tbuckley/cabot-search huggingface dataset:
Enzalutamide: Do treatment modifications allow drug continuation without losing disease control?
Authors: Emma Samah Massalha, Lenka Zvirinska
Journal: Journal of Clinical Oncology (2018)

326 Background: Enzalutamide improves progression free and overall survival in men with metastatic prostate cancer (Beer T, et al. 2014; Cabot R, et al. 2012). Grade 3 adverse events occur in up to 48% (Beer T, et al. 2014; Cabot R, et al. 2012). and lead to treatment discontinuation in up to 8% (Beer T, et al. 2014; Cabot R, et al. 2012). The purpose of this retrospective analysis is to determine whether treatment modification (TM) with dose reduction (DR), treatment break (TB) or both, still allow control of prostate cancer in men who may have otherwise stopped treatment due to intolerable side effects. Methods: All patients in North Wales, UK, who commenced enzalutamide for metastatic prostate cancer in 2016 were eligible. Data was collected and recorded from electronic notes and prescriptions. Results: 66 men aged 61 to 92 (median 77) commenced treatment with enzalutamide in 2016. 17% performance status (PS) 0, 51% PS 2, 3% PS 3. Treatment has been discontinued in 80%. Adverse events (AEs) led to discontinuation in 25% cases including 2 deaths. The most common AE was fatigue in 37%. 11 patients (17%) had TM due to AEs. Mean treatment duration was 9.6 months (range 1 to 19.2 months), without TM 8.9 months, with TM, 12.8 months. Men with PS 2 were more likely to require TM or discontinuation (D) due to AEs (29% each) compared to PS 1 (24% TM, 21% D) or PS 0 (1% TM, 27% D). TBs lasted between 2 weeks and 7 months. PSA rose during that time but quality of life improved and PSA responded once treatment was recommenced. After a TB, enzalutamide was continued for 2 to 11 months (median 5.9 months). DR did not adversely affected PSA in 6 of 7 cases and improved quality of life in 2 cases. Patients continued enzalutamide 2-12 months (median 5.9 months) after dose reduction, including 4 still on treatment. Conclusions: This shows that both treatment breaks and dose reductions can improve quality of life whilst not adversely affecting outcome. However, the numbers are small and this needs to be confirmed in a prospective study. Those with lower PS are more likely to require modification.
My present post as GP registrar is for 18 months at the same practice. What is the required notice period (it was three months as staff grade medic) and what sickness benefit would I be entitled to? Also, is my previous staff grade salary protected?
Authors: John Adsett
Journal: BMJ (2005)

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 (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.
When should I take the part 1 MRCOphth examination?
Authors: Amar Alwitry
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>
Tissue Engineering: Silicon Carbide Nanoparticles as an Effective Bioadhesive to Bond Collagen Containing Composite Gel Layers for Tissue Engineering Applications (Adv. Healthcare Mater. 5/2018)
Authors: Rana Attalla, Celine S. N. Ling, Ponnambalam Ravi Selvaganapathy
Journal: Advanced Healthcare Materials (2018)

In article number 1701385, Ponnambalam Ravi Selvaganapathy and co-workers use a lamination-based planar processing strategy enabled by nanoparticle adhesives to address one of the prominent technical challenges found in the tissue engineering field – the incorporation of perfusable hollow networks for nutrient and waste transport within artificial 3D tissue constructs. Without these vascular-like networks, the cells embedded within the constructs would quickly become necrotic. Silicon Carbide, used as a nanoadhesive, has been shown to be very effective in adhering microstructured layers of biologically important extracellular matrices containing collagen to form perfusable 3D netoworks suitable for growing cells.
Abstract P6-13-04: IMPACt trial: MammaPrint and BluePrint molecular subtyping guide treatment decisions in breast cancer
Authors: H Soliman, E Rehmus, V Shah, G Srkalovic, R Mahtani, E Levine, B Mavromatis, J Srinivasiah, M Kassar, R Gabordi, E Yoder, R Qamar, W Audeh
Journal: Cancer Research (2018)

