tbuckley/cabot-search huggingface dataset:
Pharmacokinetics and Proceedings in Clinical Application of Nucleic Acid Therapeutics
Authors: Markus Herkt, Thomas Thum
Journal: Molecular Therapy (2020)

Oligonucleotide therapeutics are a novel promising class of drugs designed to specifically target either coding or non-coding RNA molecules to revolutionize treatment of various diseases. During preclinical development, investigations of the pharmacokinetic characteristics of these oligonucleotide-based drug candidates are essential. Oligonucleotides possess a long history of chemical modifications to enhance their stability and binding affinity, as well as reducing toxicity. Phosphorothioate backbone modifications of oligonucleotides were a hallmark of this development process that greatly enhanced plasma stability and protein binding of these agents. Modifications such as 2'-O-methylation further improved stability, while other modifications of the ribose, such as locked nucleic acid (LNA) modification, significantly increased binding affinity, potency, and tissue half-life. These attributes render oligonucleotide therapeutics able to regulate protein expression in both directions depending on the target RNA. Thus, a growing interest has emerged using these oligonucleotides in the treatment of neurodegenerative and cardiac disorders as well as cancer, since the deregulation of certain coding and non-coding RNAs plays a key role in the development of these diseases. Cutting edge research is being performed in the field of non-coding RNAs, identifying potential therapeutic targets, and developing novel oligonucleotide-based agents that outperform classical drugs. Some of these agents are either in clinical trials showing promising results or are already US Food and Drug Administration (FDA) approved, with more oligonucleotides being developed for therapeutic purposes. This is the advent of mechanism-based next-generation therapeutics for a wide range of diseases.
Author Correction: Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion
Authors: Yubin Huang, Zhen Xu, Shanshan Xiong, Fangfang Sun, Guangrong Qin, Guanglei Hu, Jingjing Wang, Lei Zhao, Yu-Xiang Liang, Tianzhun Wu, Zhonghua Lu, Mark S. Humayun, Kwok-Fai So, Yihang Pan, Ningning Li, Ti-Fei Yuan, Yanxia Rao, Bo Peng
Journal: Nature Neuroscience (2020)
Effect of e-Cigarettes Plus Counseling vs Counseling Alone on Smoking Cessation
Authors: Mark J. Eisenberg, Andréa Hébert-Losier, Sarah B. Windle, Todd Greenspoon, Tim Brandys, Tamàs Fülöp, Thang Nguyen, Stéphane Elkouri, Martine Montigny, Igor Wilderman, Olivier F. Bertrand, Joanna Alexis Bostwick, John Abrahamson, Yves Lacasse, Smita Pakhale, Josselin Cabaussel, Kristian B. Filion
Journal: JAMA (2020)

