tbuckley/cabot-search huggingface dataset:
Prenatal Exposure to Nonpersistent Chemical Mixtures and Fetal Growth: A Population-Based Study
Authors: Michiel A. van den Dries, Alexander P. Keil, Henning Tiemeier, Anjoeka Pronk, Suzanne Spaan, Susana Santos, Alexandros G. Asimakopoulos, Kurunthachalam Kannan, Romy Gaillard, Mònica Guxens, Leonardo Trasande, Vincent W.V. Jaddoe, Kelly K. Ferguson
Journal: Environmental Health Perspectives (2021)

BACKGROUND: Prenatal exposure to mixtures of nonpersistent chemicals is universal.Most studies examining these chemicals in association with fetal growth have been restricted to single exposure models, ignoring their potentially cumulative impact.OBJECTIVE: We aimed to assess the association between prenatal exposure to a mixture of phthalates, bisphenols, and organophosphate (OP) pesticides and fetal measures of head circumference, femur length, and weight.METHODS: Within the Generation R Study, a population-based cohort in Netherlands (n = 776), urinary concentrations of 11 phthalate metabolites, 3 bisphenols, and 5 dialkylphosphate (DAP) metabolites were measured at <18, 18-25, and >25 weeks of gestation and averaged.Ultrasound measures of head circumference, femur length, and estimated fetal weight (EFW) were taken at 18-25 and >25 weeks of gestation, and measurements of head circumference, length, and weight were performed at delivery.We estimated the difference in each fetal measurement per quartile increase in all exposures within the mixture with quantile g-computation. RESULTS:The average EFW at 18-25 wk and >25 wk was 369 and 1,626 g, respectively, and the average birth weight was 3,451 g.Higher exposure was associated with smaller fetal and newborn growth parameters in a nonlinear fashion.At 18-25 wk, fetuses in the second, third, and fourth quartiles of exposure (Q2-Q4) had 26 g [95% confidence intervals ðCIÞ: -38, -13], 35 g (95% CI : -55, -15), and 27 g (95% CI : -54, 1) lower EFW compared with those in the first quartile (Q1).A similar dose-response pattern was observed at >25 wk, but all effect sizes were smaller, and no association was observed comparing Q4 to Q1.At birth, we observed no differences in weight between Q1-Q2 or Q1-Q3.However, fetuses in Q4 had 91 g (95% CI : -258, 76) lower birth weight in comparison with those in Q1.Results observed at 18-25 and >25 wk were similar for femur length; however, no differences were observed at birth.No associations were observed for head circumference.DISCUSSION: Higher exposure to a mixture of phthalates, bisphenols, and OP pesticides was associated with lower EFW in the midpregnancy period.In late pregnancy, these differences were similar but less pronounced.At birth, the only associations observed appeared when comparing individuals from Q1 and Q4.This finding suggests that even low levels of exposure may be sufficient to influence growth in early pregnancy, whereas higher levels may be necessary to affect birth weight.Joint exposure to nonpersistent chemicals may adversely impact fetal growth, and because these exposures are widespread, this impact could be substantial.
Abstract 11594: Deep Learning of the Retina Enables Phenome- and Genome- Wide Analyses of the Microvasculature
Authors: Seyedeh M Zekavat, Vineet Raghu, Mark Trinder, Yixuan Ye, Akhil Pampana, Sarah Urbut, Declan O'Regan, Hongyu Zhao, Patrick T Ellinor, Ayellet Segre, Tobias Elze, Janey Wiggs, James Martone, Ron A Adelman, Nazlee Zebardast, Lucian Del Priore, Jay C Wang, Pradeep Natarajan
Journal: Circulation (2021)

Introduction: The retinal fundus is a window for non-invasive assessment of the microvasculature. However, the range of phenotypes and inherited genetic variants associated with the retinal microvasculature remain unknown. Hypothesis: Deep learning of retinal fundus images enables large-scale quantification of vascular indices and an unbiased assessment of phenotypes and genetic variants linked to the microvasculature. Methods: We utilized 97,895 retinal fundus images from 54,813 UK Biobank participants (ages 40-70y, 55% female). Using convolutional neural networks to segment vessels, we calculated vascular branching complexity using fractal dimension (FD), and vascular density, and associated these indices with 1,100 incident ICD-based conditions (median 10y follow-up) and 88 quantitative traits, adjusting for age, sex, smoking status, and ethnicity. Genome-wide association study (GWAS) among 38,932 unrelated individuals was performed. Results: Low retinal vascular FD and density were significantly associated with increased risk of incident hypertension, congestive heart failure, renal failure, type 2 diabetes, sleep apnea, anemia, and multiple ocular conditions. Low retinal vascular FD and density were also linked to quantitative traits including elevated blood pressure, anemia indices, abnormal pulmonary function tests, measures of metabolic disease (high HbA1c, % body fat, BMI), and ocular traits (decreased visual acuity and increased intraocular pressure). GWAS of vascular FD and density identified loci enriched among pathways linked to angiogenesis (VEGF, PDGFR, angiopoietin, and WNT signaling pathways), and inflammation (interleukin, cytokine signaling). Conclusions: Through phenotypic and genotypic analyses, our study showed that the retinal vasculature may serve as a biomarker for future cardiometabolic and ocular disease, and provided insights on genes and biological pathways influencing microvascular indices.
