tbuckley/cabot-search huggingface dataset:
Quantification of Long-term Survival Benefit in a Comparative Oncology Clinical Study
Authors: Miki Horiguchi, Lu Tian, Hajime Uno, SuChun Cheng, Dae Hyun Kim, Deb Schrag, Lee-Jen Wei
Journal: JAMA Oncology (2018)

This study compares conventional hazard ratios and an alternative, clinically interpretable approach to quantify the long-term survival benefit in patients receiving chemotherapy with immunotherapy.
A High Menaquinone but Not Phylloquinone Intake Reduces the Incidence of Coronary Heart Disease in Women
Authors: G.C.M. Gast, N.M. de Roos, I. van der Sluijs, M.L. Bots, J.W.J. Beulens, J.M. Geleijnse, J.C. Witteman, D.E. Grobbee, P.H.M. Peeters, Y.T. van der Schouw
Journal: Circulation (2008)
Clinical Utility of Next‐generation Sequencing in the Management of Myeloproliferative Neoplasms: A Single‐Center Experience
Authors: Waleed Alduaij, Caroline J. McNamara, Andre Schuh, Andrea Arruda, Mahadeo Sukhai, Nisha Kanwar, Mariam Thomas, Jay Spiegel, James A. Kennedy, Tracy Stockley, Hubert Tsui, Rebecca Devlin, Hassan Sibai, Dawn Maze, Aaron Schimmer, Karen Yee, Steven Chan, Suzanne Kamel‐Reid, Vikas Gupta
Journal: HemaSphere (2018)

Although next-generation sequencing (NGS) has helped characterize the complex genomic landscape of myeloid malignancies, its clinical utility remains undefined. This has resulted in variable funding for NGS testing, limiting its accessibility. At our center, targeted sequencing (TAR-SEQ) using a 54-gene NGS myeloid panel is offered to all new patients referred for myeloid malignancies, as part of a prospective observational study. Here, we evaluated the diagnostic, prognostic, and potential therapeutic utility of clinical grade TAR-SEQ in the routine workflow of 179 patients with myeloproliferative neoplasms (MPN). Of 13 patients with triple negative (TN) MPN, who lacked driver mutations in JAK2, CALR, and MPL, TAR-SEQ confirmed clonal hematopoiesis in 8 patients. In patients with intermediate-risk myelofibrosis (MF), TAR-SEQ helped optimize clinical decisions in hematopoietic cell transplant (HCT)-eligible patients through identifying a high molecular risk (HMR) mutation profile. The presence of an HMR profile favored HCT in 9 patients with intermediate-1 risk MF. Absence of an HMR profile resulted in a delayed HCT strategy in 10 patients with intermediate-2 risk MF, 7 of which were stable at the last follow-up. Finally, TAR-SEQ identified patients with various targetable mutations in IDH1/2 (4%), spliceosome genes (28%), and EZH2 (7%). Some of these patients can be potential candidates for future targeted therapy trials. In conclusion, we have demonstrated that TAR-SEQ improves the characterization of TN MPN, can be integrated in clinical practice as an additional tool to refine decision making in HCT, and has the potential to identify candidates for future targeted therapy trials.
Clinical phase 1b study results for safety, pharmacokinetics and efficacy of ND-L02-s0201, a novel targeted lipid nanoparticle delivering HSP47 SIRNA for the treatment of Japanese patients with advanced liver fibrosis
Authors: N. Sakamoto, K. Ogawa, G. Suda, K. Morikawa, T. Sho, M. Nakai, H. Suzuki, N. Yamagata, Y. Tanaka, W. Ying, Y. Tamura, Y. Niitsu, K. Maruyama
Journal: Journal of Hepatology (2018)
Reliability criteria for liver stiffness measurement with ARFI
Authors: J. Boursier, C. Cassinotto, L. Adrien, S. Shili, J. Lebigot, B. Lapuyade, P. Cales, H. Jean-Baptiste, S. Michalak, B. Le Bail, V. Cartier, A. Mouries, F. Oberti, I.F. Hubert, F. Chermak, C. Aubé, V.D. Ledinghen
Journal: Journal of Hepatology (2018)
Metabolic Syndrome and Neurocognition Among Diverse Middle-Aged and Older Hispanics/Latinos: HCHS/SOL Results
Authors: Hector M. González, Wassim Tarraf, Priscilla Vásquez, Ashley H. Sanderlin, Natalya I. Rosenberg, Sonia Davis, Carlos J. Rodríguez, Linda C. Gallo, Bharat Thyagarajan, Martha Daviglus, Tasneem Khambaty, Jianwen Cai, Neil Schneiderman
Journal: Diabetes Care (2018)