Electronic cigarettes (e-cigarettes) for smoking cessation remain controversial.To evaluate e-cigarettes with individual counseling for smoking cessation.A randomized clinical trial enrolled adults motivated to quit smoking from November 2016 to September 2019 at 17 Canadian sites (801 individuals screened; 274 ineligible and 151 declined). Manufacturing delays resulted in early termination (376/486 participants, 77% of target). Outcomes through 24 weeks (March 2020) are reported.Randomization to nicotine e-cigarettes (n = 128), nonnicotine e-cigarettes (n = 127), or no e-cigarettes (n = 121) for 12 weeks. All groups received individual counseling.The primary end point was point prevalence abstinence (7-day recall, biochemically validated using expired carbon monoxide) at 12 weeks, changed from 52 weeks following early termination. Participants missing data were assumed to be smoking. The 7 secondary end points, examined at multiple follow-ups, were point prevalence abstinence at other follow-ups, continuous abstinence, daily cigarette consumption change, serious adverse events, adverse events, dropouts due to adverse effects, and treatment adherence.Among 376 randomized participants (mean age, 52 years; 178 women [47%]), 299 (80%) and 278 (74%) self-reported smoking status at 12 and 24 weeks, respectively. Point prevalence abstinence was significantly greater for nicotine e-cigarettes plus counseling vs counseling alone at 12 weeks (21.9% vs 9.1%; risk difference [RD], 12.8 [95% CI, 4.0 to 21.6]) but not 24 weeks (17.2% vs 9.9%; RD, 7.3 [95% CI, -1.2 to 15.7]). Point prevalence abstinence for nonnicotine e-cigarettes plus counseling was not significantly different from counseling alone at 12 weeks (17.3% vs 9.1%; RD, 8.2 [95% CI, -0.1 to 16.6]), but was significantly greater at 24 weeks (20.5% vs 9.9%; RD, 10.6 [95% CI, 1.8 to 19.4]). Adverse events were common (nicotine e-cigarette with counseling: 120 [94%]; nonnicotine e-cigarette with counseling: 118 [93%]; counseling only: 88 [73%]), with the most common being cough (64%) and dry mouth (53%).Among adults motivated to quit smoking, nicotine e-cigarettes plus counseling vs counseling alone significantly increased point prevalence abstinence at 12 weeks. However, the difference was no longer significant at 24 weeks, and trial interpretation is limited by early termination and inconsistent findings for nicotine and nonnicotine e-cigarettes, suggesting further research is needed.ClinicalTrials.gov Identifier: NCT02417467.
Frailty and Postoperative Morbidity and Mortality—Here, There, and Everywhere
Authors: Devon Anderson, Elizabeth C. Wick
Journal: JAMA Surgery (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Obinutuzumab vs rituximab for advanced DLBCL: a PET-guided and randomized phase 3 study by LYSA
Authors: Steven Le Gouill, Hervé Ghesquières, Lucie Oberic, Franck Morschhauser, Hervé Tilly, Vincent Ribrag, Thierry Lamy, Catherine Thieblemont, Hervé Maisonneuve, Rémy Gressin, Krimo Bouhabdallah, Corinne Haioun, Gandhi Damaj, Luc Fornecker, Réda Bouhabdallah, Pierre Feugier, David Sibon, Guillaume Cartron, Christophe Bonnet, Marc André, Loic Chartier, Philippe Ruminy, Françoise Kraeber-Bodéré, Caroline Bodet-Milin, Alina Berriolo-Riedinger, Josette Brière, Jean-Philippe Jais, Thierry Jo Molina, Emmanuel Itti, René-Olivier Casasnovas
Journal: Blood (2020)
Progression of Diabetic Retinopathy and Predictors of Its Development and Progression During Pregnancy in Patients With Type 1 Diabetes: A Report of 499 Pregnancies
Authors: Julien Bourry, Hugues Courteville, Nassima Ramdane, Elodie Drumez, Alain Duhamel, Damien Subtil, Philippe Deruelle, Anne Vambergue
Journal: Diabetes Care (2020)

OBJECTIVE Pregnancy has been associated with development and progression of diabetic retinopathy (DR), but incidence of DR remains unclear. We assessed DR progression rate and its predictors during pregnancies in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS We report the retrospective data from pregnancies in patients with type 1 diabetes followed in Lille, France (1997–2015). Eye examination was performed every 3 months or every month in case of severe nonproliferative retinopathy or progression. Progression was defined by DR degradation (≥1 stage of the Early Treatment Diabetic Retinopathy Study [ETDRS] classification); it included DR development and worsening in patients without and with prepregnancy DR, respectively. RESULTS A total of 499 pregnancies in 375 patients were included; prepregnancy retinopathy was present in 30.3%. Progression, development, and worsening rates were 21.8%, 24.4% of those without retinopathy, and 15.9% of those with retinopathy, respectively. Development of sight-threatening retinopathy was rare. Progression mainly occurred in early or midpregnancy. Elevated prepregnancy HbA1c and duration of diabetes ≥10 years were predictors of DR progression. Among pregnancies with prepregnancy DR, continuous subcutaneous insulin infusion (CSII) tended to decrease the risk of DR progression. Among CSII-treated patients, those with prepregnancy DR had a significantly decreased risk of DR progression. Among the 270 pregnancies of women with any DR during pregnancy who returned for a postpartum ophthalmologic examination, the rate of progression was only 4.1% and the rate of regression was 9.3%. CONCLUSIONS This study provides epidemiologic data on progression of retinopathy during pregnancy and will be useful for future guidelines for retinopathy screening.
Abstract 16702: Myocardial Deformation Analysis in Hypertrophic Cardiomyopathy With Sarcomere Mutations: Insights From 2,221 Patients Within the NHLBI-HCM Registry
Authors: Bobak Heydari, Alessandro Satriano, James A White, Naeem Merchant, Masliza Mahmod, Betty Raman, Kenneth Chan, Panagiotis Antiochos, Michael Jerosch-Herold, Carolyn Y Ho, William S Weintraub, Sarahfaye Dolman, Paul Kolm, Nancy Geller, Dong-Yun Kim, Patrice Desvigne-Nickens, John P Dimarco, Milind Y Desai, Hugh C Watkins, Stefan Neubauer, Christopher M Kramer, Raymond Y Kwong
Journal: Circulation (2020)

