tbuckley/cabot-search huggingface dataset:
Randomized Noninferiority Trial of Telephone vs In-Person Disclosure of Germline Cancer Genetic Test Results
Authors: Angela R Bradbury, Linda J Patrick-Miller, Brian L Egleston, Michael J Hall, Susan M Domchek, Mary B Daly, Pamela Ganschow, Generosa Grana, Olufunmilayo I Olopade, Dominique Fetzer, Amanda Brandt, Rachelle Chambers, Dana F Clark, Andrea Forman, Rikki Gaber, Cassandra Gulden, Janice Horte, Jessica M Long, Terra Lucas, Shreshtha Madaan, Kristin Mattie, Danielle McKenna, Susan Montgomery, Sarah Nielsen, Jacquelyn Powers, Kim Rainey, Christina Rybak, Michelle Savage, Christina Seelaus, Jessica Stoll, Jill E Stopfer, Xinxin (Shirley) Yao
Journal: JNCI Journal of the National Cancer Institute (2018)

Germline genetic testing is standard practice in oncology. Outcomes of telephone disclosure of a wide range of cancer genetic test results, including multigene panel testing (MGPT) are unknown. Patients undergoing cancer genetic testing were recruited to a multicenter, randomized, noninferiority trial (NCT01736345) comparing telephone disclosure (TD) of genetic test results with usual care, in-person disclosure (IPD) after tiered-binned in-person pretest counseling. Primary noninferiority outcomes included change in knowledge, state anxiety, and general anxiety. Secondary outcomes included cancer-specific distress, depression, uncertainty, satisfaction, and screening and risk-reducing surgery intentions. To declare noninferiority, we calculated the 98.3% one-sided confidence interval of the standardized effect; t tests were used for secondary subgroup analyses. Only noninferiority tests were one-sided, others were two-sided. A total of 1178 patients enrolled in the study. Two hundred eight (17.7%) participants declined random assignment due to a preference for in-person disclosure; 473 participants were randomly assigned to TD and 497 to IPD; 291 (30.0%) had MGPT. TD was noninferior to IPD for general and state anxiety and all secondary outcomes immediately postdisclosure. TD did not meet the noninferiority threshold for knowledge in the primary analysis, but it did meet the threshold in the multiple imputation analysis. In secondary analyses, there were no statistically significant differences between arms in screening and risk-reducing surgery intentions, and no statistically significant differences in outcomes by arm among those who had MGPT. In subgroup analyses, patients with a positive result had statistically significantly greater decreases in general anxiety with telephone disclosure (TD –0.37 vs IPD +0.87, P = .02). Even in the era of multigene panel testing, these data suggest that telephone disclosure of cancer genetic test results is as an alternative to in-person disclosure for interested patients after in-person pretest counseling with a genetic counselor.
BMA is concerned over specialty selection test pilot
Authors: Abi Rimmer
Journal: BMJ (2013)

The BMA’s Junior Doctors Committee has said it is concerned about the specialty selection test for doctors in training, which will be piloted in January 2014.

The committee wrote to Health Education England last week outlining its concerns about the test. It said that it was “unable to support the pilot or the future implementation of the SST [specialty selection test] as is currently proposed.”

The committee sent the letter after 5000 applicants to first year specialty training and core training programmes were emailed and invited …
Abstract 13502: Glucagon-like Peptide-1 Directly Promotes Angiogenesis via PKA/AMPK-dependent Autophagy in Endothelial Cells
Authors: Akio Monij, Yasuko K Bando, Morihiko Aoyama, Haruya Kawase, Toko Mitsui, Atsuya Shimizu, Toyoaki Murohara
Journal: Circulation (2014)

