tbuckley/cabot-search huggingface dataset:
REtrieval And Cure of Hepatitis C patients in the Utrecht province in the Netherlands: REACH
Authors: P. Kracht, J.E. Arends, K.J. van Erpecum, S.F.T. Thijsen, B. Vlaminckx, A. Weersink, M. Deege, P.H.G.M. Stadhouders, P.W. Friederich, M.A.M.T. Verhagen, G. Boland, A.I.M. Hoepelman
Journal: Journal of Hepatology (2018)
Evaluating Prognosis of Patients With Acute‐On‐Chronic Liver Failure: Is the Simplest Score Good Enough?
Authors: Ângelo Zambam de Mattos, Angelo Alves de Mattos
Journal: Hepatology (2018)

Potential conflict of interest: Nothing to report. TO THE EDITOR: This letter regards a study by O'Leary et al.,1 in which authors validated in patients with or without infections the definition of acute‐on‐chronic liver failure (ACLF) previously published by the North American Consortium for the Study of End‐Stage Liver Disease (NACSELD) in a sample exclusively composed of infected individuals. The new study demonstrated that the NACSELD definition of ACLF is associated with lower 30‐day survival and suggested that it could be used as a simple prognostic tool.1 Nevertheless, we understand that this subject deserves further discussion. There is no doubt that the NACSELD definition of ACLF and the score derived from it are simpler than those proposed by the Chronic Liver Failure Consortium (CLIF‐C). On the other hand, the NACSELD definition and score are excessively restrictive, including only 10% of patients admitted for acute decompensation of cirrhosis, while the CLIF‐C definition determined the diagnosis of ACLF in over 30% of patients with cirrhosis with acute decompensation in the original cohort and in validation cohorts, such as the one recently published by us.2 Besides being more sensitive for the diagnosis of ACLF, the CLIF‐C definition is also highly associated with lower 30‐day survival rates and even with significantly lower rates than the definition proposed by the Asian Pacific Association for the Study of the Liver,3 compared to which the NACSELD definition demonstrated a tendency of superiority.1 Another issue of discussion is the suggestion to limit resources used in patients with many organ failures. We understand that evidences are scarce regarding definitions of futility of care for these patients and that general recommendations should not be made at this time.4 A recent study demonstrated similar 12‐month survival rates for transplanted patients with ACLF grade 3 according to CLIF‐C definition when compared to transplanted patients with ACLF grade ≤2 or without ACLF.5 In conclusion, despite the benefits of a simple definition of ACLF, we believe that a more comprehensive one would probably lead to better care for these extremely ill patients, enabling them to reach transplantation. Studies comparing both NACSELD and CLIF‐C definitions could bring clarity to this matter.
Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer
Authors: G.N. Hortobagyi, S.M. Stemmer, H.A. Burris, Y.S. Yap, G.S. Sonke, S. Paluch-Shimon, M. Campone, K. Petrakova, K.L. Blackwell, E.P. Winer, W. Janni, S. Verma, P. Conte, C.L. Arteaga, D.A. Cameron, S. Mondal, F. Su, M. Miller, M. Elmeliegy, C. Germa, J. O’Shaughnessy
Journal: Annals of Oncology (2018)

BackgroundThe phase III MONALEESA-2 study demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for first-line ribociclib plus letrozole versus placebo plus letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer. Here, we report updated efficacy and safety data, together with exploratory biomarker analyses, from the MONALEESA-2 study.Patients and methodsA total of 668 postmenopausal women with HR+, HER2– recurrent/metastatic breast cancer were randomized (1 : 1; stratified by presence/absence of liver and/or lung metastases) to ribociclib (600 mg/day; 3-weeks-on/1-week-off; 28-day treatment cycles) plus letrozole (2.5 mg/day; continuous) or placebo plus letrozole. The primary end point was locally assessed PFS. The key secondary end point was overall survival (OS). Other secondary end points included overall response rate (ORR) and safety. Biomarker analysis was an exploratory end point.ResultsAt the time of the second interim analysis, the median duration of follow-up was 26.4 months. Median PFS was 25.3 months [95% confidence interval (CI) 23.0–30.3] for ribociclib plus letrozole and 16.0 months (95% CI 13.4–18.2) for placebo plus letrozole (hazard ratio 0.568; 95% CI 0.457–0.704; log-rank P = 9.63 × 10−8). Ribociclib treatment benefit was maintained irrespective of PIK3CA or TP53 mutation status, total Rb, Ki67, or p16 protein expression, and CDKN2A, CCND1, or ESR1 mRNA levels. Ribociclib benefit was more pronounced in patients with wild-type versus altered receptor tyrosine kinase genes. OS data remain immature, with 116 deaths observed; 50 in the ribociclib arm and 66 in the placebo arm (hazard ratio 0.746; 95% CI 0.517–1.078). The ORR was 42.5% versus 28.7% for all patients treated with ribociclib plus letrozole versus placebo plus letrozole, respectively, and 54.5% versus 38.8%, respectively, for patients with measurable disease. Safety results, after a further 11.1 months of follow-up, were comparable with those reported at the first analysis, with no new or unexpected toxicities observed, and no evidence of cumulative toxicity.ConclusionsThe improved efficacy outcomes and manageable tolerability observed with first-line ribociclib plus letrozole are maintained with longer follow-up, relative to letrozole monotherapy.Clinical trials numberNCT01958021
Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis
Authors: Patrice Cacoub, Anne Claire Desbois, Cloe Comarmond, David Saadoun
Journal: Gut (2018)

