tbuckley/cabot-search huggingface dataset:
Editor’s Choice: Pipe dreams
Authors: Tom Moberly
Journal: BMJ (2015)

A metaphorical bath is often cited in discussions of the workforce challenges facing the profession. In this analogy the tap represents recruitment to the profession, and the plug represents retention of those already working as doctors. This week BMJ Careers looks at how the workings of both the tap and the plug could be improved.

Abi Rimmer considers the idea that …
I am a fourth year medical student in Scotland. Will the new two year foundation programme for PRHOs be in place for August 2005? I would also like to get a PRHO post in Essex or London to be nearer to my family. How do I go about doing this?
Authors: Simon Eccles
Journal: BMJ (2004)

<i>Got 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 (www.bmjcareers.com/advicezone) 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.</i>
Abstract 16515: Atrial Strain Predicts Atrial Fibrillation in Patients With Cryptogenic Cerebrovascular Events
Authors: Faraz Pathan, Kazuaki Negishi, Eswar Sivaraj, Samuel Neilson, Rifly Rafiudeen, John Galligan, Thomas H Marwick
Journal: Circulation (2016)

Introduction: Atrial fibrillation (AF) may account for a substantial number of patients with cryptogenic ischaemic cerebrovascular accidents (CVA), and has significant therapeutic implications. Ech...
Abstract 14820: Action Potential Duration Dispersion is Still Significant Determinant in Lethal Arrhythmias Even After Successful Resuscitation by Artificial Oxygen Carrier in Hemorrhagic Shock Heart
Authors: Bonpei Takase, Kenichi Hashimoto
Journal: Circulation (2016)

Prolonged low mean systemic blood pressure<40 mmHg in hemorrhagic shock causes irreversible heart dysfunction. This “Shock Heart Syndrome” (SHS) associates with lethal arrhythmias (VT/VF) leading to adverse prognosis. In 30% repetitive bleeding of Sprague-Dawley rat’s model, we previously reported that the oxygenated liposome-encapsulated human hemoglobin (HbV) is almost comparably effective with washed red blood cell (wRBC) to improve prognosis and prevent VT/VF in SHS using optical mapping analysis (OM) with electrophysiological burst pacing (EP). However, still about 20% of rats resuscitated by HbV had VT/VF by EP. To investigate the mechanisms of lethal arrhythmogenesis in HbV resuscitation, we measured conduction time (CT) and pattern, as well as action potential duration dispersion (APDd) defined as maximum APD - minimum APD in each right and left ventricle (RV/LV) in 29 SHS rats resuscitated by HbV, and compared them with normal rats (n=6, NL-Group) using OM and EP. The SHS by HbV were divided into...
I really don't understand how the new application process will work. Can you help?
Authors: Carrie Moore
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>
Patients should be reviewed by a consultant once every 24 hours, say royal colleges
Authors: Gareth Iacobucci
Journal: BMJ (2012)

Patients in hospital have a right to the same standard of care seven days a week and should be reviewed by a consultant at least once every 24 hours in most circumstances, the Academy of Medical Royal Colleges has recommended.

In a new report published this week, the academy, which brings together 20 colleges and faculties, indentifies three key standards to ensure that all patients receive high quality, consultant led care led throughout the week.

Seven Day Consultant Present Care highlights substantial variation in the availability of consultants and other senior doctors across different locations and areas of medicine at different times in the week.1

It urges the NHS to ensure that “appropriate resources and adequate numbers of consultants” are provided at all times to deal with “unacceptable” deficiencies …
USE OF SUPRA RENAL RETRIEVABLE INFERIOR VENA CAVA (IVC) FILTER IN CONJUNCTION WITH EKOS FOR TREATMENT OF EXTENSIVE IVC THROMBOSIS
Authors: Rahul Vasudev, Sahitya Posimreddy, Upamanyu Rampal, Hiten Patel, Razan Shamoon, Mahesh Bikkina, Fayez Shamoon, Hartaj Virk
Journal: Journal of the American College of Cardiology (2018)
Metabolomics facilitates the discrimination of the specific anti-cancer effects of free- and polymer-conjugated doxorubicin in breast cancer models
Authors: Ana Armiñán, Martina Palomino-Schätzlein, Coralie Deladriere, Juan J. Arroyo-Crespo, Sonia Vicente-Ruiz, María J. Vicent, Antonio Pineda-Lucena
Journal: Biomaterials (2018)

