tbuckley/cabot-search huggingface dataset:
Differences in rates of switchbacks after switching from branded to authorized generic and branded to generic drug products: cohort study
Authors: Rishi J Desai, Ameet Sarpatwari, Sara Dejene, Nazleen F Khan, Joyce Lii, James R Rogers, Sarah K Dutcher, Saeid Raofi, Justin Bohn, John Connolly, Michael A Fischer, Aaron S Kesselheim, Joshua J Gagne
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objectives</h3> To compare rates of switchbacks to branded drug products for patients switched from branded to authorized generic drug products, which have the same active ingredients, appearance, and excipients as the branded product, with patients switched from branded to generic drug products, which have the same active ingredients as the branded product but may differ in appearance and excipients. <h3>Design</h3> Observational cohort study. <h3>Setting</h3> Private (a large commercial health plan) and public (Medicaid) insurance programs in the US. <h3>Participants</h3> Beneficiaries of a large US commercial health insurer between 2004 and 2013 (primary cohort) and Medicaid beneficiaries between 2000 and 2010 (replication cohort). <h3>Main outcome measures</h3> Patients taking branded products for one of the study drugs (alendronate tablets, amlodipine tablets, amlodipine-benazepril capsules, calcitonin salmon nasal spray, escitalopram tablets, glipizide extended release tablets, quinapril tablets, and sertraline tablets) were identified when they switched to an authorized generic or a generic drug product after the date of market entry of generic drug products. These patients were followed for switchbacks to the branded drug product in the year after their switch to an authorized generic or a generic drug product. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals after adjusting for demographics, including age, sex, and calendar year. Inverse variance meta-analysis was used to pool adjusted hazard ratios across all drug products. <h3>Results</h3> A total of 94 909 patients switched from branded to authorized generic drug products and 116 017 patients switched from branded to generic drug products and contributed to the switchback analysis. Unadjusted incidence rates of switchback varied across drug products, ranging from a low of 3.8 per 100 person years (for alendronate tablets) to a high of 17.8 per 100 person years (for amlodipine-benazepril capsules), with an overall rate of 8.2 per 100 person years across all drug products. Adjusted switchback rates were consistently lower for patients who switched from branded to authorized generic drug products compared with branded to generic drug products in the primary cohort (pooled hazard ratio 0.72, 95% confidence interval 0.64 to 0.81). Similar results (0.75, 0.62 to 0.91) were observed in the replication cohort. <h3>Conclusion</h3> Switching from branded to authorized generic drug products was associated with lower switchback rates compared with switching from branded to generic drug products.
Effect of Low-Dose Versus Standard-Dose Ticagrelor and Clopidogrel on Platelet Inhibition in Acute Coronary Syndromes
Authors: Duk-Woo Park, Pil Hyung Lee, Seongsoo Jang, Hyeong-Seok Lim, Do-Yoon Kang, Cheol Hyun Lee, Jung-Min Ahn, Sung-Cheol Yun, Seong-Wook Park, Seung-Jung Park
Journal: Journal of the American College of Cardiology (2018)
Effectiveness of preventive cognitive therapy while tapering antidepressants versus maintenance antidepressant treatment versus their combination in prevention of depressive relapse or recurrence (DRD study): a three-group, multicentre, randomised controlled trial
Authors: Claudi L H Bockting, Nicola S Klein, Hermien J Elgersma, Gerard D van Rijsbergen, Christien Slofstra, Johan Ormel, Erik Buskens, Jack Dekker, Peter J de Jong, Willem A Nolen, Aart H Schene, Steven D Hollon, Huibert Burger
Journal: The Lancet Psychiatry (2018)
Alternative Splicing of <i>FOXP3</i> Controls Regulatory T Cell Effector Functions and Is Associated With Human Atherosclerotic Plaque Stability
Authors: Anne-Laure Joly, Christina Seitz, Sang Liu, Nikolai V. Kuznetsov, Karl Gertow, Lisa S. Westerberg, Gabrielle Paulsson-Berne, Göran K. Hansson, John Andersson
Journal: Circulation Research (2018)