Background and aims Extrahepatic manifestations of HCV are responsible for morbidity and mortality in many chronically infected patients. New, interferon-free antiviral treatment regimens, which present the opportunity to treat all HCV-infected patients, call for a better understanding of the benefits of treating non-cirrhotic chronically infected individuals. Methods A systematic review was conducted. Identified studies from targeted database searches on Embase and Medline were screened. The methodological quality of the included publications was evaluated. Random-effect model meta-analyses were performed. Strength of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. Results Data were extracted from a total of 48 identified studies. Achieving sustained virological response (SVR) was associated with reduced extrahepatic mortality (vs no SVR, OR 0.44 (95% CI 0.28 to 0.67)). SVR was associated with higher complete remissions in patients with cryoglobulinemia vasculitis (OR 20.76 (6.73 to 64.05)) and a higher objective response in those with malignant B-cell lymphoproliferative diseases (OR 6.49 (2.02 to 20.85)). Achieving SVR was also associated with reduced insulin resistance at follow-up (OR 0.42 (0.33 to 0.53)) and a significant protective effect on the incidence of diabetes (OR 0.34 (0.21 to 0.56)). Lack of randomised data comparing SVR versus non-SVR patients for the relevant extrahepatic indications attenuated these analyses. Conclusion Antiviral therapy can reduce extrahepatic manifestations related to HCV when SVR is achieved. Higher quality data, and reporting over longer follow-up periods, will be required to thoroughly explore comprehensive HCV treatment strategies.
The lack of improvement in liver stiffness after SVR in HCV compensated advanced chronic liver disease is associated with the risk of presenting liver related events
Authors: M.P. Delgado, J.I.E. Mur, Víctor M.V. Blasco, M.B. Ferret, R. Esteban, M.R. Barciela, B. Minguez, S. Augustin, J. Genesca
Journal: Journal of Hepatology (2018)
Girl awarded £19m after delayed blood transfusion at birth left her with brain injuries
Authors: Clare Dyer
Journal: BMJ (2018)

A nine year old girl will receive more than £19m (€22m; $26m) in compensation from the NHS after King’s College Hospital in London admitted “shortcomings” in her neonatal care.

The girl, who has not been named, was born with severe jaundice, and her lawyers claimed that the hospital negligently delayed giving her a total blood transfusion. Had this been done, they said, she would …
Effect of goal-directed fluid therapy on early cognitive function in elderly patients with spinal stenosis: A Case-Control Study
Authors: Na Zhang, Min Liang, Dan-dan Zhang, Yi-rong Xiao, Yan-zhen Li, You-guang Gao, Hong-da Cai, Xian-zhong Lin, Cai-zhu Lin, Kai Zeng, Xiao-dan Wu
Journal: International Journal of Surgery (2018)
Analysis of a Novel <i>pncA</i> Mutation for Susceptibility to Pyrazinamide Therapy
Authors: Malancha Karmakar, Maria Globan, Janet A. M. Fyfe, Timothy P. Stinear, Paul D. R. Johnson, Natasha E. Holmes, Justin T. Denholm, David B. Ascher
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