Adding a platinum agent to neoadjuvant chemotherapy for triple-negative breast cancer: the end of the debate
Authors: F. Poggio, M. Tagliamento, M. Ceppi, M. Bruzzone, B. Conte, P. Fregatti, K. Punie, E. de Azambuja, L. Del Mastro, M. Lambertini
Journal: Annals of Oncology (2021)
Abstract 11711: Quantification of Atherosclerotic Coronary Artery Disease in the Pre/Peri-Menopausal Female Using Cardiac CTA
Authors: Anup Solsi, Roger Bies, Ralph Drosten, Rachel M Bond, Femi Oladokun, Robert Roberts, Pallavi Bellamkonda
Journal: Circulation (2021)

Introduction: Coronary Artery Disease (CAD) occurs equally in males and females and is the most common cause of death in both genders worldwide. The pre/peri-menopausal female is believed to have minimal coronary atherosclerosis based primarily on non-invasive techniques, with limited coronary angiography data. Cardiac computed tomography angiography (CCTA) is a more sensitive, non-invasive anatomical diagnostic tool for quantifying coronary atherosclerosis, but pre/peri-menopausal women have been underrepresented and underdiagnosed. The goal of this study was to quantify coronary atherosclerosis in this population. Methods: We conducted a retrospective chart review on 510 females aged 35-60 presenting with atypical chest pain and shortness of breath. These were consecutive admissions in which CCTA was performed from January 2014 to December 2019. The degree of coronary atherosclerosis was quantified using the CAD-RADS scoring system. Results: Analysis showed 68.82% of patients had no evidence of coronary atherosclerosis. 4.31% had minimal CAD, 18.24% had mild CAD, 6.47% had moderate CAD and 2.16% were found to have severe CAD. Each category of stenosis typically had multiple vessels involved. Over 65% of patients were Non-Hispanic White, 27% Hispanic, 8% African American and 4% Asian. Less than 5% of patients were discharged with statin therapy. Conclusions: This is the first study to quantify coronary atherosclerosis in the pre/peri-menopausal female. Quantification was based on coronary angiograms obtained by CCTA, currently the most sensitive diagnostic imaging technique. Despite the perceived protective nature of the premenopausal state in women, 30% of patients had detectable CAD by CCTA. 10% had greater than 50% stenosis (moderate to severe CAD), suggesting the potential for future ischemic heart disease. So few patients were discharged on statin therapy, showing the paucity of guideline therapy used in this population. These results suggest targeting preventative therapy, even late in the pre or peri-menopausal stage, such as favorable lifestyle changes and reducing known modifiable cardiac risk factors, should significantly prevent the progression of coronary atherosclerosis and its subsequent sequelae in menopause.
