tbuckley/cabot-search huggingface dataset:
Inhaled granulocyte–macrophage colony-stimulating factor for <i>Mycobacterium abscessus</i> in cystic fibrosis
Authors: John P. Scott, Yinduo Ji, Mathur Kannan, Mark E. Wylam
Journal: European Respiratory Journal (2018)

Nontuberculous mycobacteria (NTM) are an important emerging threat to cystic fibrosis (CF) patients. In North America, where the incidence of NTM in CF patients is ≥11.8%, Mycobacterium abscessus complex (MABSC), a multidrug-resistant NTM, accounts for ∼35% of these [1], is notoriously recognised as difficult to eradicate, and seriously affects morbidity and mortality in CF [2] as well as lung transplantation outcomes [3, 4]. The mechanisms for the increased incidence of MABSC infection in CF patients are not known. The immune response in CF patients is directed to the Th2 response, which is associated with poorer clinical outcome and accelerated decline in lung function. This Th2 pattern is associated with diminished interferon-γ production and lesser activation of macrophages. One activator of macrophages is granulocyte–macrophage colony-stimulating factor (GM-CSF), the Toll-like receptor activation of which includes phagocytosis, bactericidal activity, oxidative burst and cell adhesion in macrophages [5]. Two experimental findings support the plausibility that reduced GM-CSF-elicited macrophage activation may contribute to NTM and MABSC infection in CF. First, alveolar macrophages from in GM-CSF−/− mice exhibit defective phagocytosis, bacterial killing and reduced H2O2 production [6]. Second, although wild-type mouse models of M. abscessus pulmonary infection show limited morbidity and are limited in their usefulness to study NTM therapy GM-CSF knockout models of M. abscessus infection, mice either succumbed to the acute infection or the infection persisted to a chronic stage in the absence of exogenous GM-CSF [7]. Previously, we [8] and others have reported the successful use of inhaled GM-CSF to treat autoimmune pulmonary alveolar proteinosis and metastatic lung metastases [9] without toxicity. Herein, we treated two CF patients with M. abscessus who were experiencing a decline in pulmonary function and clinical stability. Inadequate innate GM-CSF may underlie the nontuberculous mycobacterium infection in cystic fibrosis <http://ow.ly/26n330iggNJ>
PHARMACODYNAMICS OF PRASUGREL AND TICAGRELOR IN PATIENTS WITH ACUTE CORONARY SYNDROME AND THE EFFECT OF SWITCHING TO CLOPIDOGREL FOR ECONOMIC AND OTHER REASONS: PLATELET REACTIVITY SUB-STUDY OF THE MULTICENTER RANDOMIZED PRAGUE-18 TRIAL
Authors: Roman Miklik, Jiri Knot, Robin Kralik, Martin Kamenik, Jiri Jarkovsky, Iuri Marinov, Zuzana Motovska
Journal: Journal of the American College of Cardiology (2018)
Trainees call for implementation of Shape of Training review to be paused
Authors: Abi Rimmer
Journal: BMJ (2015)

Fifteen organisations representing doctors in training have called for the implementation of last year’s major review of postgraduate medical education and training to be paused.

The organisations have published a joint statement in response to the UK-wide Shape of Training review, which was led by David Greenaway, vice chancellor of Nottingham University, and published in October 2013. The statement, addressed to UK health ministers, called for “a pause in any implementation of the Shape of Training recommendations” and “a full evaluation of the impact of Modernising Medical Careers before considering a further overhaul of training.” …
ABSENCE OF CORONARY ARTERY CALCIUM IS ASSOCIATED WITH A FAVORABLE ALL CAUSE AND CARDIOVASCULAR DISEASE SPECIFIC MORTALITY RISK AMONG STATIN CANDIDATES ACCORDING TO AMERICAN COLLEGE OF CARDIOLOGY/AMERICAN HEART ASSOCIATION (ACC/AHA) CHOLESTEROL MANAGEMENT GUIDELINES: CAC CONSORTIUM
Authors: Tanuja Rajan, Gowtham Grandhi, Zeina Dardari, Michael Miedema, Leslee Shaw, John Rumberger, Alan Rozanski, Mouaz H. Al-Mallah, Daniel Berman, Matthew Budoff, Michael Blaha, Khurram Nasir
Journal: Journal of the American College of Cardiology (2018)
Avelumab in patients with previously treated mesothelioma: Updated phase 1b results from the JAVELIN Solid Tumor trial.
Authors: Raffit Hassan, Anish Thomas, John J. Nemunaitis, Manish R. Patel, Jaafar Bennouna, Franklin Chen, Jean-Pierre Delord, Afshin Dowlati, Matthew H. Taylor, John D. Powderly, Ulka N. Vaishampayan, Claire F. Verschraegen, Hans Juergen Grote, Anja von Heydebreck, Kevin M. Chin, James L. Gulley
Journal: Journal of Clinical Oncology (2018)

