tbuckley/cabot-search huggingface dataset:
USEFULNESS AND SAFETY OF ACETYLCHOLINE PROVOCATION TEST IN PATIENTS WITH NO CULPRIT LESIONS IN EMERGENCY CORONARY ANGIOGRAPHY
Authors: Kazuya Tateishi, Hideki Kitahara, Yuichi Saitoh, Tadayuki Kadihira, Takashi Nakayama, Yoshihide Fujimoto, Yoshio Kobayashi
Journal: Journal of the American College of Cardiology (2018)
Degenerative cervical myelopathy
Authors: Benjamin M Davies, Oliver D Mowforth, Emma K Smith, Mark RN Kotter
Journal: BMJ (2018)

### What you need to know A 54 year old man presents with neck stiffness for about a year. He complains of numbness in his fingers and difficulty buttoning up his shirt, which has not improved following surgery for carpal tunnel syndrome. Of late, he has experienced unsteadiness and has started to use a walking stick after sustaining falls. He sees a neurologist who identifies hyperreflexia in his arms and legs. An MRI scan shows multilevel cervical spondylosis and disc herniation causing cord compression. He is diagnosed with degenerative cervical myelopathy and referred to spinal surgery for operative decompression. Degenerative cervical myelopathy (DCM), earlier referred to as cervical spondylotic myelopathy, involves spinal cord dysfunction from compression in the neck.1 Patients report neurological symptoms such as pain and numbness in limbs, poor coordination, imbalance, and bladder problems. Owing to its mobility, the vertebral column of the neck is particularly prone to degenerative changes such as disc herniation, ligament hypertrophy or ossification, and osteophyte formation. These changes are more common with age2 (box 1) and are often collectively termed spondylosis (fig 1).3 Box 1 ### How common is it? The epidemiology of DCM is poorly understood, in part because of the difficulties in diagnosis.3RETURN TO TEXT
Foundation trainees could face prescribing test
Authors: Caroline White
Journal: BMJ (2013)

Foundation year 1 trainees may have to take an additional test to assess their prescribing skills, under proposals being developed jointly by the Medical Schools Council and the British Pharmacological Society.1

The two bodies are working on a formal prescribing skills assessment, which would test core competencies in the safe and effective use of drugs, in line with the requirements set out in the General Medical Council’s 2009 document …
U.S. Food and Drug Administration Approval: Neratinib for the Extended Adjuvant Treatment of Early-Stage HER2-Positive Breast Cancer
Authors: Harpreet Singh, Amanda J. Walker, Laleh Amiri-Kordestani, Joyce Cheng, Shenghui Tang, Pamela Balcazar, Kimberly Barnett-Ringgold, Todd R. Palmby, Xianhua Cao, Nan Zheng, Qi Liu, Jingyu Yu, William F. Pierce, Selena R. Daniels, Rajeshwari Sridhara, Amna Ibrahim, Paul G. Kluetz, Gideon M. Blumenthal, Julia A. Beaver, Richard Pazdur
Journal: Clinical Cancer Research (2018)

