tbuckley/cabot-search huggingface dataset:
HER2 positivity in brain metastases from gastrointestinal primary malignancies.
Authors: Devarati Mitra, Helen Alice Shih, Kevin Oh, Priscilla Brastianos, Jennifer Y Wo, William Curry, Jeffrey W. Clark, Aparna Parikh, Ryan Bruce Corcoran, David P. Ryan, Jochen K Lennerz, Theodore Sunki Hong
Journal: Journal of Clinical Oncology (2018)

61 Background: HER2 amplification in gastrointestinal (GI) cancers, beyond gastric cancer, is uncommon and as a result infrequently tested. In breast cancer, HER2 amplification has been associated with brain metastases (BM) with associated prognostic value and therapeutic opportunity. The purpose of this project was to determine if HER2 amplification is more frequent in GI cancer patients with brain metastases. Methods: Retrospective review of our institution’s medical record system identified all patients with GI primary malignancies who had resection of BM between 1999-2015 with tissue available. Fluorescence in-situ hybridization for HER2 amplification and immunohistochemistry for HER2 expression was performed on each sample and quantified by a board-certified pathologist. Results: Twenty-five GI cancer patients with BM were identified: 40% esophageal adenocarcinoma (AC), 12% esophageal squamous cell carcinoma (SCC), 44% colorectal AC and 4% pancreatic AC. At diagnosis 36% had metastatic disease. A BM was the isolated first site of metastasis in: 11/13 esophageal cancers, 1/11 colorectal cancers and 1/1 pancreatic cancer. Two esophageal cancer patients and one colon cancer patient had BM at diagnosis but otherwise median time to BM was 30 months (range 4-127 months). There was a median of 1 BM with a maximum of 4 lesions per patient. The most common intracranial site was the cerebellum (40%) with a median metastasis size of 27 mm (range 5-55 mm). Overall, HER2 was amplified in 24% (n=6) with 4 of these patients having paired primary tumor tissue available. None of the primary tumor tissue was HER2 amplified. No colorectal cancer patients had HER2 amplification but 67% of esophageal SCC, 30% of esophageal AC and the only pancreatic AC patient had Her2 amplified and overexpressed brain metastases. Conclusions: HER2 amplification was enriched in esophageal SCC and AC patients who developed resectable BM despite none of these patients having HER2 amplification in their primary tissue. HER2 amplification testing in esophageal cancer patients with BM (regardless of histology) may lead to additional therapeutic options, even if primary tissue was negative for HER2 amplification.
Modernizing the World Health Organization List of Essential Medicines for Preventing and Controlling Cardiovascular Diseases
Authors: Sandeep P. Kishore, Evan Blank, David J. Heller, Amisha Patel, Alexander Peters, Matthew Price, Mahesh Vidula, Valentin Fuster, Oyere Onuma, Mark D. Huffman, Rajesh Vedanthan
Journal: Journal of the American College of Cardiology (2018)

The World Health Organization (WHO) Model List of Essential Medicines (EML) is a key tool for improving global access to medicines for all conditions, including cardiovascular diseases (CVDs). The WHO EML is used by member states to determine their national essential medicine lists and policies and to guide procurement of medicines in the public sector. Here, we describe our efforts to modernize the EML for global CVD prevention and control. We review the recent history of applications to add, delete, and change indications for CVD medicines, with the aim of aligning the list with contemporary clinical practice guidelines. We have identified 4 issues that affect decisions for the EML and may strengthen future applications: 1) cost and cost-effectiveness; 2) presence in clinical practice guidelines; 3) feedback loops; and 4) community engagement. We share our lessons to stimulate others in the global CVD community to embark on similar efforts.
Efficacy and safety of lipid lowering by alirocumab in chronic kidney disease
Authors: Peter P. Toth, Jamie P. Dwyer, Christopher P. Cannon, Helen M. Colhoun, Daniel J. Rader, Ashish Upadhyay, Michael J. Louie, Andrew Koren, Alexia Letierce, Jonas Mandel, Maciej Banach
Journal: Kidney International (2018)