166 Background: Avelumab, a human anti-PD-L1 IgG1 monoclonal antibody, is approved for treatment of metastatic Merkel cell carcinoma (US and EU) and advanced urothelial carcinoma progressed on platinum therapy (US). Here, we report updated phase 1b data for avelumab in patients (pts) with previously treated mesothelioma. Methods: Pts with unresectable pleural or peritoneal mesothelioma whose disease had progressed after platinum and pemetrexed therapy received avelumab 10 mg/kg IV Q2W until progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 wks (RECIST 1.1). Endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs; NCI CTCAE v4.0). Results: As of Dec 31, 2016, 53 pts were treated and followed for a median of 24.8 mos (range 16.8–27.8). Median age was 67 y (range 32–84). Pts had received a median of 2 prior lines of therapy (range 1–8). Confirmed ORR was 9.4% (95% CI 3.1–20.7; complete response in 1.9%, partial response in 7.5%). In pts with 1 (n = 18), 2 (n = 15) or ≥3 (n = 20) prior lines of therapy, ORR was 5.6%, 13.3% and 10.0% respectively. Median duration of response was 15.2 mos (95% CI 11.1–not estimable). 26 pts (49.1%) had stable disease as best response and the disease control rate was 58.5%. Median PFS was 4.1 mos (95% CI 1.4–6.2) and the 6-mo PFS rate was 38.0% (95% CI 24.2–51.7). Median OS was 10.9 mos (95% CI 7.5–21.0) and the 12-mo OS rate was 45.9% (95% CI 31.9–58.8). In evaluable pts with PD-L1+ (n = 16) and PD-L1− (n = 27) tumors (≥5% tumor cell cutoff), ORR was 18.8% (95% CI 4.0–45.6) and 7.4% (95% CI 0.9–24.3), and the 6-mo PFS rate was 37.5% (95% CI 14.1–61.2) and 42.0% (95% CI 23.1–59.8). 43 pts (81.1%) had a treatment-related (TR)AE, most commonly ( &gt; 10%) infusion-related reaction (35.8%; all grade 1/2), chills (15.1%), fatigue (15.1%) and pyrexia (11.3%). 5 pts (9.4%) had a grade ≥3 TRAE. 14 pts (26.4%) had an immune-related AE, which was grade ≥3 in 3 pts (5.7%; pneumonitis, colitis, and type 1 diabetes mellitus). No treatment-related deaths occurred. Conclusions: Avelumab showed clinical activity and acceptable safety in pts with previously treated mesothelioma. Clinical trial information: NCT01772004.
Certificate of Good Clinical Practice
Authors: Paul Grant
Journal: BMJ (2009)

This course is for all doctors interested in doing research at any level. Also, research nurses, pharmacists, and clinical research and clinical trials support staff may find the course useful.

I did the course and exam during my third year as a medical specialist registrar; this was while I was trying to get a clinical trial off the ground.

A basic understanding of Good Clinical Practice (an international set of standards regarding the organisation of research on humans) is a prerequisite for anyone carrying out or involved with clinical trials. I …
Military doctors will focus on research in times of peace, says surgeon general
Authors: Abi Rimmer
Journal: BMJ (2014)

Research will become a focus for Britain’s Defence Medical Services (DMS) after a withdrawal from Afghanistan, the services’ surgeon general has said.

Paul Evans, the surgeon general of the DMS, said that it was important for the medical military workforce to retain its skills and “impetus” after the withdrawal from Afghanistan. Speaking at a Royal Society of Medicine event in London, Evans said that carrying out research was one way that …
NHS should develop “system leaders” who work across organisations, King’s Fund says
Authors: Matthew Limb
Journal: BMJ (2015)

The NHS should do more to develop people as “system leaders” who can improve patient care by working across services and organisations, the King’s Fund has said.

The think tank has published a report by one of its senior fellows, Nicholas Timmins, which highlights the critical skills increasingly required to meet people’s complex health, care, and support needs during times of unprecedented pressures on services and finances.1 The case for “system leadership” in developing new, more sustainable, and better integrated models of care was also debated at a summit held by the King’s Fund in London on 20 May.