Abstract Background: IMPACt is a prospective, case-only study to measure the effect of MammaPrint (MP) and BluePrint (BP) on treatment decisions in breast cancer patients. Here, we report the results of the primary objective in women aged ≥18 years with histologically proven invasive stage I-II, hormone receptor (HR) positive, and HER2-negative breast cancer. Methods: The study included 369 women from 18 US institutions. The recommended treatment plan was captured before and after receiving results for MP and BP. Treatment was started after obtaining results. In addition to the effect of results on physician treatment decisions involving chemotherapy (CT) and physician confidence, the distribution of MP High Risk (HR) and Low Risk (LR) patients was also evaluated. Results: MP classified patients to 62% (n=228) LR and 38% (n=141) HR. Treatment decisions were changed for 25% (n=92) of women after receiving MP and BP results. Of the LR patients initially prescribed CT, 68% (45/66) had CT removed from their treatment recommendation. Of the HR patients who initially were not prescribed CT, 66% (42/64) had CT added. Overall, 89% (202/228) of LR patients did not receive CT, and likewise 84% (119/141) of HR patients did receive CT after receiving MP. Among those who did not change treatment (n=277), 68% of physicians reported having greater confidence in their prescribed therapy. Conclusions: The IMPACt trial shows MP generates a 25% overall treatment change in clinical practice. The highest impact is for women with LR results, where 68% are spared chemotherapy in favor of endocrine therapy alone. Additionally, 73% of physicians report having higher confidence in treatment decisions for their patient after MP. Table 1: Treatment changesTreatment Decision Pre- to Post-MPMP HRMP LRTotalCT to CT772198no CT tp CT42547CT to no CT04545no CT to no CT22157179Total141228369 Citation Format: Soliman H, Rehmus E, Shah V, Srkalovic G, Mahtani R, Levine E, Mavromatis B, Srinivasiah J, Kassar M, Gabordi R, Yoder E, Qamar R, Audeh W, IMPACt Investigators Group I. IMPACt trial: MammaPrint and BluePrint molecular subtyping guide treatment decisions in 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 P6-13-04.
Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline
Authors: A.J. Ullmann, J.M. Aguado, S. Arikan-Akdagli, D.W. Denning, A.H. Groll, K. Lagrou, C. Lass-Flörl, R.E. Lewis, P. Munoz, P.E. Verweij, A. Warris, F. Ader, M. Akova, M.C. Arendrup, R.A. Barnes, C. Beigelman-Aubry, S. Blot, E. Bouza, R.J.M. Brüggemann, D. Buchheidt, J. Cadranel, E. Castagnola, A. Chakrabarti, M. Cuenca-Estrella, G. Dimopoulos, J. Fortun, J.-P. Gangneux, J. Garbino, W.J. Heinz, R. Herbrecht, C.P. Heussel, C.C. Kibbler, N. Klimko, B.J. Kullberg, C. Lange, T. Lehrnbecher, J. Löffler, O. Lortholary, J. Maertens, O. Marchetti, J.F. Meis, L. Pagano, P. Ribaud, M. Richardson, E. Roilides, M. Ruhnke, M. Sanguinetti, D.C. Sheppard, J. Sinkó, A. Skiada, M.J.G.T. Vehreschild, C. Viscoli, O.A. Cornely
Journal: Clinical Microbiology and Infection (2018)
Neutrophil extracellular trap formation is regulated by CXCR2 in COPD neutrophils
Authors: Frauke Pedersen, Benjamin Waschki, Sebastian Marwitz, Torsten Goldmann, Anne Kirsten, Anna Malmgren, Klaus F. Rabe, Mohib Uddin, Henrik Watz
Journal: European Respiratory Journal (2018)