Metabolomics is becoming a relevant tool for understanding the molecular mechanisms involved in the response to new drug delivery systems. The applicability of this experimental approach to cell cultures and animal models makes metabolomics a useful tool for establishing direct connections between in vitro and in vivo data, thus providing a reliable platform for the characterization of chemotherapeutic agents. Herein, we used metabolomic profiles based on nuclear magnetic resonance (NMR) spectroscopy to evaluate the biochemical pathways involved in the response to a chemotherapeutic anthracycline drug (Doxorubicin, Dox) and an N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-conjugated form (HPMA-Dox) in an in vitro cell culture model and an in vivo orthotopic breast cancer model. We also used protein expression and flow cytometry studies to obtain a better coverage of the biochemical alterations associated with the administration of these compounds. The overall analysis revealed that polymer conjugation leads to increased apoptosis, reduced glycolysis, and reduced levels of phospholipids when compared to the free chemotherapeutic drug. Our results represent a first step in the application of integrated in vitro and in vivo metabolomic studies to the evaluation of drug delivery systems.
Pan-SRC kinase inhibition blocks B-cell receptor oncogenic signaling in non-Hodgkin lymphoma
Authors: Elena Battistello, Natalya Katanayeva, Elie Dheilly, Daniele Tavernari, Maria C. Donaldson, Luca Bonsignore, Margot Thome, Amanda L. Christie, Mark A. Murakami, Olivier Michielin, Giovanni Ciriello, Vincent Zoete, Elisa Oricchio
Journal: Blood (2018)
Validation of a genomic risk classifier to predict metastasis and prostate cancer-specific mortality in men with positive lymph nodes.
Authors: Bruce J. Trock, R. Jeffrey Karnes, Frank Claessens, John W. Davis, Zaid Haddad, Kasra Yousefi, Elai Davicioni, Ashley Ross
Journal: Journal of Clinical Oncology (2018)

125 Background: Men with lymph node involvement (LNI) at prostatectomy (RP) are at high risk of dying from prostate cancer. However, survival following RP is highly variable, with some men apparently cured. Nomograms developed for men with LNI have been based on series where all or the vast majority of men received adjuvant treatment. Because administration of adjuvant treatment is not universal, even for LNI, we evaluated whether the Decipher genomic classifier (GC) can improve upon clinical models to predict metastasis within 5 years (MET5) and prostate cancer specific mortality within 10 years (PCSM10) in a cohort of LNI patients, the majority of whom did not receive adjuvant treatment. Methods: 141 patients from 4 institutions (Johns Hopkins, Mayo Clinic, Leuven, MD Anderson) had LNI at RP, had adequate tissue and clinical data for analysis of MET5, and 86 were analyzed for PCSM10. 43% of men received adjuvant therapy. RP tumor tissue was analyzed by Affymetrix Human Exon 1.0 ST GeneChip; the GC was calculated based on 22 genes in the previously trained and validated algorithm. Logistic regression evaluated whether the GC, dichotomized as high risk (GC score &gt; 0.6) vs low-intermediate risk (≤0.6), improved prediction of MET5 and PCSM10 beyond that achieved with established clinical prognostic factors. Results: 62 men (43%) developed MET5, and 35 (41%) developed PCSM10. For both MET5 and PCSM10 CAPRA-S, number of positive lymph nodes, and age were significant; adjuvant therapy was not significant. GC was a significant independent strong prognostic factor when added to the clinical model for prediction of MET5, odds ratio = 4.04 (95% CI: 1.48, 11.02), p = 0.006, and prediction of PCSM10, odds ratio = 6.71 (95% CI: 2.01, 22.38), p = 0.002. Addition of GC to the clinical model improved the AUC from 0.77 to 0.79 for MET5, and from 0.65 to 0.74 for PCSM10. Conclusions: The Decipher GC significantly improves upon clinical variables to predict metastasis and prostate cancer specific mortality in men at high risk due to LNI. This is the first study to show a genomic classifier predicts outcomes in men with LNI; validation is needed to determine if Decipher can improve treatment decisions in men with LNI.
Using social media not as dangerous as it may seem, says @amcunningham
Authors: Abi Rimmer
Journal: BMJ (2015)

Social media are not as risky as they might seem and can be used to connect with others and build communities, the academic GP Anne-Marie Cunningham has said.