The report said that in some cases frontline teams would have to work to overcome professional …
Effect of CTLA-4 overexpression on response to ipilimumab in melanoma.
Authors: Mary Nesline, Igor Puzanov, Marc S. Ernstoff, Sarabjot Pabla, Jeffrey M. Conroy, Sean T. Glenn, Antonios Papanicolau-Sengos, Blake Burgher, Vincent Giamo, Jonathan Andreas, Maochun Qin, Felicia L. Lenzo, Mark Gardner, Carl Morrison
Journal: Journal of Clinical Oncology (2018)

190 Background: CD8 positive tumor infiltrating lymphocytes (TILS) are highly associated with immune response and prognosis, and are also under investigation as a marker of response to checkpoint inhibitors. Given lack of predictive biomarkers for ipilimumab, growing number of trials for new indications for combination ipilimumab + nivolumab, and evidence to support therapeutic target overexpression as markers of response, we examined the role of CTLA-4 expression and TILS in response to ipilimumab and combination ipilimumab + nivolumab in melanoma. Methods: Formalin-fixed paraffin embedded melanoma samples taken prior to treatment by ipilimumab (n = 36) or combination ipilimumab + nivolumab (n = 10) were evaluated by a comprehensive immune gene expression profile to establish the relationship between CTLA-4 and CD8 and therapeutic response (RECIST v1.1). Results: Increased CTLA-4 expression was moderately associated with increased TILS (r 2 = .41, p = .004). This was observed in the monotherapy group (r 2 = .38, p = .02), and was higher in the smaller combination therapy group, though not statistically significant (r 2 = .59, p = .06). Higher levels of TILS were observed in responders who achieved clinical benefit from either regimen within 6 months (n = 20). No significant difference was observed between responders (M = 57.1, SD = 30.2) and nonresponders (M = 48.6, SD = 32.9); t(44) = -.895, p = .376. Lower levels of CTLA-4 were observed in responders who achieved clinical benefit from either regimen within 6 months. No significant difference was observed between responders (M = 54, SD = 35) and nonresponders (M = 38.7, SD = 26.8); t(44) = 1.70, p = .09. The ratio of TILS to CTLA-4 expression was higher in responders who achieved clinical benefit within 6 months (n = 20).No significant difference was observed between responders (M = 5.2, SD = 14.0) and nonresponders (M = 1.4, SD = 2.7); t(41) = -1.2, p = .212. Conclusions: While not statistically significant, CTLA-4 expression in melanoma patients treated with either ipilimumab or combination ipilimumab + nivolumab was lower in responders compared to nonresponders. This analysis does not support the concept that over-expression of CTLA-4 is a biomarker of response to anti-CTLA-4 therapy.
Clinical utility of Foundation One tissue molecular profiling in men with metastatic prostate cancer.
Authors: Jason Zhu, Matthew D Tucker, Patrick Healy, Michael Sandon Humeniuk, Casey Jarvis, Daniel J. George, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2018)

318 Background: In the era of precision medicine, significant effort has been placed on identifying clinically actionable molecular targets to aid in the treatment of metastatic prostate cancer (mPC). Recent data supports homologous repair and mismatch repair deficiencies to guide the use of PARP inhibitors/platinum chemotherapy or pembrolizumab, respectively. We analyzed the clinical utility of Foundation One (FO) somatic genomic profiling in men with mPC. Methods: We performed a retrospective review of men with mPC in the Duke Cancer Center who received FO testing 01/2010 - 04/2017. We asked whether FO testing identified actionable genomic lesions that led to a change in clinical practice, and if men benefited from this novel genomic matched approach to treatment. Results: We identified 77 men with FO tests. Of these, 77% (59/77) had adequate tissue for FO testing. 76% had mCRPC, 42% had &gt; 3 prior systemic therapies (enzalutamide 51%, docetaxel 39%, abiraterone 41%, sip-T 34%, radium-223 22%). The most common FO genomic alterations were: TP53 deletion/mutation (37%), TMPRSS2-ERG fusion (32%), and PTEN loss (31%). FO revealed 207 genomic alterations, classified into actionable (6), potentially actionable (44), non-actionable (126), and non-informative (31). Of the 6 patients with actionable mutations (BRCA2, ATM, PALB mutation/loss), 4 (67%) received matched olaparib therapy and 3 had PSA or prolonged radiographic stabilization, with durations of therapy of 3-19 months. Of 28 men with potentially actionable genomic findings, 3 (11%) received targeted therapies, including olaparib for a CDK12 mutation, and pembrolizumab for a PMS2 mutation and for a PD-L2 genomic gain. No responses to pembro were observed; the man with a CDK12 mutation responded to olaparib for 8 months. Overall, 42% (25/59) of evaluable men did not have a targetable mutation; 4/77 (5%) had clinical benefits from testing. Conclusions: A small but significant minority (~5%) of men with mPC appear to benefit from FO somatic tumor profiling, particularly those with homologous repair deficiencies. Larger prospective studies are needed with clinical outcomes in order to further understand the clinical utility of routine FO testing in this setting.
RCGP will work with international doctors on membership exam issues
Authors: Abi Rimmer
Journal: BMJ (2014)

The Royal College of General Practitioners (RCGP) will work with international doctors’ organisations to address issues relating to its entrance exam.