Rationale: Regulatory T (Treg) cells suppress immune responses and have been shown to attenuate atherosclerosis. The Treg cell lineage-specification factor FOXP3 (forkhead box P3) is essential for Treg cells’ ability to uphold immunologic tolerance. In humans, FOXP3 exists in several different isoforms, however, their specific role is poorly understood. Objective: To define the regulation and functions of the 2 major FOXP3 isoforms, FOXP3fl and FOXP3Δ2, as well as to establish whether their expression is associated with the ischemic atherosclerotic disease. Methods and Results: Human primary T cells were transduced with lentiviruses encoding distinct FOXP3 isoforms. The phenotype and function of these cells were analyzed by flow cytometry, in vitro suppression assays and RNA-sequencing. We also assessed the effect of activation on Treg cells isolated from healthy volunteers. Treg cell activation resulted in increased FOXP3 expression that predominantly was made up of FOXP3Δ2. FOXP3Δ2 induced specific transcription of GARP (glycoprotein A repetitions predominant), which functions by tethering the immunosuppressive cytokine TGF (transforming growth factor)-β to the cell membrane of activated Treg cells. Real-time polymerase chain reaction was used to determine the impact of alternative splicing of FOXP3 in relation with atherosclerotic plaque stability in a cohort of &gt;150 patients that underwent carotid endarterectomy. Plaque instability was associated with a lower FOXP3Δ2 transcript usage, when comparing plaques from patients without symptoms and patients with the occurrence of recent (&lt;1 month) vascular symptoms including minor stroke, transient ischemic attack, or amaurosis fugax. No difference was detected in total levels of FOXP3 mRNA between these 2 groups. Conclusions: These results suggest that activated Treg cells suppress the atherosclerotic disease process and that FOXP3Δ2 controls a transcriptional program that acts protectively in human atherosclerotic plaques.
Coordinated responses to individual tumor antigens by IgG antibody and CD8+ T cells following cancer vaccination
Authors: Tyler W. Hulett, Shawn M. Jensen, Phillip A. Wilmarth, Ashok P. Reddy, Carmen Ballesteros-Merino, Michael E. Afentoulis, Christopher Dubay, Larry L. David, Bernard A. Fox
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> One of today's greatest hurdles for cancer immunotherapy is the absence of information regarding which tumor antigens are already recognized by patients receiving immunotherapies, and whether those therapies then boost or generate an immune response against tumor proteins. For CD8+ T cells in particular, patient-specific immune recognition and responses at the level of individual tumor antigens are rarely characterized. Because of this, some immunologists have turned to serum antibodies as an alternative measure of antigen-specific anti-tumor immunity. In this work, we sought to simultaneously interrogate serum IgG and CD8+ T cell recognition of individual tumor antigens to determine whether antigen-specific serum IgG antibodies provide a window into the behavior of antigen-specific CD8+ T cell responses. Using antibody-based assays to evaluate immune response repertoires and focus T cell antigen exploration could afford substantial advantages for discovering and monitoring the anti-cancer immune responses of patients enrolled on clinical trials. <h3>Methods</h3> We vaccinated female BALB/c mice with a novel combination of an autophagosome-enriched vaccine derived from 4T1 mammary carcinoma along with poly-I:C adjuvant, then screened serum for IgG binding to arrays of 15mer peptides containing known mutation sites in 4T1. Simultaneously, we primed CD8+ T cell cultures from these same animals with 8-11mer peptides derived from these antigens. These primed T cells were then stimulated to measure recognition of the peptides or live 4T1 cells by IFNγ release. <h3>Results</h3> Vaccinated animals demonstrate increases in antigen-specific CD8+ T cell recognition of 4T1 tumor cells and peptides. For proteins confirmed in 4T1 cells and vaccine by mass spectrometry, there is a correlation between this increased CD8+ T cell IFNγ release and serum IgG binding to individual peptide antigens. <h3>Conclusions</h3> These results suggest it is possible to observe some features of a patient's antigen-specific T cell repertoire via an antibody surrogate, which has implications for tumor antigen discovery and clinical monitoring of antigen-specific anti-tumor immunity.
