SLE.Phase 2, randomized, double-blind (patients, assessors, researchers, care providers), placebo-controlled, parallel-group, superiority trial. (ISRCTN: 47873003).England.Fifty-two patients who had SLE that was refractory to conventional treatment and whose physicians had recommended rituximab therapy were recruited between 2 February 2017 and 28 March 2019.Participants were treated with rituximab and 4 to 8 weeks later were randomly assigned (1:1) to receive intravenous belimumab or placebo for 52 weeks.The prespecified primary end point was serum IgG anti-double-stranded DNA (anti-dsDNA) antibody levels at 52 weeks. Secondary outcomes included incidence of disease flares and adverse events.At 52 weeks, IgG anti-dsDNA antibody levels were lower in patients treated with belimumab compared with placebo (geometric mean, 47 [95% CI, 25 to 88] vs. 103 [CI, 49 to 213] IU/mL; 70% greater reduction from baseline [CI, 46% to 84%]; P < 0.001). Belimumab reduced risk for severe flare (BILAG-2004 grade A) compared with placebo (hazard ratio, 0.27 [CI, 0.07 to 0.98]; log-rank P = 0.033), with 10 severe flares in the placebo group and 3 in the belimumab group. Belimumab did not increase incidence of serious adverse events. Belimumab significantly suppressed B-cell repopulation compared with placebo (geometric mean, 0.012 [CI, 0.006 to 0.014] vs. 0.037 [CI, 0.021 to 0.081] × 109/L) at 52 weeks in a subset of patients (n = 25) with available data.Small sample size; biomarker primary end point.Belimumab after rituximab significantly reduced serum IgG anti-dsDNA antibody levels and reduced risk for severe flare in patients with SLE that was refractory to conventional therapy. The results suggest that this combination could be developed as a therapeutic strategy.Versus Arthritis.
Abstract P152: The Association Between Menopause Age And Carotid Plaque In The Multi-Ethnic Study Of Atherosclerosis (MESA)
Authors: Carla Rodriguez, Oluseye Ogunmoroti, Brigitte Kazzi, Seamus P Whelton, Brian Rodriguez, Olatokunbo I Osibogun, Michael Honigberg, Ritu Thamman, Colleen Harrington, James H Stein, Erin D Michos
Journal: Circulation (2022)

Background: The menopause transition is associated with an accelerated rise in cardiovascular disease (CVD) risk among women. Early-onset menopause is associated with incident CVD events. Detection of subclinical atherosclerosis may be an opportunity to institute preventive efforts before the onset of clinical CVD. We assessed whether menopause age was associated with carotid plaque, a marker of subclinical atherosclerosis, in a multiethnic cohort. Methods: We studied post-menopausal women in MESA free of CVD who had age of menopause onset ascertained by questionnaire and carotid plaque measured by B-mode ultrasound at baseline. Menopause age was categorized as &lt;45, 45-&lt;50, 50-&lt;55 (ref) and ≥55 yrs. Multivariable logistic and linear regression models were performed to evaluate the association of menopause age with carotid plaque presence (yes/no) and extent (carotid plaque score (CPS)), respectively. Results: Of the 2,297 women included, 38% were White, 28% Black, 12% Chinese, and 22% Hispanic with a mean age (SD) of 64 (9) yrs. The distribution of menopause age was 22.7% at age &lt;45, 28.8% at age 45-49, 36.1% at age 50-54, 12.5% at age ≥55. Overall, carotid plaque was present in 52%. The association of carotid plaque presence/absence and CPS are shown in the Table . There was no statistically significant association of menopause age with carotid plaque presence. Compared to women with menopause age 50-55, menopause before age 45 was significantly associated with a 9% greater CPS [percent difference 9 (95% CI 2, 17) after adjusting for demographics. This was attenuated and no longer statistically significant after further adjustment for CVD risk factors. Conclusion: In a multiethnic cohort of women, a younger age of onset of menopause was associated with a greater extent of carotid plaque, which appears to be mediated through traditional CVD risk factors. Further studies are needed to evaluate the association between the age of onset of menopause and atherosclerotic risk.
Spontaneous Intracranial Hypotension
Authors: Wouter I. Schievink
Journal: New England Journal of Medicine (2021)