Introduction: Hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere genes that alter myocardial contractility and relaxation. Three-dimensional myocardial deformation analysis (3D-MDA) may elucidate left ventricular (LV) abnormalities associated with sarcomere genotype status. Hypothesis: We hypothesize that HCM patients with sarcomere mutations have changes in myocardial contractility profiles that are associated with adverse LV architectural changes. Methods: 3D-MDA was measured using validated feature-tracking software applied to 2D cine cardiac MRI studies in 2,221 genotyped patients within the NHLBI HCM Registry. Results: Baseline, cardiac MRI, and 3D MDA-derived strain characteristics stratified by sarcomere status are shown in Table 1. Sarcomere positive patients were younger, had less LV outflow tract obstruction and lower indexed LV mass, but similar LVEF and trend towards higher serum NT-proBNP levels. Maximal wall thickness, measures of diffuse myocardial fibrosis (native T1, extracellular volume fraction) were elevated with corresponding reduction in global radial strain. Global minimum principal and epicardial layer conventional strain values were higher in sarcomere positive patients. Epicardial minimum principal strain was highly correlated with indexed LV mass (r=0.42, P&lt;0.0001), maximal wall thickness (r=0.29, P&lt;0.0001), LVEF (r=-0.33, P&lt;0.0001), late gadolinium enhancement (r=0.22, P&lt;0.0001) and NT-proBNP (r=0.21, P&lt;0.0001) levels in those with sarcomere mutations. Conclusions: Sarcomere positive HCM patients had differences in myocardial deformation strain profiles that were correlated to LV architectural changes and NT-proBNP levels despite lower indexed LV mass. More sensitive measures of contractile dysfunction may help elucidate pathophysiological mechanisms by which sarcomere mutations cause disease progression and adverse clinical outcomes in HCM.
Abstract 15823: Diminished Vasoresponsiveness in Patients With Heart Failure
Authors: Olga Papazisi, Marieke E van Vessem, Saskia L Beeres, Rob B de Wilde, Remco R Berendsen, Evert de Jonge, Klautz J Robert, Leon P Aarts, Martin J Schalij, Meindert Palmen
Journal: Circulation (2020)

Introduction: Vasoplegia is a severe complication after cardiac surgery and is associated with impaired clinical outcome. Pre-operative heart failure (HF) is considered an independent predictor of post-operative vasoplegia. We hypothesize that HF patients are more susceptible to vasoplegia due to altered vascular responsiveness. In this study, vasoresponsiveness in patients undergoing cardiac surgery for HF is investigated. Methods: A prospective, observational study was conducted at Leiden University Medical Center. We included patients with HF (N=18) and without HF (N=18) who underwent cardiac surgery on cardiopulmonary bypass. Vasoresponsiveness was assessed at 4 different timepoints: 1) before induction, 2) after induction, 3) after cessation of cardiopulmonary bypass and 4) on the first postoperative day. The vascular response was recorded as change in systemic vascular resistance (SVR) after the administration of phenylephrine (bolus 2 μg/kg). Results: Thirty-six patients were included [67 (61-71) years, 78% male]. Vascular responsiveness was significantly attenuated in patients with HF compared to controls. The response to phenylephrine was already diminished at baseline in HF patients and was almost abolished after cessation of cardiopulmonary bypass (Figure). Roughly the same pattern of vasoresponsiveness was found when excluding patients that received norepinephrine. Moreover, HF patients required a significantly higher amount of noradrenaline [169.80 (IQR 14.77-318.97) ug/kg] compared to controls [3.61 (IQR 0-41.60) ug/kg] to maintain similar SVR during the first 24h postoperatively. Conclusions: The vascular responsiveness is altered in patients with HF and this might explain the higher prevalence of vasoplegia in this patient population.
Abstract 14042: Weight Loss Favorably Impacts Left Ventricular Mass and Wall Thickness by CMR and CT in Patients With Hypertrophic Cardiomyopathy: A Retrospective Case Series
Authors: Maria DeFonte, Jonathan Goldstein, Daniele Massera, Alexandra Stepanovic, Alexander Gee, Larry Latson, Leon AXEL, Mark Sherrid
Journal: Circulation (2020)