Abstract P363: Visceral, but Not Subcutaneous Adiposity by Computed Tomography is Associated With Increased Aortic Wall Thickness in Psoriasis Patients
Authors: Jacob W Groenendyk, Parag Shukla, Youssef A Elnabawi, Joshua P Rivers, Aditya Goyal, Agastya D Belur, Amit K Dey, Ahmed Sadek, Navya Nanda, Justin Rodante, Mark A Ahlman, Aditya A Joshi, Joel M Gelfand, Martin P Playford, Nehal N Mehta
Journal: Circulation (2018)

Introduction: Patients with psoriasis (PSO), an inflammatory skin disease, experience increased cardiovascular disease and obesity. Traditional measures of obesity, such as BMI and waist-to-hip ratio (WHR), do not fully capture the increased cardiovascular risk. Assessment of adipose tissue distribution via CT scan enables characterization of visceral adiposity (VAT) versus subcutaneous adiposity (SAT), which is clinically useful as excess VAT is known to be associated with cardiovascular events. Aortic Wall Thickness (AWT) is a validated measure of subclinical atherosclerosis. However, the relationship between adiposity distribution and AWT is unknown. Hypothesis: We hypothesized that VAT, but not SAT, BMI, or WHR, would be associated with increased AWT in PSO patients. Methods: Consecutive PSO patients (n=164) underwent quantification of VAT and SAT via CT, and AWT via MRI of the descending aorta. Interrelationships were analyzed via multivariable regression. Results: Patients were middle-aged (mean 50.4), predominantly male (56%), and were at low cardiovascular risk (median Framingham risk 3), despite high prevalence of hyperlipidemia (47%). VAT was significantly associated with AWT (β=0.18, p=0.04), SAT, BMI, or WHR did not demonstrate similar association. This association persisted beyond adjustment for SAT, Framingham score, insulin resistance, and systolic BP (β=0.30, p=0.03). Conclusions: Visceral adiposity demonstrated an association with AWT, a marker of early atherosclerosis, whereas subcutaneous adiposity, BMI, and WHR did not. These findings add to a growing body of literature that visceral fat and its assessment may provide incremental data for risk of subclinical CVD.
Effects of Sacubitril/Valsartan on Physical and Social Activity Limitations in Patients With Heart Failure
Authors: Alvin Chandra, Eldrin F. Lewis, Brian L. Claggett, Akshay S. Desai, Milton Packer, Michael R. Zile, Karl Swedberg, Jean L. Rouleau, Victor C. Shi, Martin P. Lefkowitz, Tzvetana Katova, John J. V. McMurray, Scott D. Solomon
Journal: JAMA Cardiology (2018)

Health-related quality of life (HRQL) of patients with heart failure is markedly reduced compared with that in patients with other chronic diseases, demonstrating substantial limitations in physical and social activities. In the Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, sacubitril/valsartan improved overall HRQL compared with enalapril, as determined by the Kansas City Cardiomyopathy Questionnaire (KCCQ).To examine the effects of sacubitril/valsartan on physical and social activities.The PARADIGM-HF trial was a randomized, double-blind, active treatment-controlled clinical trial performed from December 8, 2009, to March 31, 2014, in 8399 patients with New York Heart Association class II to IV disease and a left ventricular ejection fraction of 40% or less at 1043 centers in 38 countries. Data analysis was performed from August 1, 2017, to December 25, 2017.Sacubitril/valsartan, 200 mg twice daily, or enalapril, 10 mg twice daily.Patients completed HRQL assessments using the KCCQ at randomization, 4-month, 8-month, and annual visits. The effect of sacubitril/valsartan on components of the physical and social limitation sections of the KCCQ at 8 months and longitudinally and related biomarkers and clinical outcomes were studied.At baseline, 7618 of 8399 patients (90.7%) (mean [SD] age, 64 [11] years; 5987 [78.6%] male and 1631 [21.4%] female) completed the initial KCCQ assessment. Patients reported the greatest limitations at baseline in jogging and sexual relationships. Patients receiving sacubitril/valsartan had significantly better adjusted change scores in most physical and social activities at 8 months and during 36 months compared with those receiving enalapril. The largest improvement over enalapril was in household chores (adjusted change score difference, 2.35; 95% CI, 1.19-3.50; P < .001) and sexual relationships (adjusted change score difference, 2.72; 95% CI, 0.97-4.46; P = .002); both persisted through 36 months (overall change score difference, 1.69 [95% CI, 0.78-2.60], P < .001; and 2.36 [95% CI, 1.01-3.71], P = .001, respectively).In patients with heart failure with reduced ejection fraction, sacubitril/valsartan significantly improved nearly all KCCQ physical and social activities compared with enalapril, with the largest responses in household chores and sexual relationships. In addition to reduced likelihood of cardiovascular death, all-cause mortality, and heart failure hospitalization, sacubitril/valsartan may improve limitations in common activities in these patients.clinicaltrials.gov Identifier: NCT01035255.