Introduction: We recently reported the impact of glucagon-like peptide-1 (GLP-1) on myocardial remodeling observed in type 2 diabetic mice (T2DM) via cyclic-AMP-dependent activation of autophagy in myocardium; however, it remains unclear whether GLP-1 may modulates capillary formation in heart. Hypothesis/AIM: We thus evaluated the impact of GLP-1 on angiogenesis and its link to endothelial autophagy. Methods: T2DM was treated with Ex4 (24 nmole/kg/day for 4 weeks). Cardiac capillary density was measured by immunohistology. Cultured HUVECs were used for in vitro experiments. Changes in activities of autophagy (LC3-turnover assay and protein levels of p62 and Beclin1), and angiogenesis (tube formation assay and Akt/AMPK/eNOS activity), were evaluated.[[Unable to Display Character: &amp;#8232;]] Role of PKA was assessed by CREB phosphorylation and RNA interference (siRNA for catalytic subunit of PKA). Effect of autophagy was assessed by use of pharmacological inhibitor 3MA and siRNA of autophagy-related gene (ATG) 5 , ATG7, and p62. Results: Immunohistochemical analyses revealed that T2DM exhibited reduced cardiac capillary density, which was reversed by Ex-4 with concomitant amelioration of systemic diabetic condition. Ex-4 treated heart exhibited increase in myocardial cyclic AMP concentration. We thus observed direct impact of Ex-4 and cyclic AMP elevation on HUVECs, in which GLP-1 receptor expression was confirmed by immunoblot and QPCR. In vitro angiogenesis assay revealed that Ex-4 and PKA enhancers (10 μM forskolin and 1 mM 8-bromo-cyclic AMP) facilitated angiogenesis and autophagy in HUVECs. The PKA/AMPK/eNOS phosphorylation levels of Ex-4-treated HUVECs were elevated. Of note, each Akt activity remains unchanged. PKA inhibitors (H89, RP-cAMP, siRNA) abrogated the increase in phosphorylation of AMPK/eNOS axis induced by Ex-4 in HUVECs. Tube formation assay revealed that Ex-4 and PKA enhancers augmented in vitro angiogenesis, which were abrogated by inhibition of autophagy and AMPK using pharmacological inhibitors (3MA and compound C) and siRNA for autophagy-related gene (ATG) 5 , ATG7, p62, and catalytic subunit of AMPK. [[Unable to Display Character: &amp;#8232;]] Conclusions: GLP-1 directly promoted angiogenesis via the PKA/AMPK-dependent autophagic activation.
National interdeanery transfer system launches
Authors: Helen Jaques
Journal: BMJ (2013)

A UK interdeanery transfer system has been launched to simplify the process for junior doctors who wish to complete their training in a different geographical region to that of their initial appointment.

The system, hosted by the London Deanery, will centrally collate trainees who wish to transfer and transfer slots that are available, making it easier to match junior doctors to vacant posts across the country. The deanery said that the process would ensure consistent decision …
Deficiency in T follicular regulatory cells promotes autoimmunity
Authors: Weiwei Fu, Xindong Liu, Xiang Lin, Han Feng, Lin Sun, Shuran Li, Hairong Chen, Hong Tang, Liwei Lu, Wei Jin, Chen Dong
Journal: The Journal of Experimental Medicine (2018)