The college said that it would work with the British Association of Physicians of Indian Origin (BAPIO) and the British International Doctors Association (BIDA) to support candidates. BAPIO had previously brought a legal challenge against the RCGP and the General Medical Council over the examination for membership of the RCGP (MRCGP). 

In April a High Court judge ruled that the …
Public Health England prematurely endorses e-cigarettes
Authors: Aryeh Greenberg, Ricardo J Jose
Journal: BMJ (2018)

We were struck by the permissiveness of the report commissioned by Public Health England on e-cigarettes compared with a contemporaneous US academy report.123

The PHE review states that “e-cigarette use alone or in combination with licensed medication and behavioural support . . . appear to be helpful in the short term.”1 By contrast, the US review says, “There is insufficient …
SEX-RELATED DIFFERENCE IN THE REGRESSION OF CORONARY ATHEROSCLEROSIS WITH THE PCSK9 INHIBITOR, EVOLOCUMAB: INSIGHTS FROM GLAGOV
Authors: Peta King, Rishi Puri, Christie Ballantyne, Leslie Cho, Danielle Brennan, Helina Kassahun, Ransi Somaratne, Scott Wasserman, Steven Nissen, Stephen Nicholls
Journal: Journal of the American College of Cardiology (2018)
Professor Sir Andy Haines, director of the London School of Hygiene and Tropical Medicine
Authors: Menaka Jegatheesan, Steven Gresham
Journal: BMJ (2008)

My fondest memory of being a student is the camaraderie, making friendships with other students and being in a supportive environment. There was also a combination of interest and anxiety about starting to work with patients, and I remember having mixed feelings about going to talk to them and examine them. It’s both stressful and exhilarating when you make that transition from preclinical to clinical subjects, but as you start getting more relaxed and more assured the experience becomes rewarding. In terms of the most upsetting experience, apart from the initial experience of dissection, which you get over after the first few weeks, it was probably dealing with terminal illness in young people. Communicating with young people with incurable illness, who were not much older than you, was extremely difficult, particularly when the issues were never discussed by teachers.

International health wasn’t really taught at all when I was a student. Today there is growing awareness of the interconnectedness of the United Kingdom with the rest of the world, which …
Female surgeons use Twitter to challenge stereotypes
Authors: Abi Rimmer
Journal: BMJ (2015)

Female surgeons from around the world have taken part in a campaign aimed at challenging sex stereotypes in the specialty.

Using the social networking site Twitter, female surgeons tweeted photographs of themselves combined with the hashtag #ILookLikeASurgeon, to challenge the stereotype that most surgeons are men. 

The campaign followed the success of #ILookLikeAnEngineer, which was launched by Isis Wenger, a …
GMC outlines plans for English language checks
Authors: Matthew Limb
Journal: BMJ (2013)

The General Medical Council has published its plans for ensuring that the English language skills of doctors from other European countries are adequate for safe practice in the UK.

The GMC launched a three month consultation on the proposals on Tuesday 17 September.1 This runs alongside the Department of Health’s consultation (launched on 7 September) on changes to the Medical Act 1983 to give the GMC the necessary powers, which are due to come into effect in 2014.2

The GMC’s chief executive, Niall Dickson, said that the new checks would prevent …
EFFECT OF POTENT P2Y12 INHIBITORS ON SAFETY AND EFFICACY OF BIVALIRUDIN COMPARED TO HEPARIN IN ACUTE CORONARY SYNDROME: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS
Authors: Aakash Garg, Sunil V. Rao, Amit Rout, Mohammad Thawabi, Najam Wasty, Marc Cohen
Journal: Journal of the American College of Cardiology (2018)
Progress in the management of IPF-related acute exacerbations: a goal for patients, respirologists and intensivists
Authors: Ganesh Raghu
Journal: European Respiratory Journal (2018)