Introduction: Hypertrophic Cardiomyopathy (HCM) is a relatively common inherited heart disease with variable phenotypic expression. While pathogenic variants in sarcomeric genes are considered responsible for the development of left ventricular (LV) hypertrophy, environmental modulation of phenotype may explain the known heterogeneity. Obesity is common in HCM patients and is associated with increased LV mass in the general population. Hypothesis: We hypothesized that weight loss in obese patients with HCM would be associated with a decrease in LV mass and maximal wall thickness. Methods: Patients with HCM who achieved therapeutic weight loss and underwent cardiac MRI (CMR) or computed tomography (CT) before and afterwards were included. Standard LV measurements including wall thickness in an 18-segment model were performed blindly with respect to name, time and BMI for un-biased comparison. Results: We included 6 patients (2 female, age 55 ± 6.5 years, baseline BMI = 36.7 ± 5.2 kg/m 2 ) who achieved 16.3 ± 10.8 kg weight loss after 35 ± 12 months with diet and exercise (n=4) or bariatric surgery (n=2). After weight loss, we observed a mean proportional decrease in total LV mass of 25 ± 16% (p=0.004), and a 19 ± 7% decrease in indexed LV mass (p=0.007). Furthermore, there was a numerical decrease in mean wall thickness in 14 out of 18 LV segments measured; 9 segments had more than a 10% decrease. The most noticeable changes were at the basal inferolateral wall (25 ± 13% decrease) and basal inferoseptum (19 ± 18%) decrease (Table). Conclusions: In this series of patients with HCM, weight loss favorably affected LV mass and wall thickness. Further research is needed to explore the impact of weight loss on HCM phenotypic expression and symptoms.
Combination of endoscopic-ultrasound guided choledochoduodenostomy and gastrojejunostomy resolving combined distal biliary and duodenal obstruction
Authors: Pradermchai Kongkam, Thanawat Luangsukrerk, Kamin Harinwan, Kunvadee Vanduangden, Suppawatsa Plaidum, Rungsun Rerknimitr, Pinit Kullavanijaya
Journal: Endoscopy (2020)

A 68-year-old man presented with abdominal pain, jaundice, and weight loss for 1 month. Abdominal computed tomography revealed a periampullary mass measuring 3.5 × 3.5 × 3.2 cm with dilated bile duct ([Fig. 1]).
Insights From Rapid Deployment of a “Virtual Hospital” as Standard Care During the COVID-19 Pandemic
Authors: Kranthi Sitammagari, Stephanie Murphy, Marc Kowalkowski, Shih-Hsiung Chou, Matthew Sullivan, Stephanie Taylor, James Kearns, Thomas Batchelor, Carly Rivet, Colleen Hole, Tony Hinson, Pamela McCreary, Ryan Brown, Todd Dunn, Zeev Neuwirth, Andrew McWilliams
Journal: Annals of Internal Medicine (2020)

Pandemics disrupt traditional health care operations by overwhelming system resource capacity but also create opportunities for care innovation.
Abstract 15220: Development of a Prediction Model for Atrial Fibrillation in Patients With Heart Failure and Preserved Ejection Fraction: Secondary Analysis of Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (topcat) Trial
Authors: Khaled Elkholey, Zain Ul Abideen Asad, Lampros Papadimitriou, Udho THADANI, Stavros Stavrakis
Journal: Circulation (2020)