On July 17, 2017, the FDA approved neratinib (NERLYNX; Puma Biotechnology, Inc.) for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy. Approval was based on data from ExteNET, a randomized, double-blind, placebo-controlled multicenter trial. Women with early-stage HER2-positive breast cancer and within 2 years of completing adjuvant trastuzumab were randomized to neratinib (n = 1,420) or placebo (n = 1,420) for 1 year. The primary endpoint was invasive disease-free survival (iDFS), defined as the time between randomization date to first occurrence of invasive recurrence (local/regional, ipsilateral, or contralateral breast cancer), distant recurrence, or death from any cause, with 2 years and 28 days of follow-up. The trial showed a statistically significant treatment effect favoring neratinib with a stratified HR of 0.66 [95% confidence interval (CI), 0.49-0.90, P = 0.008]. The estimated iDFS rate at 2 years was 94.2% (95% CI, 92.6%-95.4%) in patients treated with neratinib versus 91.9% (95% CI, 90.2%-93.2%) in those receiving placebo. Diarrhea was the most common adverse event (AE), with a 40% incidence of grade 3 or 4 diarrhea, and represents the most common AE leading to treatment discontinuation. Other frequent AEs (>10% incidence) were nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, and muscle spasms. Other than diarrhea, neratinib is associated with a low incidence of severe AEs; toxicities are generally reversible and manageable with dose interruptions, dose reductions, and/or standard medical care. This article summarizes FDA decision-making and data supporting the neratinib approval. Clin Cancer Res; 24(15); 3486-91. ©2018 AACRSee related commentary by Unni et al., p. 3483.
PRIOR BALLOON VALVULOPLASTY VERSUS DIRECT TRANSCATHETER AORTIC VALVE IMPLANTATION (DIRECTAVI): PRELIMINARY FINDINGS ON THE FIRST 128 RANDOMIZED PATIENTS
Authors: Pierre Robert, Jean-Christophe Macia, Bernard Albat, Benoit Lattuca, Jessica Labour, Mariama Akodad, Thomas Gandet, Laurent Schmutz, Delphine Delseny, Eric Maupas, Christophe Piot, Frédéric Targosz, Gabriel Robert, Guillaume Cayla, Florence Leclercq
Journal: Journal of the American College of Cardiology (2018)
Sofosbuvir/velpatasvir for 12 weeks in genotype 1–4 HCV-infected liver transplant recipients
Authors: Kosh Agarwal, Lluís Castells, Beat Müllhaupt, William M.C. Rosenberg, Brian McNabb, Sarah Arterburn, Gregory Camus, John McNally, Luisa M. Stamm, Diana M. Brainard, G. Mani Subramanian, Zoe Mariño, Jean-François Dufour, Xavier Forns
Journal: Journal of Hepatology (2018)
Immunohistochemical and Image Analysis-Based Study Shows That Several Immune Checkpoints are Co-expressed in Non–Small Cell Lung Carcinoma Tumors
Authors: Edwin Roger Parra, Pamela Villalobos, Jiexin Zhang, Carmen Behrens, Barbara Mino, Stephen Swisher, Boris Sepesi, Annika Weissferdt, Neda Kalhor, John Victor Heymach, Cesar Moran, Jianjun Zhang, Jack Lee, Jaime Rodriguez-Canales, Don Gibbons, Ignacio I. Wistuba
Journal: Journal of Thoracic Oncology (2018)
I'd like to do my F2 year abroad. Is this possible?
Authors: Derek Galle
Journal: BMJ (2006)

Have a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site. <b>www.bmjcareers.com/advicezone</b>
miR-190 suppresses breast cancer metastasis by regulation of TGF-β-induced epithelial–mesenchymal transition
Authors: Yue Yu, Wei Luo, Zheng-Jun Yang, Jiang-Rui Chi, Yun-Rui Li, Yu Ding, Jie Ge, Xin Wang, Xu-Chen Cao
Journal: Molecular Cancer (2018)

Breast cancer is the most common cancer among women worldwide and metastasis is the leading cause of death among patients with breast cancer. The transforming growth factor-β (TGF-β) pathway plays critical roles during breast cancer epithelial–mesenchymal transition (EMT) and metastasis. SMAD2, a positive regulator of TGF-β signaling, promotes breast cancer metastasis through induction of EMT. The expression of miR-190 and SMAD2 in breast cancer tissues, adjacent normal breast tissues and cell lines were determined by RT-qPCR. The protein expression levels and localization were analyzed by western blotting and immunofluorescence. ChIP and dual-luciferase report assays were used to validate the regulation of ZEB1-miR-190-SMAD2 axis. The effect of miR-190 on breast cancer progression was investigated both in vitro and in vivo. miR-190 down-regulation is required for TGF-β-induced EMT. miR-190 suppresses breast cancer metastasis both in vitro and in vivo by targeting SMAD2. miR-190 expression is down-regulated and inversely correlates with SMAD2 in breast cancer samples, and its expression level was associated with outcome in patients with breast cancer. Furthermore, miR-190 is transcriptionally regulated by ZEB1. Our data uncover the ZEB1-miR-190-SMAD2 axis and provide a mechanism to explain the TGF-β network in breast cancer metastasis.
FDG PET/CT Findings in a Localized Reactive Lymphoid Hyperplasia of the Spleen
Authors: Yoshiaki Ito, Tadaki Nakahara, Yuichi Nishihara, Junichi Shiraishi, Masahiro Jinzaki
Journal: Clinical Nuclear Medicine (2018)