Spontaneous cerebrospinal fluid leakage causes orthostatic headache, and mental dullness, diplopia, and coma may occur. Most cases are due to a tear in the spinal CSF membranes. MRI shows enhancement of the dura, and special imaging, such as digital-subtraction myelography (shown in videos), may be required to show the leakage site.
Association Between Brain Substructure Dose and Cognitive Outcomes in Children With Medulloblastoma Treated on SJMB03: A Step Toward Substructure-Informed Planning
Authors: Sahaja Acharya, Yian Guo, Tushar Patni, Yimei Li, Chuang Wang, Melissa Gargone, Jason M. Ashford, Lydia Wilson, Austin Faught, Wilburn E. Reddick, Zoltan Patay, Amar Gajjar, Heather M. Conklin, Thomas E. Merchant
Journal: Journal of Clinical Oncology (2021)

To characterize the association between neurocognitive outcomes (memory and processing speed) and radiation (RT) dose to the hippocampus, corpus callosum (CC), and frontal white matter (WM) in children with medulloblastoma treated on a prospective study, SJMB03.
Abstract MP20: Global Burden Of Elevated Low-density Lipoprotein Cholesterol, 1990-2020: Findings From The Global Burden Of Disease Study 2020
Authors: Christian Razo, Catherine O Johnson, Saate Shakil, Gregory A Roth
Journal: Circulation (2022)

We evaluated low-density lipoprotein (LDL) cholesterol patterns at the population level and quantified associated cardiovascular disease (CVD) morbidity and mortality for the Global Burden of Disease (GBD) 2020 study. Using all available high-quality data, we estimated the CVD burden attributable to elevated LDL (relative to the theoretical minimum risk exposure level of 1.3-1.7 mmol/L) by age, sex, country, and year among adults &gt;25 years from 1990 - 2020. We used a spatiotemporal Gaussian process regression to estimate LDL mean and microdata to estimate standard deviation (SD) and characterize the global LDL distribution. In a meta-regression, we pooled data from 52 randomized control trials to estimate the relative risks for ischemic heart disease (IHD) and ischemic stroke. These were then used to calculate the population attributable fraction and the burden attributable to elevated LDL. We report SD and 95% uncertainty intervals (UI) in brackets. From 1990 to 2020, LDL levels measured in mmol/L increased globally from 1.4 [0.4] to 1.7 [0.4] in males, and from 1.5 [0.4] to 1.8 [0.5] in females. The highest LDL levels over the 30-year period were observed in high-income countries and Central and Eastern Europe and Central Asia. Sub-Saharan Africa had the lowest LDL levels. In 2020, a third (2.9 million [95% UI: 1.2-4.5 million]) and a fifth (1.5 million [919,750-2.1 million]) of deaths due to IHD and ischemic stroke, respectively, were attributable to elevated LDL. The estimated number of deaths and disability-adjusted life-years (DALYs) attributable to high LDL increased since 1990 reaching 4.5 million [2.6 - 6.2] deaths and 91.8 million [53.6 - 127] DALYs in 2020. More DALYs from elevated LDL were experienced by men than women (52.8 [29.7 - 73.4] vs 39 [23.9 - 53.5] million). Over the study period, the global all-age rates for deaths and DALYs per 100,000, remained unchanged at 58 [34-80] and 1,177 [688-1,629], respectively. Age-standardized deaths and DALYs due to high LDL levels decreased from 90 [55-123] to 57 [34-79] deaths per 100,000 and from 1,657 [981-2,251] to 1,610 [650-1,532] DALYs per 100,000. Age-standardized DALYs attributable to high LDL cholesterol were highest in Eastern Europe, Central Asia and North Africa and the Middle East. The lowest levels were observed in high-income Asia Pacific and Andean Latin America. The CVD burden attributable to LDL is increasing globally. In 2020, a fifth of CVD deaths and DALYs were associated with LDL. Differences between the trends of all-ages and age-standardized rates suggest that the LDL burden has been driven partially by population growth and aging. Measurement and estimation error must be considered when interpreting these trends. In addition to safe and cost-effective pharmacological and behavioral interventions, novel population level strategies are needed to reduce the LDL burden.
Pulmonary-Artery Aneurysm with Acute Dissection
Authors: Asvin M Ganapathi, Curt J Daniels
Journal: New England Journal of Medicine (2022)