Abstract 14421: Limitations of Using Unipolar Signals to Guide Outflow Tract Premature Ventricular Contraction Ablation
Authors: Syed Rafay Ali Sabzwari, Shu Chang, James Mann, Lukasz Cerbin, Christopher Barrett, Alexis Tumolo, Michael Rosenberg, John J West, Jose Sanchez, Amneet Sandhu, Paul D Varosy, Ryan G Aleong, Matthew Zipse, William Sauer, Wendy S Tzou
Journal: Circulation (2021)

Introduction: Unipolar electrogram (EGM) signals are universally used to annotate earliest activation and guide ablation (Abl) of focal arrhythmias. However, their utility in mapping PVCs is limited given 3-dimensionality of wave front propagation, especially when the source is intramural. Hypothesis: 1) earliest onset of bipolar activation would better guide mapping and Abl in these cases, versus maximum unipolar dV/dt or QS morphology; and 2) differences would be greater for intramural outflow tract (OT) PVCs versus those eliminated with RVOT Abl only. Methods: Consecutive patients undergoing successful RVOT or RVOT+LVOT PVC Abl at our center from 2017-2020 were retrospectively analyzed. Bipolar and Unipolar EGMs at successful Abl sites were compared. Results: Of 71 patients, 41 had only RVOT and 30 had RVOT + LVOT Abl. All had acute and long-term PVC suppression over mean 22.6 ± 11.6 month follow-up. Mean EGM difference was 7.6 ± 4.7 ms in the RVOT group vs 18.9 ± 10.5 ms in RVOT+LVOT group (p&lt;0.01). QS unipolar EGM was seen in 95% of RVOT patients, 88% of which were at the anterior RVOT/crux, vs 40% of RVOT+LVOT patients (p&lt;0.016). Activation was equally earliest from the posteroseptal RVOT and adjacent LVOT site in 73%, and most of these sites did not have a QS unipolar EGM (Figure). Conclusions: Bipolar EGM activation timing guided successful ablation of OT PVCs better than unipolar EGM analysis. A QS unipolar EGM did not reliably predict best ablation sites, especially for intramural PVCs.
RTID-04. GLIOTARGET: A DANISH NATIONWIDE PHASE I/II PLATFORM TRIAL FOCUSING ON INDIVIDUALIZED TARGETED TREATMENT FOR NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS BASED ON GENOMIC PROFILING
Authors: Vincent Fougner, Benedikte Hasselbalch, Thomas Urup, Ulrik Lassen, Hans Poulsen
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION The survival in glioblastoma has been unchanged since 2005. The introduction of targeted treatments, which have improved survival in several cancers has yet to influence the treatment of glioblastoma. In Gliotarget, we will individualize the targeted treatment, and give it in the primary setting alongside standard therapy with the intention to improve the likelihood of effect. METHODS Gliotarget is a biomarker enriched phase I/II platform trial with initially 4 predefined biomarker selected arms, one miscellaneous biomarker arm and one control arm. All patients receive standard therapy with concomitant radiochemotherapy and adjuvant Temozolomide. The experimental treatment is given alongside the adjuvant Temozolomide. Molecular analysis, including Whole Genome Sequencing, is performed on all patients, to identify actionable biomarkers. The miscellaneous arm gathers patients with not previously defined biomarkers upon which the weekly molecular tumor board decides to treat. Gliotarget includes newly diagnosed IDH-wt glioblastoma patients. In addition, to exclude the patients where the inherent poor prognosis might conceal the drug efficacy, the patients must have a 50% probability of being alive 12 months after initial surgery, according to a prognostic model developed in our institution. The sample size is calculated with Simon’s two-stage design using treatment effect at 9-months progression free survival (PFS9). We anticipate 9 patients for stage one and 24 in total, for each arm. Treatment effect is defined as 65% of the patients in an experimental arm reaching PFS9. For the survival analysis, supplementing the control arm data with leveraged external controls taken from our prospectively registered database will decrease the probability of false positive results. CONCLUSION Gliotarget complements the field of ongoing platform trials with its distinctive trial design. The chosen biomarkers and treatments will be presented at the annual meeting. Enrollment is set to open in Q4 2021.
Abstract 11300: Identification of Two Distinct Phenotypes Among Hospitalized Covid-19 Patients Using Latent Class Analysis
Authors: Catherine Teng, Pengyang Li, Qi Liu
Journal: Circulation (2021)

Introduction: COVID-19 pneumonia is a heterogeneous disorder with a complex pathogenesis. Underlying subgroups may exist among patients who are admitted to the hospital with COVID-19 infection. Methods: We reviewed the charts of adult patients who were hospitalized primarily for COVID-19 at Greenwich Hospital. We performed latent class analysis using variables based on patient demographics (age, sex, race, and body mass index), comorbidities (hypertension, diabetes, coronary artery disease, chronic heart failure, chronic kidney disease, neurological disease, and pre-existing respiratory disease), laboratory results, and treatment information (medications received during hospitalization, hospital length of stay, maximized oxygen requirement, and requirement for intubation). Results: Two phenotypes were identified: C1 and C2. C1 (n=193) included older individuals with a higher mortality rate (25.4% vs 8.97%, p&lt;0.001) and more comorbidities such as hypertension (88.6% vs 22.8%, p&lt;0.001), coronary artery disease (32.1% vs 0.0%, p&lt;0.001), chronic heart failure (20.7% vs 0%, p&lt;0.001), diabetes mellitus (38.3% vs 17.6%, p&lt;0.001), chronic kidney disease (25.4% vs 2.8%, p&lt;0.001), pre-existing respiratory disease (24.9% vs 11.0%, p=0.004), and pre-existing neurological disease (32.1% vs 3.5%, p&lt;0.001). C2 (n=290) consisted of individuals who were younger (53.7 years vs 79.5 years, p&lt;0.001), more likely to be obese (40.3% vs. 28.0%, p=0.007), mostly male (70.3% vs 52.3%, p&lt;0.001), and mostly non-white (69.7% vs. 28.5%, p&lt;0.001), with higher levels of inflammatory markers such as C-reactive protein (18.3±43.4 vs. 10.7±13.7 mg/L, p=0.006) and alanine aminotransferase (209±512 vs. 96.2±204 U/L, p=0.001). Conclusions: Using latent class analysis, we identified two clinical phenotypes of patients who were admitted to the hospital for COVID-19. Our findings may reflect different pathophysiologic processes that lead to moderate to severe COVID-19 and may be useful in the identification of treatment targets and the selection of patients with severe COVID-19 disease for future clinical trials.