Abstract A 38-year-old man with sigmoid colon cancer underwent a preoperative contrast-enhanced CT which incidentally revealed a modestly enhancing splenic mass. FDG PET/CT showed mildly increased uptake in the splenic lesion in contrast to prominently increased uptake in the colonic tumor. In addition, the splenic mass demonstrated only slightly increased signal intensity in diffusion-weighted MRI, suggesting low probability of metastasis. Splenectomy nonetheless was performed at surgery of the colon cancer. The histopathologic examination showed aggregated lymphoid follicles with germinal centers in the splenic lesion and made the diagnosis of localized reactive lymphoid hyperplasia a rare benign lymphoid tumor.
Abstract P3-04-08: Genomic analysis of breast papillomas
Authors: KJ Elder, T Kader, P Hill, K Opeskin, DL Goode, J-M Pang, SB Fox, GB Mann, IG Campbell, KL Gorringe
Journal: Cancer Research (2018)

Abstract Background: Papillomas are often found co-existing with breast carcinoma yet they are not considered to be a true precursor of the disease. Previous studies have shown that some cases may carry copy number alterations (CNA) or mutations in AKT1/PIK3CA (Troxell et al., 2010, Modern Pathology 23: 27-37) suggesting this lesion may have malignant potential. To date, a detailed study of both pure papillomas (not associated with cancer) and those seen in the same breast as a carcinoma has not been undertaken. Therefore, we set out to investigate the molecular changes associated with this lesion and whether papillomas can be clonally related to synchronous breast carcinoma. Method: Papilloma cases were identified from a hospital database and independently reviewed by consultant pathologists followed by micro-dissection of formalin-fixed paraffin-embedded tumour tissue and DNA extraction. For CNA detection either Affymetrix Molecular inversion Probe (MIP) 330K arrays were used or low-coverage whole genome sequencing using 5-10 ng of DNA (Kader et al., 2016, Genome Medicine 8: 121) where there was insufficient DNA for MIP arrays. We applied either of these 2 methods to 24 cases of pure papilloma as well as 20 papilloma with synchronous ductal carcinoma in situ (DCIS) and/or invasive ductal carcinoma (IDC). Additionally, targeted exon sequencing of breast cancer driver genes was performed for a subset of cases. Results: Among the pure papillomas 31% (5/16) showed CN change with, the most frequent change being 16q loss (2/16). Of the papillomas synchronous with DCIS/IDC analysed to date, 2/5 were shown to be clonal with the co-existing carcinoma. Final CNA analysis will be presented for 24 pure papilloma cases and 20 synchronous cases. Targeted sequencing revealed that all for pure papillomas analysed to date harboured somatic mutations in PIK3CA (3/4 cases) and PIK3R1 (1/4,) suggesting that most papillomas are driven by alterations in the PI3-kinase/AKT pathway. The final sequencing data to be presented will include an additional 5 pure papillomas and 10 synchronous cases. Conclusion: Our observation that 40% of papillomas are clonal to breast carcinoma suggests that DCIS or IDC can arise from a common ancestor as co-existing papillomas, however, most papillomas co-existing with carcinoma are likely to be independent in our cohort. Citation Format: Elder KJ, Kader T, Hill P, Opeskin K, Goode DL, Pang J-M, Fox SB, Mann GB, Campbell IG, Gorringe KL. Genomic analysis of breast papillomas [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-04-08.
OnabotulinumtoxinA: A Review in the Prevention of Chronic Migraine
Authors: James E. Frampton, Stephen Silberstein
Journal: Drugs (2018)