A 35-year-old woman with idiopathic pulmonary arterial hypertension and a known pulmonary-artery aneurysm presented with a 1-day history of chest pain. A new pulmonary-artery dissection flap was observed on imaging. She received extracorporeal membrane oxygenation as a bridge to bilateral lung transplantation and replacement of the main pulmonary artery and valve.
Erratum for Euro Surveill. 2021;26(28)
Journal: Eurosurveillance (2022)

© This work is licensed under a Creative Commons Attribution 4.0 International License. Closure This is a corrected article applying to the following content: Real-world data shows increased reactogenicity in adults after heterologous compared to homologous prime-boost COVID-19 vaccination, March−June 2021, England
178P Germline genetic variants associated with different premalignant lesions in the bronchial epithelium
Authors: T.S. Gerashchenko, A.A. Khozyainova, A.A. Schegoleva, R.S. Vorobiev, E. Rodionov, M. Artomov, E.B. Topolnitskiy, N.A. Shefer, O.V. Pankova, V.M. Perelmuter, E.V. Denisov
Journal: Annals of Oncology (2022)
Abstract EP15: Changes In Metabolite Levels After An Oral Glucose Challenge Are Associated With Incident Cardiovascular Disease And Death
Authors: Daniel Gonzalez Izundegui, Patricia E Miller, Martin Larson, Vasan S Ramachandran, Matthew G Nayor
Journal: Circulation (2022)

Objective: We evaluated whether intra-individual changes in blood metabolites in response to an oral glucose challenge were associated with incident CVD and mortality. Methods: An oral glucose tolerance test (OGTT; 75g glucose) was administered to a subsample of non-diabetic Framingham Heart Study participants (n=361). Metabolite profiling was performed on blood samples drawn before and 2 hours post OGTT. We compared pre- and post-OGTT log2(metabolite levels) using t-tests; for each metabolite with statistically significant changes from pre- to post-OGTT (Δmetabolites), we calculated log2(post/pre) and standardized values to mean=0, standard deviation=1. We constructed multivariable-adjusted Cox models relating each Δmetabolite with CVD and death. Models were adjusted for clinical risk factors of age, sex, baseline metabolite level, diabetes, systolic blood pressure, hypertension treatment, BMI, smoking, and total/HDL cholesterol. Results: Our sample included 42% women, with a mean age of 56±9 years, and body mass index of 30.2±5.3 kg/m 2 . The pre- to post-OGTT change (Δmetabolite) was statistically significant for 170 metabolites (at FDR ≤0.05). A total of 132 CVD events and 144 deaths occurred during follow up (mean 23±5 years for CVD, 26±2 years for death). In Cox models, four Δmetabolites were associated with incident CVD and six Δmetabolites were associated with death, at P&lt;0.05 ( Table ). Notably, baseline metabolite levels were not associated with either outcome in models excluding Δmetabolites. Significant Δmetabolites included those with established roles in cardiometabolic disease (e.g., glutamate, α-ketoglutarate, N-methylmalonamic acid) and metabolites with less defined roles (e.g., glucoronate, lipid species). Conclusion: Intra-individual changes in circulating metabolites in response to an OGTT were associated with CVD and death beyond their resting measures. Dynamic changes in metabolite levels with an OGTT have potential relevance for understanding and predicting CVD risk.