NOD-like receptor X1 functions as a tumor suppressor by inhibiting epithelial-mesenchymal transition and inducing aging in hepatocellular carcinoma cells
Authors: Bo Hu, Guang-Yu Ding, Pei-Yao Fu, Xiao-Dong Zhu, Yuan Ji, Guo-Ming Shi, Ying-Hao Shen, Jia-Bin Cai, Zhen Yang, Jian Zhou, Jia Fan, Hui-Chuan Sun, Ming Kuang, Cheng Huang
Journal: Journal of Hematology & Oncology (2018)

This study was performed to investigate the role of nucleotide-binding oligomerization domain (NOD)-like receptor X1 (NLRX1) in regulating hepatocellular carcinoma (HCC) progression. Expression levels of NLRX1 in clinical specimens and cell lines were determined by reverse transcription-polymerase chain reaction (RT-PCR) and western blot (WB). Transwell assays were conducted to evaluate the effect of NLRX1 on cell invasion, and flow cytometry was used to assess apoptosis. Expression patterns of key molecules in the phosphoinositide 3-kinase (PI3K)-AKT pathways were determined via WB. The effect of NLRX1 on cell senescence was evaluated with β-galactosidase assays. Kaplan-Meier analyses and Cox regression models were used for prognostic evaluation. NLRX1 was downregulated in tumor tissue compared with adjacent normal liver tissue. Low tumor NLRX1 expression was identified as an independent indicator for HCC prognosis (recurrence: hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.26–2.76, overall survival [OS] 2.26, 95% CI 1.44–3.56). NLRX1 over-expression (OE) significantly inhibited invasiveness ability and induced apoptosis in HCC cells. In vivo experiments showed that NLRX1 knock-down (KD) significantly promoted HCC growth. Mechanistically, NLRX1 exhibited a suppressor function by decreasing phosphorylation of AKT and thus downregulating Snail1 expression, which inhibited epithelial-mesenchymal-transition (EMT) in HCC cells. Moreover, NLRX1 OE could induce cell senescence via an AKT-P21-dependent manner. NLRX1 acted as a tumor suppressor in HCC by inducing apoptosis, promoting senescence, and decreasing invasiveness by repressing PI3K-AKT signaling pathway. Future investigations will focus on restoring expression of NLRX1 to provide new insights into HCC treatment.
2018 update of the EULAR recommendations for the management of Behçet’s syndrome
Authors: Gulen Hatemi, Robin Christensen, Dongsik Bang, Bahram Bodaghi, Aykut Ferhat Celik, Farida Fortune, Julien Gaudric, Ahmet Gul, Ina Kötter, Pietro Leccese, Alfred Mahr, Robert Moots, Yesim Ozguler, Jutta Richter, David Saadoun, Carlo Salvarani, Francesco Scuderi, Petros P Sfikakis, Aksel Siva, Miles Stanford, Ilknur Tugal-Tutkun, Richard West, Sebahattin Yurdakul, Ignazio Olivieri, Hasan Yazici
Journal: Annals of the Rheumatic Diseases (2018)

Several new treatment modalities with different mechanisms of action have been studied in patients with Behçet's syndrome (BS). The aim of the current effort was to update the recommendations in the light of these new data under the auspices of the European League Against Rheumatism (EULAR) Standing Committee for Clinical Affairs. A task force was formed that included BS experts from different specialties including internal medicine, rheumatology, ophthalmology, dermatology, neurology, gastroenterology, oral health medicine and vascular surgery, along with a methodologist, a health professional, two patients and two fellows in charge of the systematic literature search. Research questions were determined using a Delphi approach. EULAR standardised operating procedures was used as the framework. Results of the systematic literature review were presented to the task force during a meeting. The former recommendations were modified or new recommendations were formed after thorough discussions followed by voting. The recommendations on the medical management of mucocutaneous, joint, eye, vascular, neurological and gastrointestinal involvement of BS were modified; five overarching principles and a new recommendation about the surgical management of vascular involvement were added. These updated, evidence-based recommendations are intended to help physicians caring for patients with BS. They also attempt to highlight the shortcomings of the available clinical research with the aim of proposing an agenda for further research priorities.