Cunningham is an associate academic GP at Cardiff University’s Institute of Medical Education and is followed by 14 800 people on Twitter. Speaking at the Medical Women’s Federation spring conference in Manchester on Friday 15 May, she discussed the peaks and potential pitfalls …
Prostate cancer presentation, treatment selection, and outcomes among men with HIV/AIDS: A clinical, stage, and age-matched analysis.
Authors: Maria Ruden, Christopher Olivares, Mathew Q Fakhoury, Patricia Q Vidal, Courtney MP Hollowell, Sarah P Psutka
Journal: Journal of Clinical Oncology (2018)

245 Background: The clinical presentation, oncologic outcomes and the optimal management of prostate cancer (PC) among human immunodeficiency virus-seropositive (HIV+) men are poorly described. Our objective was to compare the clinical characteristics, treatment decisions and oncologic outcomes in a contemporary series of HIV+ and HIV negative (HIV-) men with PC. Methods: Clinical data for 3135 men treated for PC at Cook County Hospital (2000-16) were reviewed. HIV+ patients (N = 46) were matched 1:2-3 by age and clinical stage to HIV-negative controls (N = 137). Clinicopathologic features, primary treatment, and oncologic outcomes were compared with Kaplan Meier and Cox proportional hazards analyses. Results: HIV- and HIV+ patients were similar with respect to median age (58.2 vs. 57.2 years, p = 0.2), initial PSA (10.6 vs. 10.5 ng/mL, p = 1), clinical stage (94% cT1/2 vs. 88%, p = 0.4), 8% cN1 vs. 6.5%, p = 1; 10.9% cM1 vs. 10.9%, p = 1), ECOG performance status (0-1 in 99% vs. 100%, p = 1). Among HIV+ men, 67.4% had a history of AIDS, and 91.3% were on HAART at diagnosis with median viral load and CD4+ count of 40 copies/mL and 400 cells/mm 3 . Median time from HIV diagnosis to PC diagnosis was 8.6 years. Among men with localized disease (N = 153), HIV+ men (N = 37) were more likely to receive radiation therapy (59.5% vs. 44.8%) or no therapy at all (13.5% vs. 4.3%) and less likely to receive surgery (16.2% vs. 30.2%), or to initiate active surveillance (10.8% vs. 16.4%; p = 0.04 overall) than HIV-. There were no differences in rates of biochemical recurrence (Hazard ratio [HR] 0.79; p = 0.6), clinical progression (HR 0.89, p = 0.8), castration resistance (HR 0.71, p = 0.1), or PC-death (HR 3, p = 0.1). However, HIV+ status was associated with an increased risk of all-cause death (HR 2.89, p = 0.04) with median follow-up of 4.2 years (range 0-14). Conclusions: Matched by age and stage, HIV+ men with localized PC were observed to receive surgery and definitive treatment overall at significantly lower rates than HIV- controls. Oncologic outcomes were similar between HIV+ and HIV- men. Further research is necessary to define optimal PC treatment selection in men with HIV.
Will regulatory issues continue to be a major barrier to access to bedaquiline and delamanid?
Authors: Tiziana Masini, Janika Hauser, Rutendo Kuwana, Nguyen Nhat Linh, Ernesto Jaramillo
Journal: European Respiratory Journal (2018)

In 2016, 600 000 people are estimated to have been eligible for multidrug-resistant (MDR) tuberculosis (TB) treatment [1]. Bedaquiline and delamanid are the first two new anti-TB compounds to have become available in over four decades and were approved by stringent regulatory authoritiesa in 2012 and 2014 respectively [3, 4]. The global introduction of bedaquiline and delamanid has not kept pace with the dire need for these potentially life-saving drugs [5, 6]. Despite a number of initiatives intending to enable access [7–14], the number of patients who have received these drugs remains unacceptably low. Very few MDR-TB high burden countries have fully integrated either bedaquiline or delamanid into their National TB Programmes (NTPs) [1, 15, 16]. While costs and concerns over adverse events may have contributed to hesitation in the adoption of bedaquiline and delamanid, a frequently cited cause for delay is the lack of national regulatory approval.b Although subject to an often long process, regulatory approval is meant to serve a public good and remains essential for sustainable import, programmatic use and therefore patient access to the drugs [17]. Despite being referenced in past reports [18], the challenges faced by drug manufacturers and National Medicines Regulatory Authorities (NMRAs) when registering the drugs have not yet been investigated more completely. National regulatory approval of life-saving TB drugs to be streamlined via improved communication and information sharing <http://ow.ly/8Ti130i8mID>
Inflammation Intensity–Dependent Expression of Osteoinductive Wnt Proteins Is Critical for Ectopic New Bone Formation in Ankylosing Spondylitis
Authors: Xiang Li, Jianru Wang, Zhongping Zhan, Sibei Li, Zhaomin Zheng, Taiping Wang, Kuibo Zhang, Hehai Pan, Zemin Li, Nu Zhang, Hui Liu
Journal: Arthritis & Rheumatology (2018)