An intramuscular formulation of onabotulinumtoxinA (onabotA; Botox®) is currently the only therapy specifically approved for the prevention of headaches in adults with chronic migraine (CM) in the EU and North America. This article provides a narrative review of relevant data on the drug in this indication from an EU perspective. OnabotA was originally approved on the basis of pooled data from two phase III studies (PREEMPT 1 and 2). In these pivotal studies, injection of up to five cycles of onabotA (155–195 U/cycle) at 12-week intervals was generally well tolerated and effective in producing statistically significant and clinically meaningful improvements in headache symptoms, acute headache pain medication usage, headache impact and health-related quality of life in adults with CM, of whom approximately two-thirds were acute medication overusers and approximately one-third had failed to respond to ≥ 3 prior oral prophylactic therapies. More recently, the efficacy and tolerability of onabotA over a period of 1 year in the PREEMPT programme has been substantiated and extended by the results of a long-term phase IV study (COMPEL), in which patients received up to nine treatment cycles over a period of 2 years, and by findings from several real-world clinical practice studies from Europe, including the prospective multinational REPOSE and CM-PASS studies. In conclusion, the totality of evidence from clinical trials and real-world studies indicates that onabotA is an effective and generally well tolerated option for the prevention of CM that may be particularly useful for patients who have previously failed to respond to or are intolerant of commonly prescribed oral prophylactics.
RNA-sequencing to identify three different molecular grades and immune checkpoint cascades with distinct clinical behaviour in NMIBC.
Authors: Thenappan Chandrasekar, Alexandre Zlotta, Jess Shen, Aidan Noon, Haiyan Jiang, Annette Erlich, Cynthia Kuk, Ruoyu Ni, Balram Sukhu, Kin Chan, Morgan Roupret, Thomas Seisen, Eva Comperat, Joan Sweet, Girish S. Kulkarni, Neil Eric Fleshner, Azar Azad, Theodorus van der Kwast, Jeff L Wrana
Journal: Journal of Clinical Oncology (2018)

412 Background: NMIBC has a highly variable clinical behavior not adequately predicted by histological grade or clinical parameters. Some are indolent; others quickly progress to MIBC. Discrepancies between phenotype and genotype is compounded further by interobserver variability in pathological grading. There is an unmet need to improve the prediction of NMIBC. Methods: Whole transcriptomic analysis of 178 bladder tumors (158 NMIBC, 20 MIBC/metastatic) was performed from FFPE tissue incorporating messenger RNA expression, splice variants, gene fusion, mutation detection and immune checkpoint inhibitor cascades. CTLA, PD-1, LAG3, TIM3, TIGIT and B7 were compiled as an index including all major cascade genes. Data were integrated and tested for correlations with pathological grading and clinical outcomes. Conventional pathological grading for WHO 1973 (Grade 1, 2, 3) and 2004 (LG vs HG) classifications was reviewed by 3 expert uro-pathologists. Kappa statistic for interobserver variability was calculated. For validation we used an independent RNA-seq dataset (n = 209, Hedegaard et al. 2016 Cancer Cell). Results: Unsupervised clustering of RNA-Seq data distinguished 3 molecular subtypes of NMIBC; Molecular Grade Related Index (MGRI) 1, MGRI2, MGRI3. MGRI1 comprised of almost exclusively LG tumors. MGRI3 clustered with HG MIBC. Kappa for interobserver variability of expert pathologists was 0.40 and 0.78 in 1973 and 2004 WHO classification, respectively. FGFR3 mutations, FGFR3::TACC3 fusion events and MGRI1 genes were associated with components of xenobiotic metabolism (p = 2.51x10 -09 ) signalling systems, in particular, GTPase regulation (p = 0.002), respiratory cycle genes (p = 0.004), HOX cluster (p = 0.005). MGRI independently predicted progression to MIBC (n = 138, HR = 2.96, 95%CI = 1.70-5.13, p = 1.20x10 -04 ). 5-year PFS in a combined data set (n = 347) differed significantly for MGRI1 (100%) vs MGRI2 (92.2%) vs MGRI3 (73.5%, p = 1.99x10 -05 , Gray’s test). PD-1 ICC independently predicted progression (OR = 2.85, p &lt; 0.05). Conclusions: RNA-seq delineates 3 molecular classes of NMIBC with different risks of progression to MIBC compared to conventional histologic grading.
NHS leaders must help staff keep patient data safe, experts say
Authors: Matthew Limb
Journal: BMJ (2016)

NHS leaders must do more to ensure that their staff are able to keep patients’ personal data secure, two government commissioned reviews have found.