Serological assessment of type ΧVΙ collagen in patients with colorectal cancer and ulcerative colitis.
Authors: Christina Jensen, Signe Holm Nielsen, Joachim Høg Mortensen, Jens Kjeldsen, Lone Gabriels Klinge, Aleksander Krag, Henrik Harling, Lars N Jørgensen, Morten A Karsdal, Nicholas Willumsen
Journal: Journal of Clinical Oncology (2018)

698 Background: Altered extracellular matrix (ECM) remodeling is an important part of the pathology of gastrointestinal (GI) disorders. In the intestine, type XVI collagen (col-16) plays a role in pathogenesis by affecting ECM architecture and induce cell invasion. Measuring col-16 in serum may therefore have biomarker potential in GI disorders such as colorectal cancer (CRC) and ulcerative colitis (UC). The aim of this study was to determine whether col-16 can serve as a biomarker for altered ECM remodeling in patients with CRC and UC. Methods: A monoclonal antibody was raised against the C-terminal end of col-16 (C16-C) and a competitive enzyme-linked immunosorbent assay (ELISA) was developed and technically validated. Levels of C16-C were measured in serum from patients with CRC (before (n = 50) and three months after (n = 23) tumor resections), UC (n = 39) and healthy controls (n = 50). Results: The C16-C ELISA was specific towards the C-terminal of col-16. C16-C was significantly elevated both in serum from patients with CRC (p = 0.0026) and UC (p &lt; 0.0001) compared to controls. No difference was detected in levels of C16-C between patients with CRC at baseline and three months after tumor resections (p &gt; 0.999). Levels of C16-C identified patients with a GI disorder with a positive predictive value of 0.9 and an odds ratio of 12 (95%CI = 4.5-29.5, p &lt; 0.0001). Conclusions: The newly developed assay detected significantly elevated levels of C16-C in serum from patients with GI disorders compared to controls suggesting its potential as a biomarker in this setting. Future studies are needed to validate these findings.
Commentary: Issues in the Risk Assessment of Chromium
Authors: Roy E. Albert
Journal: Environmental Health Perspectives (1991)

Although hexavalent chromium is well established as a human carcinogen by the inhalation route, there are significant uncertainties in the quantitative estimation of cancer risk. One of the important uncertainties is the assumption that the carcinogenic potency, determined under conditions of occupational exposure where most workers were cigarette smokers, applies to the nonsmoking individual in the general population. There is substantial evidence that carcinogenicity is a function of the rate of cell turnover in the target tissue. The chromate worker would be expected to have a relatively high rate of cell proliferation in the bronchial mucosa due to airborne irritants and smoking. The potency of chromium might therefore be relatively high under conditions of occupational exposure. This problem in quantitative risk assessment applies equally well to another important indoor pollutant, radon.
Defining Impaired Respiratory Health. A Paradigm Shift for Pulmonary Medicine
Authors: Paul A. Reyfman, George R. Washko, Mark T. Dransfield, Avrum Spira, MeiLan K. Han, Ravi Kalhan
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Respiratory research has historically focused on identifying risk factors for and treatment of established lung disease. Public health approaches to common conditions, however, mandate that health promotion is a central feature of disease prevention. While smoking initiation prevention and cessation efforts are essential to respiratory health promotion, there are far fewer accepted strategies of preventative care in respiratory medicine compared with cardiovascular medicine. A key reason for this is the absence of a comprehensive body of research guiding the assessment of risk for respiratory disease as has been established for cardiovascular disease. Recent evidence provides insight into how the respiratory community can shift research priorities towards developing a definition of respiratory health spanning ideal health, impaired health, and disease. Central to defining respiratory health are the dual concepts of pulmonary reserve as reflected by peak respiratory health in young adulthood and susceptibi...