Chronic obstructive pulmonary disease (COPD) is characterised by persistent neutrophilic inflammation of the airways, which is associated with enhanced neutrophil extracellular trap (NET) formation of airway neutrophils [1–3]. NETs are web-like extracellular structures consisting of neutrophil DNA components and degradative enzymes ( e.g. neutrophil elastase and myeloperoxidase) which are released from azurophilic granules by activated neutrophils [4]. Initially found to immunoregulate host defence responses during bacterial infections, emerging data indicate that exaggerated NET formation and/or delayed NET clearance may inflict tissue damage and organ dysfunction in a range of human inflammatory diseases independent of infections [5, 6]. Recently, we found NET formation of sputum neutrophils and extracellular DNA levels in sputum supernatant to be significantly enhanced in patients with stable COPD irrespective of the current smoking state or the purulence of the sputum samples [1]. Several studies, including our own, show that the amount of NET formation and/or level of extracellular DNA in patients with stable COPD correlate with the airflow limitation, suggesting that NET formation by airway neutrophils may contribute to the lung tissue damage observed in COPD [1–3]. However, the underlying mechanisms inducing NET formation in COPD neutrophils are largely unexplored. Furthermore, it is unknown whether neutrophils undergo NETosis following migration into the lung tissues or whether neutrophils are constitutively poised to undergo this response in circulation during COPD-related inflammation. It is notable that there is an increase in the release of cell-free DNA and myeloperoxidase that are active constituents of NETs in peripheral blood in COPD patients [7–9]. Here, we aimed to compare NET formation in autologous neutrophils derived from peripheral blood and sputum from COPD patients ex vivo . We also investigated whether the selective CXCR2 antagonist AZD5069, that has been shown to block trafficking of neutrophils from blood into airways in bronchiectasis patients [10] and more recently in a small cohort of neutrophilic asthma patients [11], could dampen NET formation in COPD-derived neutrophils ex vivo . CXCR2 might have a crucial role in neutrophil extracellular trap formation in COPD neutrophils <http://ow.ly/LRst30iE1Bw>
Medical graduates feel better prepared than their predecessors
Authors: Matthew Limb
Journal: BMJ (2016)

Medical graduates feel better prepared for clinical practice now than those who graduated in the 1990s, a team at Oxford University has found.

The researchers found that between 1999 and 2012 there was an increase in how well prepared for clinical practice medical school graduates felt. Danish graduates reported higher rates of preparedness that those in the UK showing that there was “scope for further improvement,” according to the researchers. There were also “significant differences” in perceived preparedness between white and non-white doctors.

Researchers from Oxford’s Nuffield department of population health sampled two recent cohorts of UK trained doctors—those who qualified in 2011 and 2012. Responses were then compared …
Chemiluminescence imaging of Duox2-derived hydrogen peroxide for longitudinal visualization of biological response to viral infection in nasal mucosa
Authors: Hyun Jik Kim, Young Hun Seo, Sujin An, Ara Jo, Ick Chan Kwon, Sehoon Kim
Journal: Theranostics (2018)

Rationale: Hydrogen peroxide (H 2 O 2 ) provides an important mechanism for resisting infectious pathogens within the respiratory tract, and accordingly, the in situ analysis of H 2 O 2 generation in real time provides a valuable tool for assessing immune response.Methods: In this study, we applied a chemiluminescent nanoparticle-based real-time imaging approach to noninvasive evaluation of the Duox2-mediated H 2 O 2 generation after viral infection, and assessed its usefulness for analytical purposes in mouse nasal mucosa.The chemiluminescent nanoprobe employed herein (BioNT) possesses appropriate physicochemical properties, such as high sensitivity and selectivity toward H 2 O 2 , no background noise, deliverability to the respiratory tract, and capability of multiple injections to a single animal subject for long-term repetitive imaging.Results: The favorable characteristics of BioNT allowed for a longitudinal study with the same mice to noninvasively evaluate the long-term evolution of endogenous H 2 O 2 in the nasal epithelium after infection with influenza A virus (WS/33/H1N1).We found that nasal epithelial cells by themselves respond to viral infection by generating H 2 O 2 , and that the in vivo cumulative H 2 O 2 level in the nasal mucosa peaks at day 3 post-infection.Such in vitro and in vivo temporal behaviors of the endogenous H 2 O 2 generation showed a good correlation with those of Duox2 expression after infection.This correlation could be further confirmed with Duox2-deficient subjects (Duox2-knockdown NHNE cells and Duox2-knockout mutant mice) where no H 2 O 2 -induced chemiluminescence was detectable even after viral infection.Importantly, upon knock-down of Duox2 expression, the condition of mice caused by viral infection in the upper airway was significantly aggravated, evidencing the involvement of Duox2 in the immune defense.Conclusion: All these results reveal a critical role of Duox2 in the infection-induced H 2 O 2 production and the H 2 O 2 -mediated immune response to infection in the respiratory tract, well elucidating the potential of BioNT as a noninvasive tool for fundamental in vivo studies of infectious diseases.
“Lost boys” to clean up the leadership mess
Authors: Woody Caan
Journal: BMJ (2005)