T follicular regulatory (Tfr) cells are a new subset of regulatory T (T reg) cells localized in the germinal center to limit the humoral response. Until now, the physiological function of Tfr cells has been largely unknown. In this study, we developed a Bcl6fl/flFoxp3Cre mouse to analyze the function of Tfr cells in immune and autoimmune responses. These mice exhibited enhanced immunity to influenza virus; moreover, Bcl6fl/flFoxp3Cre/Cre mice developed late-onset spontaneous autoimmune diseases, affecting the salivary glands with lymphocyte infiltration and antibody deposition. In a mouse experimental Sjögren’s syndrome model, ablation of Bcl6 in T reg cells greatly enhanced disease development. Conversely, Bcl6fl/flCd4Cre mice were protected in the model. Thus, our study indicates that Tfr cells control autoimmune diseases and can be targeted in infectious and autoimmune disease.
THIRTY DAY CLINICAL OUTCOMES FOLLOWING IMPLEMENTATION OF CYP2C19 GENOTYPE-GUIDED DUAL ANTIPLATELET THERAPY
Authors: Melissa Klein, Vindhya B. Sriramoju, Alexandra Cervantes, Nicholas Varunok, Shivanshu Madan, Karen Weck, Craig Lee, George Stouffer
Journal: Journal of the American College of Cardiology (2018)
INFLUENCE OF METABOLIC SYNDROME AND ITS COMPONENTS ON DISEASE PROGRESSION AND OUTCOMES IN AORTIC STENOSIS IN PATIENTS WITH BICUSPID AORTIC VALVES
Authors: Sooyoun Lee, Chi Young Shim, In-Jeong Cho, Hyuk-Jae Chang, Geu-Ru Hong, Dal Soo Lim, Sook-Jin Lee, Mi-Young Park, Jong-Won Ha, Namsik Chung
Journal: Journal of the American College of Cardiology (2018)
DIFFERENT INFLUENCE OF MITRACLIP THERAPY ON MITRAL VALVE GEOMETRY BETWEEN PATIENTS WITH ATRIAL AND FUNCTIONAL MITRAL REGURGITATION: A REAL TIME THREE-DIMENSIONAL TRANSESOPHAGEAL ECHOCARDIOGRAPHY STUDY
Authors: Takafumi Nagaura, Atsushi Hayashi, Satoshi Yamaguchi, Jun Yoshida, Tetsuo Kamiyama, Florian Rader, Robert Siegel, Saibal Kar, Takahiro Shiota
Journal: Journal of the American College of Cardiology (2018)
Ethical Obligations Regarding Short-Term Global Health Clinical Experiences: An American College of Physicians Position Paper
Authors: Matthew DeCamp, Lisa Soleymani Lehmann, Pooja Jaeel, Carrie Horwitch
Journal: Annals of Internal Medicine (2018)

This American College of Physicians position paper aims to inform ethical decision making surrounding participation in short-term global health clinical care experiences. Although the positions are primarily intended for practicing physicians, they may apply to other health care professionals and should inform how institutions, organizations, and others structure short-term global health experiences. The primary goal of short-term global health clinical care experiences is to improve the health and well-being of the individuals and communities where they occur. In addition, potential benefits for participants in global health include increased awareness of global health issues, new medical knowledge, enhanced physical diagnosis skills when practicing in low-technology settings, improved language skills, enhanced cultural sensitivity, a greater capacity for clinical problem solving, and an improved sense of self-satisfaction or professional satisfaction. However, these activities involve several ethical challenges. Addressing these challenges is critical to protecting patient welfare in all geographic locales, promoting fair and equitable care globally, and maintaining trust in the profession. This paper describes 5 core positions that focus on ethics and the clinical care context and provides case scenarios to illustrate them.
A randomized phase 2 study of nivolumab monotherapy versus nivolumab combined with ipilimumab in patients with metastatic or unresectable gastrointestinal stromal tumor (GIST).
Authors: Arun S. Singh, Bartosz Chmielowski, J. Randolph Hecht, Lee S. Rosen, Xiaoyan Wang, Sandra Brackert, Carlos R. Adame, Paulina J Linares, Elena Schink, Lisa Marie Marubio, Frederick C. Eilber
Journal: Journal of Clinical Oncology (2018)