Background: Atrial fibrillation (AF) is a common comorbidity in heart failure with preserved ejection fraction (HFpEF) and portends an increased risk of cardiovascular events. We sought to identify predictors and develop a risk score of incident AF among patients with HFpEF. Methods: This was an exploratory, post-hoc analysis of the TOPCAT trial. Patients without known AF were included. Cox regression was used to identify independent predictors of incident AF. A risk score was derived from the weighed sum of the regression coefficients of each independent risk factor in the final model using Cox regression analysis. Results: A total of 2174 patients (mean age 67.0±9.4 years; female 55%) without known AF at baseline were included. During a median follow-up of 3 years, 102 (4.7%) patients developed new onset AF. Diabetes (HR=2.1, 95% CI 1.4-3.1; p=0.0002), peripheral arterial disease (HR=2.0, 95% CI 1.2-3.4; p=0.006), elevated (&gt;144meq/dL) sodium (HR=2.1, 95% CI 1.4-3.1; p=0.0002) independently predicted incident AF, whereas current use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was protective (HR=0.61, 95% CI 0.38-0.99, p=0.048). Based on the simplified risk score which included these 4 variables, annualized AF incidence rates were 0.8%, 1.8%, and 3.6% in the low (score=0), intermediate (score=1 or 2), and high-risk (score &gt;2) groups, respectively (log rank P&lt;0.0001; Figure). Compared to the low risk group, the intermediate and high risk groups had a 2.5-fold and 5-fold increase in the risk of incident AF, respectively (HR=2.5, 95% CI 1.5-4.0, p=0.0003 and HR=4.9, 95% CI 2.9-9.4, p&lt;0.0001, respectively). Model discrimination was good (c-statistic=0.67; 95% CI 0.61-0.72). Conclusions: A simplified risk score derived from clinical and laboratory characteristics predicts incident AF in patients with HFpEF and, upon further validation, may be used clinically for risk stratification or for AF screening in high risk groups. Figure
Abstract 15624: Intraprocedural Stent Thrombosis: A Case Report With Review of Literature
Authors: Anubhav Jain, Ankita Aggarwal, Nitya Beriwal
Journal: Circulation (2019)

Introduction: Intraprocedural stent thrombosis (IPST), defined as the development of occlusive or nonocclusive new thrombus in or adjacent to a recently implanted stent before completion of PCI is ...
Abstract 17179: Stress-Mediated Platelet Activation Contributes to Thrombosis: Findings From the American Heart Association Go Red for Women Strategically Focused Research Network
Authors: Tessa J Barrett, Emma M Corr, Angela Lee, Tanya M Spruill, Harmony Reynolds, Judith S Hochman, Kathryn J Moore, Jeffrey S Berger
Journal: Circulation (2020)

Background: Psychological stress is a risk factor for cardiovascular disease (CVD). Despite advancements in CV-prevention, CVD remains the global leading cause of disease burden, suggesting that additional factors contribute to sustained CV risk. The mechanisms by which stress contributes to increased CVD are largely unknown. However, in preclinical models increased sympathetic nervous system activity promotes systemic inflammation (e.g. monocyte activation, cytokine production), and may underlie increased CVD risk. We investigated perceived stress in women with MI and its association with platelet activity, and validated our findings in a murine model. Methods: Monocyte-platelet aggregates (MPA) and psychological stress, using the validated Perceived Stress Scale (PSS4), were measured in women post MI (n=96; median age 62.2 years) and in control women (n=31; 66.7 years). A mouse model of chronic variable stress was utilized to explore the impact of stress on platelet activity and risk of thrombosis-mediated death. Results: Perceived stress was higher in MI patients than matched women (p=0.009). Platelet activity, assessed by MPA, was significantly elevated in MI vs. controls (p=0.0025). MPA significantly correlated with PSS4 scores (R=0.412, p =0.009). In a female mouse model of chronic variable stress, circulating MPA was increased in stressed mice compared to controls (p&lt;0.05), and platelet activation markers P-selectin and JON/A were increased on platelets from stressed mice relative to stress free mice (p&lt;0.05). Using a platelet mediated thrombosis model, time to thrombosis and survival was reduced in stressed mice. Conclusion: Platelet activity was increased at the time of MI in women, and positively associated with stress. In a mouse model, we find that stress is a significant contributor to increased platelet reactivity, and promotes thrombosis-mediated death. Cross-talk between platelets and monocytes is a critical mechanism linking thrombosis and inflammation, thus stress-induced MPAs may represent an unexplored pathway linked to stress-mediated CVD-risk. Future studies will examine whether reducing stress reduces platelet hyperactivity and MI risk.