M.K. was supported by the Melbourne Research Scholarship from the University of Melbourne. D.B.A was funded by a Newton Fund RCUK-CONFAP Grant awarded by The Medical Research Council (MRC) and Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) (MR/M026302/1), the Jack Brockhoff Foundation (JBF 4186, 2016), and a C. J Martin Research Fellowship from the National Health and Medical Research Council of Australia (APP1072476).
Human skin-derived precusor cells: A potential source for cellular therapy of the liver
Authors: J.D. Kock, R.M. Rodrigues, M. Najar, L. Verhoye, O. Govaere, L. Lootens, P.V. Eenoo, N. Sanders, L. Lagneaux, G. Leroux-Roels, T. Roskams, P. Meuleman, T. Vanhaecke, V. Rogiers
Journal: Journal of Hepatology (2018)
RANKL deletion in periodontal ligament and bone lining cells blocks orthodontic tooth movement
Authors: Chia-Ying Yang, Hyeran Helen Jeon, Ahmed Alshabab, Yu Jin Lee, Chun-Hsi Chung, Dana T. Graves
Journal: International Journal of Oral Science (2018)

Abstract The bone remodeling process in response to orthodontic forces requires the activity of osteoclasts to allow teeth to move in the direction of the force applied. Receptor activator of nuclear factor-κB ligand (RANKL) is essential for this process although its cellular source in response to orthodontic forces has not been determined. Orthodontic tooth movement is considered to be an aseptic inflammatory process that is stimulated by leukocytes including T and B lymphocytes which are presumed to stimulate bone resorption. We determined whether periodontal ligament and bone lining cells were an essential source of RANKL by tamoxifen induced deletion of RANKL in which Cre recombinase was driven by a 3.2 kb reporter element of the Col1α1 gene in experimental mice (Col1α1.CreER TM + .RANKL f/f ) and compared results with littermate controls (Col1α1.CreER TM− .RANKL f/f ). By examination of Col1α1.CreER TM+ .ROSA26 reporter mice we showed tissue specificity of tamoxifen induced Cre recombinase predominantly in the periodontal ligament and bone lining cells. Surprisingly we found that most of the orthodontic tooth movement and formation of osteoclasts was blocked in the experimental mice, which also had a reduced periodontal ligament space. Thus, we demonstrate for the first time that RANKL produced by periodontal ligament and bone lining cells provide the major driving force for tooth movement and osteoclastogenesis in response to orthodontic forces.
416Investigating the role of the IL-36/IL1Rrp2 pathway in the inflammatory response of normal and aged cardiac microcirculation
Authors: D Kavanagh, G Neag, N Kalia
Journal: Cardiovascular Research (2018)

Background: Atherosclerosis development is enhanced by both local and systemic immune responses and mast cells have been shown to accumulate inside atherosclerotic plaques where these cells can degranulate and contribute to disease progression.Our research focused on pathways via which mast cells can elicit their atherogenic effects, such as by shaping the adaptive immune reaction through a direct interaction with CD4þ T-cells.In this study, we thus aimed to analyze the interplay between mast cells and CD4þ T-cells in atherosclerosis.Methods: and Results: In LDLr-/-mice fed a Western-type diet (WTD), the MHC-IIþ/ FceRIaþCD117þ mast cell population in the peritoneum increased significantly (0 wk-WTD:30.461.7%; 4 wk-WTD:52.565.9%,P¼0.01).To examine the efficacy of the MHC-II expressing mast cells in vivo, we injected i/p the Ea-peptide (1mg/mL), which is specifically presented by MHC-II molecules.After 24 hours, we detected Ea-peptide fragments on the peritoneal mast cell surface (PBS:2.360.2%;Ea:7.461.7%;P¼0.02).Interestingly, we also observed that bone marrow derived mast cells (BMMCs) treated in vitro with 10% serum of LDLr-/-mice fed a WTD diet for 4 weeks, showed enhanced MHC-II expression on their surface (chow-MCs: 3.160.3%vs WTD-MCs: 10.2560.1%,P<0.0001).To further investigate the effect of hyperlipidemia in the antigen presentation capacity of mast cells to CD4þ T-cells, we made use of the Ovalbumin presentation system by which CD4þ T-cells from genetically modified OT-II mice can specifically respond to OVA-peptide (OVAp) fragments.Therefore, we co-cultured OVAp-pretreated (10lm/mL) BMMCs under either chow or WTD serum conditions, with OT-II CD4þ T-cells, previously activated by aCD3/aCD28.The proliferation rate of CD4þ T-cells was markedly increased in the WTD condition as measured by [3H]-Thymidine incorporation, (chow-MC: 903362222 dpm compared to WTD-MC: 2533262889 dpm, P<0.0001).Conversely, the aortic CD4þ content of mast cell deficient mice on WTD, showed a reduction in ki67þ/CD4þ proliferation (apoE-/-: 30.965.2% vs apoE/KitW-sh/W-sh: 13.161.2%;P¼0.006) with a pronounced decline in the number of TH1 T-betþ/CD4þ T-cells (apoE-/-:148.4624.5 cells; apoE/KitW-sh/W-sh:45.1616.4cells, P¼0.004).Of clinical relevance, upon examination of 20 human plaques obtained by endarterectomy surgery, we observed that 18.564.4% of human mast cells express HLA-DR (the human equivalent of MHC-II) suggesting that mast cells may be capable of antigen presentation inside the human atherosclerotic plaque. Conclusion:We have increasing evidence that mast cells may function as non-classical antigen presenting cells in atherosclerosis, possibly by influencing the pro-atherogenic TH1 cells inside the plaque microenvironment.Further studies on the role of mast cells as modulators of adaptive immunity may reveal novel means to intercept atherosclerosis development.
TNFRSF19 Inhibits TGFβ Signaling through Interaction with TGFβ Receptor Type I to Promote Tumorigenesis
Authors: Chengcheng Deng, Yu-Xin Lin, Xue-Kang Qi, Gui-Ping He, Yuchen Zhang, Hao-Jiong Zhang, Miao Xu, Qi-Sheng Feng, Jin-Xin Bei, Yi-Xin Zeng, Lin Feng
Journal: Cancer Research (2018)