55 Background: The therapy with tyrosine kinase inhibitors changed the prognosis of patients with advanced GIST. Unfortunately, most of the tumors become resistant to therapy and patients succumb to the disease. New therapies for this patient population are needed. Here we report interim analyses of safety and efficacy in advanced GIST patients treated with immunotherapy. Methods: Patients with advanced/metastatic GIST progressing on at least imatinib were enrolled on a randomized, parallel group, unblinded phase 2 trial of either nivolumab(nivo) (240 mg Q2wks) or nivo (240 mg Q2wks) with ipilimumab(ipi) (1mg/kg Q6wks) for up to 2 years. The primary endpoint was the objective response rate (ORR) of nivo alone or nivo + ipi by RECIST 1.1 criteria. Patients were randomized 1:1 and the response was assessed every 8 weeks. With a sample size of 20 per group, an exact binomial test with a nominal 0.050 one-sided significance level will have 82% power to detect the difference between the null hypothesis response rate 1.5% and the alternative response rate of 15%. Secondary objectives are to ascertain the PFS, CBR, RR by Choi criteria and safety. Blood and biopsies are also being collected. Results: To date, 14 patients (median # of prior therapies: 4) have started on trial and 8 remain on treatment. In the nivo only arm, 3/7 patient had SD for a CBR of 42.8 %. The median PFS of the nivo arm was 8 weeks. In the nivo + ipi arm, 1/5(20%) patients had a PR and 1/5 have SD for a CBR of 40%; 2 patients were censored. The median PFS of the nivo + ipi arm was 8.43 weeks. 1 patient in the nivo arm had grade 3 fatigue and 1 patient in the nivo + ipi arm had grade 3 diarrhea. Pretreatment biopsies have been obtained in all patients and blood has been collected on all patients for correlative analysis. Conclusions: In a heavily pretreated GIST population, durable responses and disease control were observed. To date, the drugs have been well tolerated and no new safety signals have been observed in this disease state. Clinical trial information: NCT02880020.
BMA is urged to reopen negotiations with government on changes to NHS pension scheme
Authors: Helen Jaques
Journal: BMJ (2013)

Doctors have urged the BMA to hold further “urgent” negotiations with the government over changes to the NHS pension scheme.

Representatives at the association’s annual meeting in Edinburgh agreed this week that changes to the NHS pension scheme passed by parliament in April would have significant detrimental effects on doctors’ morale, recruitment, and retention.

Last year the government proposed changing the NHS pension scheme by replacing the current final salary pension arrangements with a career average scheme and by increasing the normal pension age in line with the state pension age.1 …
Masters degree in performance and media health
Authors: Chris Bowen
Journal: BMJ (2007)

Credit: COMSTOCK COMPLETE



FURTHER INFORMATION 

On my course there were medics, agents, orchestral musicians, singers, and music teachers. The course is not vocational training but provides an excellent overview of performing arts medicine and would suit any doctor who wishes to manage performing artists.

The degree is offered by Thames Valley University in Ealing, London. It was set up by performance psychologist Andrew Evans with the participation …
Diggers by the doctors' residence⇓
Authors: Nicola Sharp
Journal: BMJ (2004)

“I need your help, Douglas.” Martha sat in the coffee room in the theatre suite under a large banner which read: MISS MARTHA MILLSTONE'S SIT-IN. SAVE OUR SERVICES.

“I've come to tell you something important,” said Douglas. “I've made a decision.”

“Never mind about that,” said Martha. “Think about me stuck here in theatre twenty four hours a day, trying to save the hospital.”

“You like theatre, mother. It's your favourite place.”

“Humph,” said Martha.

“I've been thinking,” said Douglas.

“Don't think, act,” said Martha.

“And I've decided—”

“You must get two things for me, your father and some whisky.”

“I'll ask Dad to bring the whisky.”

“You can't do that. He thinks I've given up.”

“You shouldn't really be drinking, mother. Not at work.”

“I've been drinking all my working life. It hasn't done me any harm. Now go and do as I say.”

“But I need to tell you about my decision.”

“Get the whisky first.”

\* * *|

“What are those diggers doing by the doctors' residence?” asked Janet. The junior doctors crowded around the seminar room window.

“Why have they torn up the car park?” asked Alice.

“What's the crane doing?” asked Douglas.

“You …
COX-2/PGE2 Axis Regulates HIF2α Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment
Authors: Xiao-Feng Dong, Tian-Qi Liu, Xu-Ting Zhi, Jie Zou, Jing-Tao Zhong, Tao Li, Xiang-Lan Mo, Wei Zhou, Wen-Wen Guo, Xia Liu, Yuan-Yuan Chen, Meng-Yang Li, Xiao-Gang Zhong, Ya-Min Han, Zhong-Hao Wang, Zhao-Ru Dong
Journal: Clinical Cancer Research (2018)