It is not surprising that Lowry feels like a little boy, unwanted and alone “in the dark” about the future of public health.1 Woodall rails against public health “mediocrity” and longs for people to come to his aid “to clean up the mess.”2 I have described the way that many professionals in 21st century public health feel like “orphans”3: rejected and then angry …
NT-PROBNP PREDICTS MORTALITY IN ELDERLY AND VERY ELDERLY PATIENTS WITH CHRONIC SYSTOLIC HEART FAILURE
Authors: Giuseppe Vergaro, Alberto Aimo, Chiara Arzilli, Luc Zyw, Alessandro Valleggi, Alberto Giannoni, Concetta Prontera, Andrea Barison, Roberta Poletti, Alessandra Gabutti, Chiara Mammini, Claudio Passino, Michele Emdin
Journal: Journal of the American College of Cardiology (2018)
Occupational exposures and 20-year incidence of COPD: the European Community Respiratory Health Survey
Authors: Theodore Lytras, Manolis Kogevinas, Hans Kromhout, Anne-Elie Carsin, Josep M Antó, Hayat Bentouhami, Joost Weyler, Joachim Heinrich, Dennis Nowak, Isabel Urrutia, Jesús Martinez-Moratalla, José Antonio Gullón, Antonio Pereira-Vega, Chantal Raherison-Semjen, Isabelle Pin, Pascal Demoly, Bénédicte Leynaert, Simona Villani, Thorarinn Gislason, Cecilie Svanes, Mathias Holm, Bertil Forsberg, Dan Norbäck, Amar J Mehta, Nicole Probst-Hensch, Geza Benke, Rain Jogi, Kjell Torén, Torben Sigsgaard, Vivi Schlünssen, Mario Olivieri, Paul D Blanc, Roel Vermeulen, Judith Garcia-Aymerich, Deborah Jarvis, Jan-Paul Zock
Journal: Thorax (2018)

Occupational exposures have been associated with an increased risk of COPD. However, few studies have related objectively assessed occupational exposures to prospectively assessed incidence of COPD, using postbronchodilator lung function tests. Our objective was to examine the effect of occupational exposures on COPD incidence in the European Community Respiratory Health Survey.General population samples aged 20-44 were randomly selected in 1991-1993 and followed up 20 years later (2010-2012). Spirometry was performed at baseline and at follow-up, with incident COPD defined using a lower limit of normal criterion for postbronchodilator FEV1/FVC. Only participants without COPD and without current asthma at baseline were included. Coded job histories during follow-up were linked to a Job-Exposure Matrix, generating occupational exposure estimates to 12 categories of agents. Their association with COPD incidence was examined in log-binomial models fitted in a Bayesian framework.3343 participants fulfilled the inclusion criteria; 89 of them had COPD at follow-up (1.4 cases/1000 person-years). Participants exposed to biological dust had a higher incidence of COPD compared with those unexposed (relative risk (RR) 1.6, 95% CI 1.1 to 2.3), as did those exposed to gases and fumes (RR 1.5, 95% CI 1.0 to 2.2) and pesticides (RR 2.2, 95% CI 1.1 to 3.8). The combined population attributable fraction for these exposures was 21.0%.These results substantially strengthen the evidence base for occupational exposures as an important risk factor for COPD.
Systemic effect of radiotherapy (RT) followed by programmed death 1 (PD-1) inhibitors in non-small-cell lung cancer (NSCLC).
Authors: Maria Bassanelli, Diana Giannarelli, Alain Gelibter, Fabiana Letizia Cecere, Rita Chiari, Silvana Giacinti, Simone Scagnoli, Michele Milella, Biagio Ricciuti, Michela Roberto, Valentina Magri, Virginia Ferraresi, Marta Brambilla, Mario Santarelli, Paolo Marchetti, Enrico Cortesi, Anna Ceribelli
Journal: Journal of Clinical Oncology (2018)