<i>Interobserver Variability with the Diagnosis of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) ¿Is the Threshold of 20% Bone Marrow Blasts Reproducible?</i>
Authors: Patricia Font Lopez, Javier Loscertales, Montserrat Lopez Rubio, María Teresa Cedena, Carlos Soto, Cristina Seri, Pilar Ricard, Mónica Ballesteros, Celina Benavente, Miguel Piris-Villaespesa, Carolina Muñoz, Luis García Alonso, Alfredo Bermejo, Gloria Perez Segura, Sandra Gomez Rojas, Lucia Castilla, Carlos Jimenez Chillon, Ariana Ortuzar, Jose Maria Bellon, Jesus Villarrubia, Jose L. Diez-Martin, Ana Villegas
Journal: Blood (2021)
Scrutinizing Privacy in Multi-Omics Research: How to Provide Ethical Grounding for the Identification of Privacy-Relevant Data Properties
Authors: C. W. Safarlou, A. L. Bredenoord, R. Vermeulen, K. R. Jongsma
Journal: The American Journal of Bioethics (2021)

This article refers to:Toward a Framework for Assessing Privacy Risks in Multi-Omic Research and Databases
Abstract 12245: Surface Lin28a Expression Indicative of Cellular Stress Directed Towards Senescence
Authors: Kathleen M Broughton, Carolina Esquer, Oscar Echeagaray, Mark A Sussman
Journal: Circulation (2021)

Introduction: Declining cellular functional capacity resulting from stress or aging is a primary contributor to impairment of myocardial performance. Molecular pathway regulation of biological processes in cardiac interstitial cells (CICs) is pivotal in stress and aging responses. Altered localization of the RNA binding protein Lin28A has been reported in response to environmental stress, but the role of Lin28A in response to stress in CICs has not been explored. Hypothesis: Lin28A redistribution is indicative of stress response in CIC associated with aging and senescence. Methods and Results: Localization of Lin28A was assessed by multiple experimental analyses and treatment conditions and correlated to oxidative stress, senescence, and ploidy in adult murine CICs. Surface Lin28A expression is present on 5% of fresh CICs and maintained through passage 2, increasing to 21% in hyperoxic conditions but lowered to 14% in physiologic normoxia. Surface Lin28A is coincident with elevated Beta-galactosidase (Beta-gal) expression in CICs expanded in hyperoxia, and also increases with polyploidization and binucleation of CICs regardless of oxygen culture. Transcriptional profiling of CICs using single cell RNASeq reveals upregulation of pathways associated with oxidative stress in CICs exhibiting surface Lin28A. Induction of surface Lin28A by oxidative stress is blunted by treatment of cells with the antioxidant Trolox in a dose-dependent manner, with 300uM Trolox exposure maintaining characteristics of freshly isolated CICs possessing low expression of surface Lin28A and Beta-gal with predominantly diploid content. Conclusion: Surface Lin28A is a marker of environmental oxidative stress in CICs and antioxidant treatment antagonizes this phenotype. The biological significance of Lin28 surface expression and consequences for myocardial responses may provide important insights regarding mitigation of cardiac stress and aging.