Hispanics/Latinos have the highest risks for metabolic syndrome (MetS) in the U.S. and are also at increased risk for Alzheimer disease. In this study, we examined associations among neurocognitive function, MetS, and inflammation among diverse middle-aged and older Hispanics/Latinos.Cross-sectional data (2008-2011) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) were analyzed to examine associations between neurocognition and MetS among diverse Hispanics/Latinos (N = 9,136; aged 45-74 years).MetS status was associated with lower global neurocognition, mental status, verbal learning and memory, verbal fluency, and executive function. Age significantly modified the associations between MetS and learning and memory measures. Significant associations between MetS and neurocognition were observed among middle-aged Hispanics/Latinos, and all associations remained robust to additional covariates adjustment.We found that MetS was associated with lower neurocognitive function, particularly in midlife. Our findings support and extend current hypotheses that midlife may be a particularly vulnerable developmental period for unhealthy neurocognitive aging.
Necroptosis signalling pathway in hepatic fibrosis; role of receptor-interacting serine-threonine kinase 3 and mixed lineage kinase domain-like in cirrhosis
Authors: W. Saeed, D.W. Jun, E. Kim, B.-K. Kang, J.Y. Jeong, S.B. Ahn, M.M. Kim, H. Oh, K.S. Jang, E.C.J. Jang, J.H. Sohn
Journal: Journal of Hepatology (2018)
Self-Renewal and Toll-like Receptor Signaling Sustain Exhausted Plasmacytoid Dendritic Cells during Chronic Viral Infection
Authors: Monica Macal, Yeara Jo, Simone Dallari, Aaron Y. Chang, Jihong Dai, Shobha Swaminathan, Ellen J. Wehrens, Patricia Fitzgerald-Bocarsly, Elina I. Zúñiga
Journal: Immunity (2018)
Regional variations in the development of acute-on-chronic liver failure (ACLF) in patients with cirrhosis and bacterial infections
Authors: F. Wong, V. Singh, P. Caraceni, R. Maiwall, S. Piano, S. Marciano, J. Fernandez, C. Alessandria, E. Soares, D.J. Kim, S.E. Kim, M. Marino, J. Vorobioff, R. de Cassia Ribeiro Barea, M. Merli, L. Elkrief, V. Manuel, V. Blasco, A. Krag, S. Singh, L.A. Lesmana, C. Toledo, V. Xavier, N. Intagliata, L. Rabinowich, T. Bruns, E.L. Yoon, M. Girala, N.T. Pyrsopoulos, T.H. Kim, S.Y. Yim, F. Durand, A. Gadano, P. Angeli
Journal: Journal of Hepatology (2018)
Pituitary Diseases and Bone
Authors: Gherardo Mazziotti, Stefano Frara, Andrea Giustina
Journal: Endocrine Reviews (2018)