177 Background: RT-induced abscopal effect seems increase the efficacy of immunotherapy. The aim of this study was to evaluate the outcome of patients (pts) with NSCLC previously undergone to RT before receiving PD-1 inhibitors. Methods: We conducted an observational, retrospective analysis of 63 consecutive pts with advanced NSCLC who received RT followed by PD-1 inhibitors at five Italian institutions. Tumor response to treatment was defined according to Response Evaluation Criteria in Solid Tumors version 1.1. Median overall survival (OS) and the 95% confidence interval (CI) were estimated with the Kaplan -Meier method. Results: 63 pts (median age 66 years; male:60.3%) with advanced NSCLC (adenocarcinoma [adc]:71.4%; squamous cells [sqc]:28.6%) were treated with PD-1 inhibitors after RT. RT was delivered a median of 70 days before the start of immunotherapy.47 pts(74.5%)received extracranical RT and 16 pts (25.7%) performed cranial irradiation. Median OS was 11.7 months (mo) [95% CI, 4.7-18.7] (adc: 13.0 mo [95% CI,7.3-18.7], sqc 5.1 mo [95%CI,2.9-7.3]). Median progression free survival (PFS) was 5.1 mo [95% CI,2.5-7.7] (adc: 9.0 mo[ 95% CI,2.6-15.3]; sqc: 3.5 mo [95% CI,2.0-5.1]). A better performance status (PS) according to ECOG scale was associated with an improved OS (PS 0[21 pts]: 15.4 mo [95% CI,10.8-19.9]; PS1[33 pts]: 11.7 mo [95%CI,4.0-19.4]; PS2[9 pts]: 4.1 mo [95% CI,0.9-7.3]). Median OS in 46 pts who received ≤ 1 previous systemic therapy was 13.0 mo [95% CI, 9.4-16.6] and in 17 pts who received ≥2 previous treatments was 7.4 mo [95% CI, 3.1-11.7]. Median OS in 45 pts aged &lt; 70 years was 11.7 mo [95% CI, 4.7-18.7] and in 18 elderly (≥ 70 years) was 6.5 mo [95% CI, 0.0-17.7]. 9(14.3%) partial response, 23(36.5%) stable disease and 25(39.7%) progressive disease have been observed. Conclusions: The synergic combination of RT and PD-1 inhibitors leads to an enhancement of systemic antitumor immune responses, triggering the abscopal effect, resulting in prolonged OS.
MicroRNA-663 induces immune dysregulation by inhibiting TGF-β1 production in bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus
Authors: Linyu Geng, Xiaojun Tang, Kangxing Zhou, Dandan Wang, Shiying Wang, Genhong Yao, Weiwei Chen, Xiang Gao, Wanjun Chen, Songtao Shi, Nan Shen, Xuebing Feng, Lingyun Sun
Journal: Cellular and Molecular Immunology (2018)
Trauma and Burns Course
Authors: Krzysztof Rakowski, Niroshan Sivathasan
Journal: BMJ (2010)

The Trauma and Burns Course is a one day course organised by the plastic surgery department at Queen Victoria Hospital NHS Foundation Trust, East Grinstead, West Sussex. The day is made up of a series of lectures focusing on the assessment of non-orthopaedic trauma. All the lectures are presented by consultants.