Purpose: Hypoxia-inducible factor-2α (HIF2α) is regarded as a preferential target for individualized hepatocellular carcinoma (HCC) treatment and sorafenib resistance. Our study aimed to identify the regulatory mechanisms of HIF2α activity under hypoxic conditions. We sought to determine whether the COX-2/PGE2 axis is involved in the regulatory mechanisms of HIF2α activity and of sorafenib resistance in hypoxic HCC cells.Experimental Design: The cell viability, migration, and invasion abilities were measured to analyze the effects of HIF2α on hypoxic HCC cells. Both in vitro and in vivo HCC models were used to determine whether the COX-2/PGE2 axis is a driver of HIF2α level and activity, which then reduces the sensitivity of sorafenib treatment in hypoxic HCC cells.Results: Under hypoxic conditions, the COX-2/PGE2 axis effectively stabilized HIF2α and increased its level and activity via decreasing von Hippel-Lindau protein (p-VHL) level, and also enhanced HIF2α activity by promoting HIF2α nuclear translocation via MAPK pathway. The activation of HIF2α then led to the enhanced activation of VEGF, cyclin D1, and TGFα/EGFR pathway to mediate HCC development and reduce the sensitivity of sorafenib. More importantly, COX-2-specific inhibitors synergistically enhanced the antitumor activity of sorafenib treatment.Conclusions: Our data obtained demonstrate that the COX/PGE2 axis acts as a regulator of HIF2α expression and activity to promote HCC development and reduce sorafenib sensitivity by constitutively activating the TGFα/EGFR pathway. This study highlights the potential of COX-2-specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment. Clin Cancer Res; 24(13); 3204-16. ©2018 AACR.
NON-INVASIVE DETECTION OF HYPERKALEMIA WITH A SMARTPHONE ELECTROCARDIOGRAM AND ARTIFICIAL INTELLIGENCE
Authors: Conner D. Galloway, Alexander V. Valys, Frank L. Petterson, Vivek P. Gundotra, Daniel L. Treiman, David E. Albert, John J. Dillon, Zachi I. Attia, Paul A. Friedman
Journal: Journal of the American College of Cardiology (2018)
Evaluation of predictive biomarkers for nivolumab in metastatic clear cell renal cell carcinoma (mccRCC) using RECIST and immune-related (IR) RECIST.
Authors: Jean-Christophe Pignon, Opeyemi Jegede, Christine Horak, Megan Wind-Rotolo, Paul J. Catalano, Jonian Grosha, Abdallah Flaifel, Jesse Novak, Kathleen Margaret Mahoney, Gordon J. Freeman, Arlene Sharpe, Catherine J. Wu, F. Stephen Hodi, Robert J. Motzer, Toni K. Choueiri, Michael B. Atkins, David F. McDermott, Sabina Signoretti
Journal: Journal of Clinical Oncology (2018)

619 Background: Development of predictive biomarkers would help select patients more likely to respond to nivolumab (nivo) in mccRCC. Here we evaluated biomarkers for nivo using endpoints based on either RECIST 1.1 (ORR and PFS) or irRECIST (irORR and irPFS), which were proposed to more accurately predict benefit of immunotherapy. Methods: We retrospectively analyzed tumor tissues from the Checkmate 010 trial (PMID: 25452452). PD-L1 expression on tumor cells (TC) was studied by IHC. Percentages of CD8 + tumor infiltrating cells (TIC) expressing the immune checkpoints PD1, TIM3 and LAG3 (either alone or in various combination) were determined by immunofluorescence (IF) and their predictive value assessed by the presence of a dose response relationship (DRR) with PFS or irPFS. The candidate biomarkers were then correlated with clinical outcomes using optimized cutoffs. Results: As previously shown, TC PD-L1 expression was not associated with PFS or ORR. In contrast, pts with TC PD-L1 ≥1% had longer median irPFS and higher irORR (Table). None of the TIC phenotypes determined by IF displayed a DRR with PFS. Conversely, we found that % of CD8 + TIC that are PD1 + TIM3 - LAG3 - (% CD8 + PD1 + TIM3 - LAG3 - TIC) was correlated with irPFS (HR = 0.58, p = 0.007). At the optimized cutoff (36%), pts with high % CD8 + PD1 + TIM3 - LAG3 - TIC had longer median irPFS and higher irORR (Table). Notably, combination of TC PD-L1 expression with % CD8 + PD1 + TIM3 - LAG3 - TIC identified 3 groups of pts for which irPFS and irORR were significantly different (Table). Conclusions: Our results suggest that, in mccRCC, tumor-immune biomarkers for nivo response show improved association with clinical endpoints defined by irRECIST relative to RECIST. The increased predictive value of TC PD-L1 combined with immune checkpoints expression on CD8 + TIC seen in this cohort requires independent validation. [Table: see text]
Gastrointestinal Symptoms in Diabetes: Prevalence, Assessment, Pathogenesis, and Management
Authors: Yang T. Du, Christopher K. Rayner, Karen L. Jones, Nicholas J. Talley, Michael Horowitz
Journal: Diabetes Care (2018)