Neuroendocrinology of bone is a new area of research based on the evidence that pituitary hormones may directly modulate bone remodeling and metabolism. Skeletal fragility associated with high risk of fractures is a common complication of several pituitary diseases such as hypopituitarism, Cushing disease, acromegaly, and hyperprolactinemia. As in other forms of secondary osteoporosis, pituitary diseases generally affect bone quality more than bone quantity, and fractures may occur even in the presence of normal or low-normal bone mineral density as measured by dual-energy X-ray absorptiometry, making difficult the prediction of fractures in these clinical settings. Treatment of pituitary hormone excess and deficiency generally improves skeletal health, although some patients remain at high risk of fractures, and treatment with bone-active drugs may become mandatory. The aim of this review is to discuss the physiological, pathophysiological, and clinical insights of bone involvement in pituitary diseases.
Repurposing rosiglitazone, a PPAR-γ agonist and oral antidiabetic, as an inhaled formulation, for the treatment of PAH
Authors: Jahidur Rashid, Ahmad Alobaida, Taslim A. Al-Hilal, Samia Hammouda, Ivan F. McMurtry, Eva Nozik-Grayck, Kurt R. Stenmark, Fakhrul Ahsan
Journal: Journal of Controlled Release (2018)
Complement C3 Drives Autophagy-Dependent Restriction of Cyto-invasive Bacteria
Authors: Matthew T. Sorbara, Elisabeth G. Foerster, Jessica Tsalikis, Mena Abdel-Nour, Joseph Mangiapane, Imogen Sirluck-Schroeder, Ivan Tattoli, Rob van Dalen, David E. Isenman, John R. Rohde, Stephen E. Girardin, Dana J. Philpott
Journal: Cell Host & Microbe (2018)
Arginase 2 Suppresses Renal Carcinoma Progression via Biosynthetic Cofactor Pyridoxal Phosphate Depletion and Increased Polyamine Toxicity
Authors: Joshua D. Ochocki, Sanika Khare, Markus Hess, Daniel Ackerman, Bo Qiu, Jennie I. Daisak, Andrew J. Worth, Nan Lin, Pearl Lee, Hong Xie, Bo Li, Bradley Wubbenhorst, Tobi G. Maguire, Katherine L. Nathanson, James C. Alwine, Ian A. Blair, Itzhak Nissim, Brian Keith, M. Celeste Simon
Journal: Cell Metabolism (2018)
Association between use of systematic reviews and national policy recommendations on screening newborn babies for rare diseases: systematic review and meta-analysis
Authors: Sian Taylor-Phillips, Chris Stinton, Lavinia Ferrante di Ruffano, Farah Seedat, Aileen Clarke, Jonathan J Deeks
Journal: BMJ (2018)

Abstract Objective To understand whether international differences in recommendations of whether to screen for rare diseases using the newborn blood spot test might in part be explained by use of systematic review methods. Design Systematic review and meta-analysis. Data sources Website searches of 26 national screening organisations. Eligibility criteria for study selection Journal articles, papers, legal documents, presentations, conference abstracts, or reports relating to a national recommendation on whether to screen for any condition using the newborn blood spot test, with no restrictions on date or language. Data extraction Two reviewers independently assessed whether the recommendation for or against screening included systematic reviews, and data on test accuracy, benefits of early detection, and potential harms of overdiagnosis. Analysis The odds of recommending screening according to the use of systematic review methods was estimated across conditions using meta-analysis. Results 93 reports were included that assessed 104 conditions across 14 countries, totalling 276 recommendations (units of analysis). Screening was favoured in 159 (58%) recommendations, not favoured in 98 (36%), and not recommended either way in 19 (7%). Only 60 (22%) of the recommendations included a systematic review. Use of a systematic review was associated with a reduced probability of screening being recommended (23/60 (38%) v 136/216 (63%), odds ratio 0.17, 95% confidence interval 0.07 to 0.43). Of the recommendations, evidence for test accuracy, benefits of early detection, and overdiagnosis was not considered in 115 (42%), 83 (30%), and 211 (76%), respectively. Conclusions Using systematic review methods is associated with a reduced probability of screening being recommended. Many national policy reviews of screening for rare conditions using the newborn blood spot test do not assess the evidence on the key benefits and harms of screening.
403Induction of interferon-related genes limits the cardiotoxicity of liposomal doxorubicin in pigs
Authors: D Lukovic, K Zlabinger, A Spannbauer, A Gugerell, N Pavo, D Traxler, A Jakab, J Bergler-Klein, M Gyongyosi, J Winkler
Journal: Cardiovascular Research (2018)