England’s national data guardian, Fiona Caldicott, and the Care Quality Commission (CQC) investigated data security in hospitals and GP surgeries and found that staff members were widely committed to upholding it.12 However, they also found that day to day practices often did not live up to organisations’ policies, staff training was highly variable, and there was “no consistent culture” to share learning from data security breaches.

Caldicott said that NHS leaders should “take responsibility for data in …
FRACTIONAL FLOW RESERVE BUT NOT INSTANTANEOUS WAVE-FREE RATIO DETECTS PLAQUE VULNERABILITY
Authors: Roel Driessen, Wijnand Stuijfzand, Pieter Raijmakers, Ibrahim Danad, James K. Min, Jonathon Leipsic, Amir Ahmadi, Peter van de Ven, Albert van Rossum, Jagat Narula, Paul Knaapen
Journal: Journal of the American College of Cardiology (2018)
Abstract P2-12-13: Withdrawn
Authors: H Kotani, M Terada, M Mori, N Horisawa, K Sugino, M Iwase, S Oonishi, A Kataoka, Y Adachi, N Gondou, A Yoshimura, M Hattori, M Sawaki, H Iwata
Journal: Cancer Research (2018)

Abstract This abstract was withdrawn by the authors.
Selective inhibition of the p38α MAPK–MK2 axis inhibits inflammatory cues including inflammasome priming signals
Authors: Chun Wang, Susan Hockerman, E. Jon Jacobsen, Yael Alippe, Shaun R. Selness, Heidi R. Hope, Jeffrey L. Hirsch, Stephen J. Mnich, Matthew J. Saabye, William F. Hood, Sheri L. Bonar, Yousef Abu-Amer, Ariela Haimovich, Hal M. Hoffman, Joseph B. Monahan, Gabriel Mbalaviele
Journal: The Journal of Experimental Medicine (2018)