Abstract Genetic susceptibility underlies the pathogenesis of cancer. We and others have previously identified a novel susceptibility gene TNFRSF19, which encodes an orphan member of the TNF receptor superfamily known to be associated with nasopharyngeal carcinoma (NPC) and lung cancer risk. Here, we show that TNFRSF19 is highly expressed in NPC and is required for cell proliferation and NPC development. However, unlike most of the TNF receptors, TNFRSF19 was not involved in NFκB activation or associated with TRAF proteins. We identified TGFβ receptor type I (TβRI) as a specific binding partner for TNFRSF19. TNFRSF19 bound the kinase domain of TβRI in the cytoplasm, thereby blocking Smad2/3 association with TβRI and subsequent signal transduction. Ectopic expression of TNFRSF19 in normal epithelial cells conferred resistance to the cell-cycle block induced by TGFβ, whereas knockout of TNFRSF19 in NPC cells unleashed a potent TGFβ response characterized by upregulation of Smad2/3 phosphorylation and TGFβ target gene transcription. Furthermore, elevated TNFRSF19 expression correlated with reduced TGFβ activity and poor prognosis in patients with NPC. Our data reveal that gain of function of TNFRSF19 in NPC represents a mechanism by which tumor cells evade the growth-inhibitory action of TGFβ. Significance: TNFRSF19, a susceptibility gene for nasopharyngeal carcinoma and other cancers, functions as a potent inhibitor of the TGFβ signaling pathway. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3469/F1.large.jpg. Cancer Res; 78(13); 3469–83. ©2018 AACR.
Pro-fibrogenic mediator osteopontin is intimately involved in chronic hepatitis B and promotes cccDNA production
Authors: S. Phillips, J. Coombes, S. Mistry, M. Simonova, T. Hadzhiolova, S. Pavlova, K. Katzarov, P. Kennedy, U. Gill, T. Pereira, F.E. Pereira, R. Williams, W. Syn, S. Chokshi
Journal: Journal of Hepatology (2018)
AXL increase in NASH patients and anti-fibrotic efficacy of AXL inhibition in experimental NASH
Authors: A. Tutusaus, E.D. Gregorio, B. Cucarull, H. Cristobal, I. Graupera, G. Gausdal, A. Holmes, J. Lores, P.G. de Frutos, M. Mari, A. Morales
Journal: Journal of Hepatology (2018)
Application of patient-derived liver cancer cells for personalized treatment approach: from phenotypic characterization to therapeutic target identification
Authors: D. Castven, D. Becker, C. Czauderna, D. Wilhelm, J. Andersen, S. Strand, S. Heilmann-Heimbach, W. Roth, N. Hartmann, B. Straub, F. Mahn, S. Franck, S. Pereira, M. Hartmann, A. Haupts, A. Vogel, M.-A. Wörns, A. Weinmann, S. Heinrich, H. Lang, S. Thorgeirsson, P. Galle, J. Marquardt
Journal: Journal of Hepatology (2018)
Peroral endoscopic dual myotomy (dual POEM) for achalasia with severe esophageal dilatation
Authors: Xiang-Lei Yuan, Wei Liu, Lian-Song Ye, Ping Yan, Yu Wang, Naveed Khan, Bing Hu
Journal: Endoscopy (2018)