Introduction:The most common pathological change in critical illness is multiple organ failure, including cardiac complications, which often leads to early death.However, the underlying molecular mechanisms are not fully understood.Recently, the secondary hit by circulating histones causes great attention.Method: Both septic animal models and patients with sepsis were investigated.Circulating histones were detected and their association with organ injury markers was analyzed.Intervention with anti-histone antibodies was carried out to confirm the cause-effect relationship.Results: Circulating histones were dramatically elevated in both animal models and septic patients.Their levels were strongly associated with the severity of organ injury, particularly cardiac injury marker, cardiac troponins.Using anti-histone scFv in mouse models could significantly reduce the release of cardiac troponins as well as the incidence of the cardiac arrhythmia, and cardiac failure induced by histone infusion or sepsis.In addition, histones binding prothrombin initialized coagulation and significantly contribute to dysregulated coagulation leading to disseminated intravascular coagulation (DIC) and microcirculation impairment.Conclusion: Circulating histones play critical roles in sepsis, including inflammation, coagulation activation, and multiple organ injury, particularly cardiac complications.This lays a foundation for future anti-histone intervention to reduce the unacceptably high mortality rates of sepsis.
An Antibody Targeting the Fusion Machinery Neutralizes Dual-Tropic Infection and Defines a Site of Vulnerability on Epstein-Barr Virus
Authors: Joost Snijder, Michael S. Ortego, Connor Weidle, Andrew B. Stuart, Matthew D. Gray, M. Juliana McElrath, Marie Pancera, David Veesler, Andrew T. McGuire
Journal: Immunity (2018)
Insulin regulates astrocyte gliotransmission and modulates behavior
Authors: Weikang Cai, Chang Xue, Masaji Sakaguchi, Masahiro Konishi, Alireza Shirazian, Heather A. Ferris, Mengyao E. Li, Ruichao Yu, Andre Kleinridders, Emmanuel N. Pothos, C. Ronald Kahn
Journal: Journal of Clinical Investigation (2018)

Complications of diabetes affect tissues throughout the body, including the central nervous system. Epidemiological studies show that diabetic patients have an increased risk of depression, anxiety, age-related cognitive decline, and Alzheimer's disease. Mice lacking insulin receptor (IR) in the brain or on hypothalamic neurons display an array of metabolic abnormalities; however, the role of insulin action on astrocytes and neurobehaviors remains less well studied. Here, we demonstrate that astrocytes are a direct insulin target in the brain and that knockout of IR on astrocytes causes increased anxiety- and depressive-like behaviors in mice. This can be reproduced in part by deletion of IR on astrocytes in the nucleus accumbens. At a molecular level, loss of insulin signaling in astrocytes impaired tyrosine phosphorylation of Munc18c. This led to decreased exocytosis of ATP from astrocytes, resulting in decreased purinergic signaling on dopaminergic neurons. These reductions contributed to decreased dopamine release from brain slices. Central administration of ATP analogs could reverse depressive-like behaviors in mice with astrocyte IR knockout. Thus, astrocytic insulin signaling plays an important role in dopaminergic signaling, providing a potential mechanism by which astrocytic insulin action may contribute to increased rates of depression in people with diabetes, obesity, and other insulin-resistant states.
Angiopoietin-2 as therapeutic target for pathological angiogenesis and inflammation in non-alcoholic steatohepatitis
Authors: S. Lefere, F. Van de Velde, S. Raevens, S. Van Campenhout, A. Vandierendonck, S. Neyt, C. Vanhove, A. Hoorens, C. Casteleyn, X. Verhelst, H. Van Vlierberghe, B. Lapauw, A. Geerts, L. Devisscher
Journal: Journal of Hepatology (2018)
Recommendations for the Evaluation for Autoimmune Liver Disease in Nonalcoholic Fatty Liver Disease
Authors: Donelle Cummings, Richard Ferstenberg
Journal: Hepatology (2018)