I appreciate the expressed views of F. Vincent and colleagues, regarding the need to address treatment consideration of acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF). While the mortality of patients manifesting AE of IPF is unfortunately high, F. Vincent and colleagues argue that supportive care in the intensive care unit (ICU) is an appropriate consideration, including noninvasive and/or mechanical ventilation for patients. Indeed, well-informed patients may opt for such aggressive supportive measures in the ICU, and for some patients listed for lung transplantation, such aggressive supportive measures may serve as a "bridge" for a suitable lung to become available during a set time. Such decisions will need to be made on a case by case basis and tailored to patients' preferred choices, advance directives that patients may have in place and other individual needs. In addition, other confounding factors, such as comorbid conditions if present, which may have a poor outcome otherwise, should be taken into consideration when providing aggressive supportive care in the ICU for patients manifesting AE of IPF. Until clinical trial results are available, treatment decisions for acute exacerbations of IPF must be made on an individual basis <http://ow.ly/FFxi30hY7uz>
Development of a scoring system to predict hepatocellular carcinoma in Asians on antivirals for chronic hepatitis B
Authors: Yao-Chun Hsu, Terry Cheuk-Fung Yip, Hsiu J. Ho, Vincent Wai-Sun Wong, Yen-Tsung Huang, Hashem B. El-Serag, Teng-Yu Lee, Ming-Shiang Wu, Jaw-Town Lin, Grace Lai-Hung Wong, Chun-Ying Wu
Journal: Journal of Hepatology (2018)
Editor’s Choice: Class action
Authors: Tom Moberly
Journal: BMJ (2015)

The narrow tranche of society from which today’s doctors are drawn is emphasised in work discussed by Caroline White this week (http://careers.bmj.com/careers/advice/view-article.html?id=20021262). White looks at the efforts of the Selecting for Excellence Executive Group (SEEG) and others to improve access of students from disadvantaged groups to the medical profession.

Those from privileged backgrounds continue to be over-represented …
NOVEL ASSAY TO CALCULATE DONOR FRACTION OF CELL-FREE DNA IN HEART TRANSPLANTATION
Authors: William Ragalie, Karl Stamm, Pip Hidestrand, Mats Hidestrand, Mahnke Donna, Huan Ling Liang, Mary Goetsch, Gail Stendahl, Pippa Simpson, Ronit Katz, Aoy Tomita-Mitchell, Steven J. Kindel, Steven Zangwill, Michael Mitchell
Journal: Journal of the American College of Cardiology (2018)
Royal colleges concerned about junior contract’s impact on women
Authors: Abi Rimmer
Journal: BMJ (2016)

Medical royal colleges have expressed concerns that a new contract for junior doctors in England could unfairly disadvantage women.

On Thursday 31 March, NHS Employers published the new contract.1 At the same time the Department of Health published an equality analysis of the draft contract.2

Following its publication, a number of doctors expressed concerns about the analysis, which said that some aspects of the new contract would be “disadvantageous” to those who worked part time.3

The Royal College of Obstetrics and Gynaecology (RCOG), the Royal College of Physicians of Edinburgh …
WORLDWIDE PREVALENCE OF HYPERTENSION: A POOLED META-ANALYSIS OF 1670 STUDIES IN 71 COUNTRIES WITH 29.5 MILLION PARTICIPANTS
Authors: Hosni Salem, Doaa M. Hasan, Aya Eameash, Hazem Abd El-Mageed, Sama Hasan, Rehab Ali
Journal: Journal of the American College of Cardiology (2018)
The Expanding World of N-MYC–Driven Tumors
Authors: David S. Rickman, Johannes H. Schulte, Martin Eilers
Journal: Cancer Discovery (2018)

Enhanced and deregulated expression of N-MYC, a member of the MYC family of transcription factors, drives the development of multiple tumors, including tumors of the nervous and hematologic systems and neuroendocrine tumors in other organs. This review summarizes the cell-of-origin, biological features, associated signaling pathways, and current treatment strategies for N-MYC-driven tumors. We also highlight biological differences within specific tumor types that are driven by the different MYC proteins.Significance: N-MYC is a driver of multiple tumor types that are derived through a mechanism that involves direct differentiation within the same lineage (e.g., in the case of neuroblastoma, medulloblastoma, and acute myeloid leukemia) and is often associated with a poor prognosis. Emerging data suggest that N-MYC also drives other tumor types through a mechanism that promotes a lineage switch and that this switch may be exploited for therapeutic purposes. Cancer Discov; 8(2); 150-63. ©2018 AACR.
Price and the Evolution of the Physical Examination
Authors: John Kugler
Journal: JAMA Cardiology (2018)

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