Although the high effectiveness of endoscopic or surgical myotomy for treating achalasia has been well recognized, persistent or recurrent symptoms may develop following the procedure [1] [2]. A review has summarized the negative predictors of myotomy for achalasia patients, which include severe preoperative dysphagia and the presence of an enlarged esophagus [3]. Subsequent reports revealed that repeated myotomy on the same side or the opposite side can be performed with positive outcomes in such patients [1] [4] [5]. Herein, we describe a peroral endoscopic dual myotomy (dual POEM) technique, in which dual myotomies are performed during a single procedure, to avoid repeat intervention for achalasia patients with negative predictors.
Association of Expectations of Training With Attrition in General Surgery Residents
Authors: Jonathan S. Abelson, Julie A. Sosa, Matthew M. Symer, Jialin Mao, Fabrizio Michelassi, Richard Bell, Art Sedrakyan, Heather L. Yeo
Journal: JAMA Surgery (2018)

Attrition from general surgery training is highest during internship. Whether the expectations and attitudes of new trainees affect their subsequent risk of attrition is unknown.To identify the expectations of general surgery residency associated with attrition from training.This prospective observational cohort study included categorical general surgery interns entering training in the 2007-2008 academic year. Residents were surveyed regarding their expectations of training and of life as an attending at the start of their intern year (June 1 to August 31, 2007). Expectations were grouped into factors by principal component analysis, and a multivariable model was created using these factors in addition to known demographic and program characteristics associated with attrition. Follow-up was completed on December 31, 2016.Attrition from training was determined by linkage to American Board of Surgery resident files through 2016, allowing 8 additional years of follow-up.Of 1048 categorical surgery interns in the study period, 870 took the survey (83.0% response rate), and 828 had complete information available for analysis (524 men [63.3%], 303 women [36.6%], and 1 missing information [0.1%]). Most were white (569 [69.1%]) and at academic programs (500 [60.4%]). Six hundred sixty-six residents (80.4%) completed training. Principal component analysis generated 6 factors. On adjusted analysis, 2 factors were associated with attrition. Interns who choose their residency based on program reputation (factor 2) were more likely to drop out (odds ratio, 1.08; 95% CI, 1.01-1.15). Interns who expected as an attending to work more than 80 hours per week, to have a stressful life, and to be the subject of malpractice litigation (career life expectation [factor 6]) were less likely to drop out (odds ratio, 0.90; 95% CI, 0.82-0.98).Interns with realistic expectations of the demands of residency and life as an attending may be more likely to complete training. Medical students and residents entering training should be given clear guidance in what to expect as a surgery resident.
An Autopsy Case of Progressive Supranuclear Palsy With Incidental <i>ATXN2</i> Expansion
Authors: Ahro Kim, Sung-Hye Park, Beomseok Jeon
Journal: JAMA Neurology (2018)

Discussion | This pilot study successfully explored the effect size of timolol eyedrops on migraine headaches.Several participants responded extremely well to the timolol.Further research is needed to determine what patient factors might predict responsiveness to timolol.Limitations.Study limitations include a small sample size, a lack of investigator masking, and an imperfect placebo, as artificial tears tend to cause less of a burning sensation than timolol.With a half-life of 4 hours, timolol ophthalmic is unlikely to have had an association with repeated headaches or beyond the 3-day washout period.Four 50-μL drops of timolol, 0.5%, represent 1 mg of timolol, which compares with an oral prophylactic dosage of 10 to 30 mg of timolol daily.Future research should aim for a target enrollment of more than 86 participants and explore optimal dosing regimens.
Bile acid monitoring to support safety and efficacy of Myrcludex B in combination with Tenofovir in patients with chronic HBV/HDV co-infection
Authors: M. Haag, U. Hofmann, T.E. Mürdter, G. Heinkele, A. Blank, W.-E. Haefeli, H. Wedemeyer, P. Bogomolov, A. Alexandrov, K. Schöneweis, S. Urban, M. Schwab
Journal: Journal of Hepatology (2018)
Abstract 17212: High Levels of LDL-C, apoB, and non-HDL-C in Patients With Coronary Microvascular Dysfunction
Authors: Hiroshi Takahashi, Shigemasa Tani, Kimio Kikushima, Shingo Furuya, Takehiko Washio, Shinichirou Niizuma, Kenji Kawauchi, Masashi Kobori, Masakazu Matsuzaki, Tadashi Ashida, Naoya Matsumoto
Journal: Circulation (2016)

Introduction: Patients with coronary microvascular dysfunction (CMD) reportedly have high rates of major adverse outcomes, such as death, myocardial infarction, and congestive heart failure. Howeve...