p38α activation of multiple effectors may underlie the failure of global p38α inhibitors in clinical trials. A unique inhibitor (CDD-450) was developed that selectively blocked p38α activation of the proinflammatory kinase MK2 while sparing p38α activation of PRAK and ATF2. Next, the hypothesis that the p38α–MK2 complex mediates inflammasome priming cues was tested. CDD-450 had no effect on NLRP3 expression, but it decreased IL-1β expression by promoting IL-1β mRNA degradation. Thus, IL-1β is regulated not only transcriptionally by NF-κB and posttranslationally by the inflammasomes but also posttranscriptionally by p38α–MK2. CDD-450 also accelerated TNF-α and IL-6 mRNA decay, inhibited inflammation in mice with cryopyrinopathy, and was as efficacious as global p38α inhibitors in attenuating arthritis in rats and cytokine expression by cells from patients with cryopyrinopathy and rheumatoid arthritis. These findings have clinical translation implications as CDD-450 offers the potential to avoid tachyphylaxis associated with global p38α inhibitors that may result from their inhibition of non-MK2 substrates involved in antiinflammatory and housekeeping responses.
Exposure to Electronic Cigarette Advertising Among Middle and High School Students — United States, 2014–2016
Authors: Kristy Marynak, Andrea Gentzke, Teresa W. Wang, Linda Neff, Brian A. King
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Electronic cigarettes (e-cigarettes) are the most commonly used tobacco product among U.S. middle and high school students (1). Exposure to e-cigarette advertisements is associated with higher odds of current e-cigarette use among middle and high school students (2-4). To assess patterns of self-reported exposure to four e-cigarette advertising sources (retail stores, the Internet, television, and newspapers and magazines), CDC analyzed data from the 2014, 2015, and 2016 National Youth Tobacco Surveys (NYTSs). Overall, exposure to e-cigarette advertising from at least one source increased each year during 2014-2016 (2014: 68.9%, 18.3 million; 2015: 73.0%, 19.2 million; 2016: 78.2%, 20.5 million). In 2016, exposure was highest for retail stores (68.0%), followed by the Internet (40.6%), television (37.7%), and newspapers and magazines (23.9%). During 2014-2016, youth exposure to e-cigarette advertising increased for retail stores (54.8% to 68.0%), decreased for newspapers and magazines (30.4% to 23.9%), and did not significantly change for the Internet or television. A comprehensive strategy to prevent and reduce youth use of e-cigarettes and other tobacco products includes efforts to reduce youth exposure to e-cigarette advertising from a range of sources, including retail stores, television, the Internet, and print media such as newspapers and magazines (5).
Prediction of response to trasutuzumab/pertuzumab/taxane therapy by microRNA in HER2 positive advanced breast cancer
Authors: A. Kawachi, A. Shimomura, J. Matsuzaki, J. Kawauchi, S. Takizawa, H. Sakamoto, C. Shimizu, K. Tamura, T. Ochiya
Journal: Annals of Oncology (2018)
Exacerbations of Chronic Obstructive Pulmonary Disease and Cardiac Events. A <i>Post Hoc</i> Cohort Analysis from the SUMMIT Randomized Clinical Trial
Authors: Ken M. Kunisaki, Mark T. Dransfield, Julie A. Anderson, Robert D. Brook, Peter M. A. Calverley, Bartolome R. Celli, Courtney Crim, Benjamin F. Hartley, Fernando J. Martinez, David E. Newby, Alexa A. Pragman, Jørgen Vestbo, Julie C. Yates, Dennis E. Niewoehner
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are common, associated with acute inflammation, and may increase subsequent cardiovascular disease (CVD) risk.Objectives: Determine whether AECOPD events are associated with increased risk of subsequent CVD.Methods: We performed a secondary cohort analysis of the SUMMIT (Study to Understand Mortality and Morbidity) trial, a convenience sample of current/former smokers with moderate COPD from 1,368 centers in 43 countries. All had CVD or increased CVD risk. AECOPD was defined as an increase in respiratory symptoms requiring treatment with antibiotics, systemic corticosteroids, and/or hospitalization. CVD events were a composite outcome of cardiovascular death, myocardial infarction, stroke, unstable angina, and transient ischemic attack. All CVD events were adjudicated. Cox proportional hazards models compared the hazard for a CVD event before AECOPD versus after AECOPD.Measurements and Main Results: Among 16,485 participants in SUMMIT, 4,704 participants had at least one AECOPD and 688 had at least one CVD event. The hazard ratio (HR) for CVD events after AECOPD was increased, particularly in the first 30 days after AECOPD (HR, 3.8; 95% confidence interval, 2.7–5.5) and was elevated up to 1 year after AECOPD. The 30-day HR after hospitalized AECOPD was more than twofold greater (HR, 9.9; 95% confidence interval, 6.6–14.9).Conclusions: In patients with COPD with CVD or risk factors for CVD, exacerbations confer an increased risk of subsequent CVD events, especially in hospitalized patients and within the first 30 days after exacerbation. Patients and clinicians should have heightened vigilance for early CVD events after AECOPD.Clinical trial registered with www.clinicaltrials.gov (NCT 01313676).
DETERMINANTS AND CLINICAL IMPLICATION OF POST PROCEDURAL FRACTIONAL FLOW RESERVE AS A PREDICTOR OF MAJOR ADVERSE CARDIAC EVENTS IN PATIENTS
Authors: Masahiro Hoshino, Taishi Yonetsu, Yoshihisa Kanaji, Eisuke Usui, Hiroaki Ohya, Yohei Sumino, Masahiro Hada, Rikuta Hamaya, Tetsumin Lee, Tsunekazu Kakuta
Journal: Journal of the American College of Cardiology (2018)