To the Editor We read with interest the article published by Chalisani et al.(1) These Guidelines provide clarity for the diagnosis and management of NAFLD. However, we feel that routine diagnosis of nonalcoholic fatty liver disease (NAFLD) can be simplified. As highlighted by the Guidelines, clinicians must explore common alternative causes when evaluating a patient with mild liver function abnormalities and risk factors for metabolic syndrome.(1) These include excessive alcohol intake, hepatitis B and C viral infection, medications, hemochromatosis, and Wilson's disease.(1) Workup often involves evaluation for autoantibodies to exclude autoimmune hepatitis (AIH). Current evidence demonstrates that autoantibodies, including ANA and anti‐SMA, can be detected in up to one third of patients with NAFLD.(2) Of note, the presence or absence of autoantibodies is not related to the degree of fibrosis found on liver biopsy.(3) Ravi et al. have shown that autoimmune markers in NAFLD do not influence the natural history or disease course.(5) In Adams' study, 225 patients with suspected NAFLD underwent liver biopsy.(4) Only 1 patient met diagnostic criteria for AIH according to the criteria of the International Autoimmune Hepatitis Group. It therefore seems that ordering autoantibody studies is not helpful for diagnosing NAFLD. Imaging studies, such as ultrasound, are part of the workup of patients with liver function tests less than 2‐3 times the upper limit of normal (ULN). However, the role of imaging is not explored in the literature discussing the role of autoimmune markers in NAFLD. We propose that the workup of suspected NAFLD include hepatitis B antigen, hepatitis C antibody, iron studies, total iron‐binding capacity, and abdominal ultrasound. Antimitochondrial antibodies may be added when alkaline phosphatase is elevated. These tests are likely to support or refute the diagnosis of NAFLD in virtually every case. Patients with suspected AIH requiring treatment will likely have symptoms and/or liver function tests several times above the ULN. A request for autoimmune markers can be limited to patients with these more specific findings. Potential conflict of interest Nothing to report.
Predictors of HBeAg loss and seroconversion by baseline clinical features and viral deep sequencing after 144 weeks of treatment with Tenofovir Alafenamide or Tenofovir Disoproxil Fumarate
Authors: Y.-S. Lim, None Shalimar, X. MA, A. Shukla, H.N. Trinh, P. Andreone, J.-S. Hwang, V. Suri, G. Wu, A. Gaggar, J.F. Flaherty, W.-C. Chow, P. Marcellin, N. Izumi
Journal: Journal of Hepatology (2018)
TCTAP A-078 Subclinical Leaflet Thrombosis in Transcatheter and Surgical Bioprosthetic Aortic Valve Detected by Multidetector Computed Tomography Is Associated with Adverse Cerebrovascular Events: A Meta-analysis of Observational Studies
Authors: Hashrul Rashid, Ameera Amiruddin, Abdul Rahman Ihdayhid, Liam McCormick, Nitesh Nerlekar, Arthur Nasis, James Cameron, Robert Gooley, Adam Brown
Journal: Journal of the American College of Cardiology (2018)
Abstract 15414: Cardiac Dyssynchrony and Strain Do Not Predict Deterioration of Ventricular Function in Patients With Repaired Tetralogy of Fallot
Authors: Linyuan Jing, Jonathan D Suever, Richard J Charnigo, Sudad Alhadad, Evan Stearns, Dimitri Mojsejenko, Christopher M Haggerty, Kelsey Hickey, Anne M Valente, Tal Geva, Andrew J Powell, Brandon K Fornwalt
Journal: Circulation (2015)