If you haven't measured something, you really don't know much about it.-Karl Pearson (attributed)Gastrointestinal (GI) symptoms represent an important and often unappreciated cause of morbidity in diabetes, although the significance of this burden across the spectrum of patients and the underlying pathophysiology, including the relationship of symptoms with glycemic control, remain poorly defined. The relevance of GI symptoms and the necessity for their accurate assessment have increased with the greater focus on the gut as a therapeutic target for glucose lowering. This review addresses the prevalence, assessment, pathogenesis, and management of GI symptoms in diabetes, beginning with broad principles and then focusing on specific segments of the GI tract. We initially performed a literature search of PubMed by using synonyms and combinations of the following search terms: "gastrointestinal symptoms", "diabetes", "prevalence", "pathogenesis", "diagnosis", and "management". We restricted the search results to English only. Review papers and meta-analyses are presented as the highest level of evidence where possible followed by randomized controlled trials, uncontrolled trials, retrospective and observational data, and expert opinion.
Doctors defend specialist skills and CCT
Authors: Helen Jaques
Journal: BMJ (2013)

BMA representatives have stood up for specialist rather than generalist postgraduate training and for the certificate of completion of training (CCT) as the educational gold standard.

Doctors at the BMA’s annual representatives meeting in Edinburgh passed motions voting down the possibility of generalist only doctors and calling on the association to uphold the CCT and its equivalents as the internationally recognised end points of postgraduate training.

Speaking for the motion, foundation doctor Luke Boyle said that proposals in the ongoing “Shape of Training” review to adjust the balance between generalist and specialist …
Goldilocks Dosing of TKIs: A Dose that Is Just Right Leads to Optimal Outcomes
Authors: Brian I. Rini
Journal: Clinical Cancer Research (2018)

Abstract Higher concentrations of TKIs, such as pazopanib, are associated with improved outcomes in advanced RCC. A phase III trial failed to show disease-free survival benefit to pazopanib in the adjuvant setting, but improved DFS was seen in patients with higher Ctrough levels, supporting adequate drug exposure for optimal clinical outcome. Clin Cancer Res; 24(13); 2979–80. ©2018 AACR. See related article by Sternberg et al., p. 3005
Digoxin and Mortality in Patients With Atrial Fibrillation
Authors: Renato D. Lopes, Roberto Rordorf, Gaetano M. De Ferrari, Sergio Leonardi, Laine Thomas, Daniel M. Wojdyla, Peter Ridefelt, John H. Lawrence, Raffaele De Caterina, Dragos Vinereanu, Michael Hanna, Greg Flaker, Sana M. Al-Khatib, Stefan H. Hohnloser, John H. Alexander, Christopher B. Granger, Lars Wallentin
Journal: Journal of the American College of Cardiology (2018)
PROGNOSTIC VALUE OF THE INDEX OF MICROCIRCULATORY RESISTANCE AFTER PERCUTANEOUS CORONARY INTERVENTION IN PATIENTS WITH STABLE CORONARY ARTERY DISEASE
Authors: Takeshi Nishi, Tadashi Murai, Giovanni Ciccarelli, Yuhei Kobayashi, Katsuhisa Waseda, Atsushi Hirohata, Tetsuya Amano, Emanuele Barbato, Tsunekazu Kakuta, William Fearon
Journal: Journal of the American College of Cardiology (2018)