To investigate the molecular mechanism underlying inflammation-related ectopic new bone formation in ankylosing spondylitis (AS).Spinal tissues and sera were collected from patients with AS and healthy volunteers and examined for the expression of Wnt proteins. An in vitro cell culture system mimicking the local inflammatory microenvironment of bone-forming sites was established to study the relationship between inflammation and Wnt expression, the regulatory mechanism of inflammation-induced Wnt expression, and the role of Wnt signaling in new bone formation. Modified collagen-induced arthritis (CIA) and proteoglycan-induced spondylitis (PGIS) animal models were used to confirm the key findings in vivo.The levels of osteoinductive Wnt proteins were increased in sera and spinal ligament tissues from patients with AS. Constitutive low-intensity tumor necrosis factor (TNF) stimulation, but not short-term or high-intensity TNF stimulation, induced persistent expression of osteoinductive Wnt proteins and subsequent bone formation through NF-κB (p65) and JNK/activator protein 1 (c-Jun) signaling pathways. Furthermore, inhibition of either the Wnt/β-catenin or Wnt/protein kinase Cδ (PKCδ) pathway significantly suppressed new bone formation. The increased expression of Wnt proteins was confirmed in both the modified CIA and PGIS models. A kyphotic and ankylosing phenotype of the spine was seen during long-term observation in the modified CIA model. Inhibition of either the Wnt/β-catenin or Wnt/PKCδ signaling pathway significantly reduced the incidence and severity of this phenotype.Inflammation intensity-dependent expression of osteoinductive Wnt proteins is a key link between inflammation and ectopic new bone formation in AS. Activation of both the canonical Wnt/β-catenin and noncanonical Wnt/PKCδ pathways is required for inflammation-induced new bone formation.
Point of care diagnostics for tuberculosis
Authors: A.L. García-Basteiro, A. DiNardo, B. Saavedra, D.R. Silva, D. Palmero, M. Gegia, G.B. Migliori, R. Duarte, E. Mambuque, R. Centis, L.E. Cuevas, S. Izco, G. Theron
Journal: Pulmonology (2018)

The goals of the End TB strategy, which aims to achieve a 90% reduction in tuberculosis (TB) incidence and a 95% reduction in TB mortality by 2035, will not be achieved without new tools to fight TB. These include improved point of care (POC) diagnostic tests that are meant to be delivered at the most decentralised levels of care where the patients make the initial contact with the health system, as well as within the community. These tests should be able to be performed on an easily accessible sample and provide results in a timely manner, allowing a quick treatment turnaround time of a few minutes or hours (in a single clinical encounter), hence avoiding patient loss-to-follow-up. There have been exciting developments in recent years, including the WHO endorsement of Xpert MTB/RIF, Xpert MTB/RIF Ultra, loop-mediated isothermal amplification (TB-LAMP) and lateral flow lipoarabinomannan (LAM). However, these tests have limitations that must be overcome before they can be optimally applied at the POC. Furthermore, worrying short- to medium-term gaps exist in the POC diagnostic test development pipeline. Thus, not only is better implementation of existing tools and algorithms needed, but new research is required to develop new POC tests that allow the TB community to truly make an impact and find the "missed TB cases".
Evaluation of a lung cancer RNA expression subtyping panel and comparison with histologic diagnosis in lung tumor samples from multiple data sets including The Cancer Genome Atlas (TCGA).
Authors: Mark Robert Miglarese, Matthew Wilkerson, Cheng Fan, Hawazin Faruki, David N. Hayes, Charles M. Perou, Myla Lai-Goldman
Journal: Journal of Clinical Oncology (2014)