Objectives: Patients with repaired tetralogy of Fallot (rTOF) suffer from progressive ventricular dysfunction decades after their initial surgical repair. This study sought to determine whether measures of ventricular strain and dyssynchrony could predict deterioration of ventricular function in patients with rTOF. Methods: A database search identified all patients at a single institution with rTOF who underwent cardiac magnetic resonance (CMR) at least twice, greater than 6 months apart, without intervening surgical or catheter procedures. Five primary potential predictors were derived from the first CMR using a custom feature tracking algorithm: left (LV), right (RV) and inter-ventricular dyssynchrony, and LV and RV peak circumferential strains. Three outcomes were defined as measures of progression over time: RV end-diastolic volume, RV ejection fraction (EF), and LV EF. A multivariate linear mixed model, subject to backward elimination of extraneous terms, was fit to investigate relationships between predictors and outcomes. Ten potential confounders (see table footnote) measured at baseline were also included in the model. Results: A cohort of 153 patients with rTOF (23±14 years, 50% male) were included. The mean time between the first and last CMR was 2.9±1.3 years. None of the 5 primary predictors were significantly associated with change over time in the 3 outcomes in the multivariate model, though RV circumferential strain was associated with RV EF at baseline (table). Only 1-16% of the variability in the change over time in the 3 outcomes could be explained by the predictors in the multivariate model. Conclusions: In patients with rTOF, measures of ventricular dyssynchrony and strain were not significantly related to changes in ventricular size and function over time in a multivariate analysis. The ability to predict deterioration in ventricular function using all potential predictors is limited.
Prognostic Significance of Nuisance Bleeding in Anticoagulated Patients With Atrial Fibrillation
Authors: Emily C. O’Brien, DaJuanicia N. Holmes, Laine E. Thomas, Gregg C. Fonarow, Larry A. Allen, Bernard J. Gersh, Peter R. Kowey, Daniel E. Singer, Michael D. Ezekowitz, Gerald V. Naccarelli, Jack E. Ansell, Paul S. Chan, Kenneth W. Mahaffey, Alan S. Go, James V. Freeman, James A. Reiffel, Eric D. Peterson, Jonathan P. Piccini, Elaine M. Hylek
Journal: Circulation (2018)

Bleeding is commonly cited as a reason for stopping oral anticoagulants (OACs). Whether minor bleeding events (nuisance bleeding, NB) in patients with atrial fibrillation on OACs are associated with OAC discontinuation, major bleeding, and stroke/systemic embolism (SSE) is unknown.Within the ORBIT-AF prospective, outpatient registry (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation), we identified 6771 patients ≥18 years of age at 172 sites with atrial fibrillation and eligible follow-up visits. NB was ascertained from the medical record and was defined as minor bleeding that did not require medical attention (eg, bruising, hemorrhoidal bleeding). We used multivariable pooled logistic regression modeling to evaluate the associations between NB and major bleeding and SSE in the 180 days after documentation of NB. Our unit of analysis was the patient visit, occurring at ≈6-month intervals for a median of 1.5 years following enrollment. Changes in anticoagulation treatment satisfaction after NB were examined descriptively in a subset of patients.The median age of the overall population was 75.0 (interquartile range, 67.0-81.0); 90.0% were white and 42.5% were female. Among 6771 patients (18 560 visits), n=1357 (20.0%) had documented NB, for an incidence rate of 14.8 events per 100 person-years. Over 96.4% of patients remained on OAC therapy after the NB event. Overall, 287 (4.3%) patients experienced major bleeding and 64 (0.96%) had a SSE event during follow-up. NB was not associated with a significant increased risk of major bleeding over 6 months in models adjusting for the ATRIA bleeding score (Anticoagulation and Risk Factors in Atrial Fibrillation) (odds ratio, 1.04; 95% confidence interval, 0.68-1.60; P=0.86). NB was also not associated with increased SSE risk over 6 months in models adjusting for the CHA2DS2-VASc risk score (odds ratio, 1.24; 95% confidence interval, 0.53-2.91; P=0.62).NB is common among patients with atrial fibrillation on OACs. However, NB was not associated with a higher risk of major bleeding or SSE over the next 6 months, suggesting its occurrence should not lead to changes in anticoagulation treatment strategies in OAC-treated patients.URL: https://www.clinicaltrials.gov . Unique identifier: NCT01165710.
FDA launches criminal investigation of unauthorised herpes vaccine trial
Authors: Owen Dyer
Journal: BMJ (2018)

The US Food and Drug Administration has launched a criminal investigation into a herpes vaccine trial carried out by a microbiologist who injected participants with his experimental live herpes simplex virus (HSV-2) vaccine in Illinois hotel rooms, with no apparent safety oversight, consent forms, or ethics approval.

The vaccine’s creator, William Halford, of Southern Illinois University, who performed the hotel room injections, died from cancer last June aged 48. But four FDA sources told Kaiser Health News1 that the drug agency’s Office of Criminal Investigations is looking into whether anyone else from the university or from Halford’s company, Rational Vaccines, broke laws or FDA rules in helping him.

Rational Vaccines …