Abstract 14347: Sleep Apnea and Left Atrial Dilatation in Patients With Atrial Fibrillation Prior to Catheter Ablation
Authors: Nobuaki Tanaka, Masato Okada, Koji Tanaka, Yuko Hirao, Shinichi Harada, Katsuomi Iwakura, Kenshi Fujii, Atsunori Okamura
Journal: Circulation (2021)

Introduction: Sleep apnea and left atrial dilatation are both risk factors for an arrhythmia recurrence after catheter ablation (CA) of atrial fibrillation (AF). Negative intrathoracic pressure fluctuations during an obstructive apnea episode may cause the left atrium to distend and stretch its wall. Whether sleep apnea is associated with left atrial dilatation in patients receiving CA of AF remains unknown. Methods: This study was conducted under a retrospective, single-center, observational design. The data were derived from screening tests for sleep apnea, which were routinely performed in patients scheduled to receive CA of AF in our institution. After excluding patients who were already diagnosed with sleep apnea, we enrolled 1265 consecutive patients (age 65±11 years, 27.8% females, and 46.2% of non-paroxysmal AF) who underwent both home sleep apnea testing and multidetector computed tomography (MDCT) before the CA of AF. The severity of the sleep apnea was evaluated by the apnea-hypopnea index (AHI) using a watch-type peripheral arterial tonometry. Left atrial dilatation was evaluated by the left atrial maximum volume (LA max V) using 256-slice MDCT. Results: The age was 65±11 years, 27.8% were females, and 46.2% had non-paroxysmal AF. The mean AHI was 20.3±15.3 and LA max V 104.9±33.9 ml (R 2 =0.075, p&lt;0.0001). LA dilatation, defined by an LA max V≥100 ml, was more frequently observed in patients with an AHI≥15 than those with an AHI&lt;15 (62.5% vs. 40.2%, p&lt;0.0001). We examined an LA max V≥100 ml as a predictor. After an adjustment by an advanced age (≥65 years), non-paroxysmal AF, male sex, obesity, hypertension, and congestive heart failure, all of which were significant predictors of an LA max V≥100ml in the univariate analysis, moderate or severe sleep apnea (AHI≥15) was a significant predictor of an LA max V≥100 ml (odds ratio 1.49, 95% confidence interval 1.13-1.97, p=0.0049). Conclusion: Among the patients scheduled to receive catheter ablation of AF, moderate or severe sleep apnea was independently associated with left atrial dilatation.
PATH-31. METHYLATION SUBCLASS RECEPTOR TYROSINE KINASE II AS A DRIVER FOR SEIZURES IN IDH-WILDTYPE GLIOBLASTOMA
Authors: Richard Drexler, Alicia Eckhardt, Manfred Westphal, Ulrich Schüller, Lasse Dührsen, Franz Ricklefs
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Seizures are a common symptom of patients suffering from glioblastoma and there is evidence that these tumours are morphologically different. However, the relationship of DNA methylation and glioblastoma-related seizures has not been well characterized. Only one study described an amplification of genes encoding receptor tyrosine kinases (RTK) as a positive predictor for intraoperative seizures during craniotomy. METHODS 59 patients who underwent surgery with confirmed IDH-wildtype glioblastoma, WHO grade 4, were included. Genome-wide DNA methylation profiling was performed using an 850k Illumina EPIC array and classified by the DKFZ brain tumor classifier. Methylation glioblastoma subclasses and gene alterations were correlated with clinical characteristics including preoperative and long-term seizures. RESULTS Overall, 18 of 59 patients (30.5%) presented with seizures of whom suffered 8 (44.4%) from a focal and 10 (55.6%) from a generalized seizure. Correlation of preoperative seizures with glioblastoma subclasses and DNA genes identified a higher incidence of preoperative seizures in patients with the glioblastoma subclass of receptor tyrosine kinase II (RTK; EGFR amplified) (p=0.031). In addition, these patients were more likely to present with generalized seizures (p=0.05). In multivariate analysis, temporal location (p=0.014, OR 5.785) but moreover RTK II (p=0.024, OR 7.052) was most predictive for preoperative seizures. Furthermore, recurrent seizures with an increased antiepileptic medication at last follow-up (mean: 9.2 months) occurred more often in RTK II-glioblastoma (p&amp;lt; 0.05). Kaplan-Meier curves showed no significant association between the presentation of seizures and overall or progression-free survival. In addition, further survival analyses did not reveal a correlation of methylation glioblastoma subgroups with the outcome. CONCLUSION Our study showed a strong correlation of the RTK II methylation subclass with preoperative and long-term seizures in patients suffering from glioblastoma.