7566 Background: Lung cancer subtypes are described by morphological and molecular characteristics. Differentiation between various subtypes is important for guiding patient management. Variability in morphology, limited tissue, and the need for performing a growing number of genomic tests pose challenges to the current diagnostic standard. Methods: The Lung Subtype Panel (LSP), a previously published 57 gene expression panel for prediction of lung tumor morphologic class (Wilkerson et al.JMD 2013), was investigated using 2,168 lung cancer samples from multiple publically available data sets (TCGA, NCI, UNC, Duke, Expo, Seoul, Tokyo, and France). Data sets with both gene expression data and morphologic classification were selected. Three platforms for gene expression were represented: Affymetrix U133+2 (n=883), Agilent 44K (n=334), and Illumina RNA-seq (n=951). A centroid predictor was used to assign an expression-defined histologic class. Predicted results were compared with tumor morphologic classification and percent agreement was calculated. Results: Ten lung tumor RNA expression datasets were combined into three platform specific data sets comprised of a diverse patient population, including smokers and nonsmokers with Stage I – Stage IV disease. Using the centroid predictor for two classes only (adenocarcinoma or squamous cell carcinoma), the agreement of the predictor with morphologic classification ranged from 79%-94% across the 3 data sets. Analysis of the 4-class predictor is underway and will be reported. To estimate an error rate in morphologic classification, a subset of tumors were reviewed by multiple pathologists, which showed an agreement rate of 65% (CI 49%-73%). Conclusions: In multiple datasets with over two thousand lung cancer samples, molecular profiling using the Lung Subtype Panel compared favorably to light microscopic derived diagnoses, and showed a higher level of agreement than seen by reassessment by multiple pathologists. RNA-based tumor subtyping can provide valuable information, especially when tissue is limiting and the overall morphologic diagnosis remains unclear.
ALTERNATIVE METRICS BY SYSTEMATIC REVIEW INCLUSION STATUS OF STUDIES OF CATHETER ABLATION FOR ATRIAL FIBRILLATION: FINDINGS FROM THE SMASH-AF META-ANALYSIS STUDY COHORT
Authors: Fahd Yunus, George Leef, Andrew Cluckey, Mariam Askari, Mintu Turakhia, Alexander Perino
Journal: Journal of the American College of Cardiology (2018)
Elective target pressure is undermining emergency surgical teams, forum warns
Authors: Caroline White
Journal: BMJ (2013)

Increasing specialisation and a focus on elective targets have depleted the pool of surgeons available to meet rising demands for emergency surgery, the Surgical Forum of Great Britain and Ireland says.

A discussion paper from the forum says that a radical rethink of surgical training is now urgently needed.1 The report says that surgery faces several challenges, chief among which is the mismatch between demand for general emergency surgical skills and the supply of suitably trained surgeons.

Surgical emergencies are now the most common reason for surgical admission in the United Kingdom, and set to increase as the population ages. According to the …
FROPOFOL PREVENTS DISEASE PROGRESSION IN HYPERTROPHIC CARDIOMYOPATHY
Authors: Yiyuan Huang, Haisong Lu, Fazhao Li, Wenjie Liu, Xianfeng Ren, Weiming Bu, Kellie A. Woll, Leslie A. Leinwand, Roselle Abraham, Roderic Eckenhoff, Wei Dong Gao
Journal: Journal of the American College of Cardiology (2018)
Abstract P2-08-01: Loss of function of Brca1 or Gata3 induces basal-like breast cancer
Authors: X-H Pei, HL Chan, L Zhang, C Wang, DJ Robbins, T Capobianco, F Bai
Journal: Cancer Research (2018)

Abstract BACKGROUND: Breast cancer is mainly divided into estrogen receptor (ER)-positive luminal and ER-negative basal-like tumors. Luminal-type tumors are associated with better survival and respond to hormone therapies whereas basal-like tumors are more aggressive and associated with a poor prognosis. Mammary epithelia are mainly composed of luminal and basal cells that are maintained by luminal and basal progenitors, respectively. The maintenance of luminal cell fate is orchestrated by networks of transcription factors, including BRCA1 and GATA3. Functional loss of BRCA1 by germline or somatic mutation or by promoter methylation is associated with more than one third of basal-like breast cancers. GATA3 expression is reduced in basal-like breast cancers and cancers that metastasize. Overexpression of GATA3 in cancer cells inhibits tumor formation. Deletion of Brca1 or Gata3 in mice results in early lethality or growth defects. How BRCA1 and GATA3 suppress breast cancer remains elusive. METHODS: We generated mice lacking Brca1 or Gata3 in mammary epithelia. Due to the proliferative defects and induction of p18Ink4c (p18), an inhibitor of CDK4/6, in mammary epithelial cells of these mice, we then generated mice lacking Brca1 or Gata3 in p18 deficient mammary epithelia. We determined spontaneous mammary tumor development in mutant mice and the mechanisms underlying the role of Brca1 and Gata3 in suppressing tumorigenesis and progression. RESULTS: Depletion of Brca1 or Gata3 led to growth defects of mammary epithelial cells, which was rescued by loss of p18. Depletion of Brca1 or Gata3 in a p18 null background induced heterogeneous mammary tumors with less luminal and more basal-like features and accelerated metastasis. Deletion of Brca1 eliminated Gata3 expression in human and mouse mammary tissues and cells. How Brca1 interacts with Gata3 to control mammary tumor development and progression is currently under investigation. CONCLUSION: Our results suggest that loss of function of either Brca1 or Gata3 induces basal-like mammary tumors in p18 deficient background. Citation Format: Pei X-H, Chan HL, Zhang L, Wang C, Robbins DJ, Capobianco T, Bai F. Loss of function of Brca1 or Gata3 induces basal-like breast cancer [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 P2-08-01.