The course is aimed at doctors and nurses in emergency medicine, but a number of surgical trainees, paramedics, and medical students also attended, all of whom commented that they found the level …
miR-125b-5p and miR-99a-5p downregulate human γδ T-cell activation and cytotoxicity
Authors: Yuli Zhu, Siya Zhang, Zinan Li, Huaishan Wang, Zhen Li, Yu Hu, Hui Chen, Xuan Zhang, Lianxian Cui, Jianmin Zhang, Wei He
Journal: Cellular and Molecular Immunology (2018)
In suspected OSA, home respiratory polygraphy was noninferior to polysomnography for reducing symptoms
Authors: KoKo Aung
Journal: Annals of Internal Medicine (2018)

Source Citation Corral J, Sánchez-Quiroga MA, Carmona-Bernal C, et al; Spanish Sleep Network. Conventional polysomnography is not necessary for the management of most patients with suspected obstructive sleep apnea. Noninferiority, randomized controlled trial. Am J Respir Crit Care Med. 2017;196:1181-90. 28636405
Cyclin D1-mediated microRNA expression signature predicts breast cancer outcome
Authors: Guangxue Wang, Michael Gormley, Jing Qiao, Qian Zhao, Min Wang, Gabriele Di Sante, Shengqiong Deng, Lin Dong, Tim Pestell, Xiaoming Ju, Mathew C. Casimiro, Sankar Addya, Paolo Fortina, Ayden Tozeren, Qinchuan Li, Zuoren Yu, Richard G. Pestell
Journal: Theranostics (2018)

Background: Genetic classification of breast cancer based on the coding mRNA suggests the evolution of distinct subtypes.Whether the non-coding genome is altered concordantly with the coding genome and the mechanism by which the cell cycle directly controls the non-coding genome is poorly understood.Methods: Herein, the miRNA signature maintained by endogenous cyclin D1 in human breast cancer cells was defined.In order to determine the clinical significance of the cyclin D1-mediated miRNA signature, we defined a miRNA expression superset from 459 breast cancer samples.We compared the coding and non-coding genome of breast cancer subtypes.Results: Hierarchical clustering of human breast cancers defined four distinct miRNA clusters (G1-G4) associated with distinguishable relapse-free survival by Kaplan-Meier analysis.The cyclin D1-regulated miRNA signature included several oncomirs, was conserved in multiple breast cancer cell lines, was associated with the G2 tumor miRNA cluster, ERα + status, better outcome and activation of the Wnt pathway.The coding and non-coding genome were discordant within breast cancer subtypes.Seed elements for cyclin D1-regulated miRNA were identified in 63 genes of the Wnt signaling pathway including DKK.Cyclin D1 restrained DKK1 via the 3'UTR.In vivo studies using inducible transgenics confirmed cyclin D1 induces Wnt-dependent gene expression. Conclusion:The non-coding genome defines breast cancer subtypes that are discordant with their coding genome subtype suggesting distinct evolutionary drivers within the tumors.Cyclin D1 orchestrates expression of a miRNA signature that induces Wnt/β-catenin signaling, therefore cyclin D1 serves both upstream and downstream of Wnt/β-catenin signaling.
EFFECT OF CHRONIC KIDNEY DISEASE ON DIFFERENT INTENSITY STATIN UTILIZATION IN PATIENTS WITH CORONARY ARTERY DISEASE: A SINGLE TERTIARY CENTER EXPERIENCE
Authors: Efstratios Koutroumpakis, Heather Stahura, Elvira Gosmanova, Stephanie Jou, Edward Philbin, William Boden, Radmila Lyubarova
Journal: Journal of the American College of Cardiology (2018)