Individuals with chronic kidney disease are at increased risk of premature cardiovascular disease. Among them, many with elevated low-density lipoprotein cholesterol (LDL-C) are unable to achieve optimal LDL-C on statins and require additional lipid-lowering therapy. To study this, we compared the LDL-C-lowering efficacy and safety of alirocumab in individuals with hypercholesterolemia with impaired renal function, defined as eGFR 30-59 ml/min/1.73 m2, to those without impaired renal function eGFR ≥60 ml/min/1.73 m2. A total of 4629 hypercholesterolemic individuals without or with impaired renal function, pooled from eight phase 3 ODYSSEY trials (double-blind treatments of 24-104 weeks), were on alirocumab 150 mg or 75/150 mg every two weeks vs. placebo or ezetimibe. Overall, 10.1% had impaired renal function and over 99% were receiving statin treatment. Baseline LDL-C in alirocumab and control groups was comparable in subgroups analyzed. LDL-C reductions at week 24 ranged from 46.1 to 62.2% or 48.3 to 60.1% with alirocumab among individuals with or without impaired renal function, respectively. Similar reductions were observed for lipoprotein (a), non-high-density lipoprotein cholesterol, apolipoprotein B, and triglycerides. Safety data were similar in both treatment subgroups, regardless of the degree of CKD. Renal function did not change over time in response to alirocumab. This post hoc efficacy analysis is limited by evaluation of alirocumab treatment effects on renal and lipid parameters by serum biochemistry. Thus, alirocumab consistently lowered LDL-C regardless of impaired renal function, with safety comparable to control, among individuals with hypercholesterolemia who nearly all were on statin treatment.
Activity-Dependent Downscaling of Subthreshold Synaptic Inputs during Slow-Wave-Sleep-like Activity In Vivo
Authors: Ana González-Rueda, Victor Pedrosa, Rachael C. Feord, Claudia Clopath, Ole Paulsen
Journal: Neuron (2018)

Activity-dependent synaptic plasticity is critical for cortical circuit refinement. The synaptic homeostasis hypothesis suggests that synaptic connections are strengthened during wake and downscaled during sleep; however, it is not obvious how the same plasticity rules could explain both outcomes. Using whole-cell recordings and optogenetic stimulation of presynaptic input in urethane-anesthetized mice, which exhibit slow-wave-sleep (SWS)-like activity, we show that synaptic plasticity rules are gated by cortical dynamics in vivo. While Down states support conventional spike timing-dependent plasticity, Up states are biased toward depression such that presynaptic stimulation alone leads to synaptic depression, while connections contributing to postsynaptic spiking are protected against this synaptic weakening. We find that this novel activity-dependent and input-specific downscaling mechanism has two important computational advantages: (1) improved signal-to-noise ratio, and (2) preservation of previously stored information. Thus, these synaptic plasticity rules provide an attractive mechanism for SWS-related synaptic downscaling and circuit refinement.
Implementation of the 2017 Berlin Concussion in Sport Group Consensus Statement in contact and collision sports: a joint position statement from 11 national and international sports organisations
Authors: Jon S Patricios, Clare L Ardern, Michael David Hislop, Mark Aubry, Paul Bloomfield, Carolyn Broderick, Patrick Clifton, Ruben J Echemendia, Richard G Ellenbogen, Éanna Cian Falvey, Gordon Ward Fuller, Julie Grand, Dallas Hack, Peter Rex Harcourt, David Hughes, Nathan McGuirk, Willem Meeuwisse, Jeffrey Miller, John T Parsons, Simona Richiger, Allen Sills, Kevin B Moran, Jenny Shute, Martin Raftery
Journal: British Journal of Sports Medicine (2018)

The 2017 Berlin Concussion in Sport Group Consensus Statement provides a global summary of best practice in concussion prevention, diagnosis and management, underpinned by systematic reviews and expert consensus. Due to their different settings and rules, individual sports need to adapt concussion guidelines according to their specific regulatory environment. At the same time, consistent application of the Berlin Consensus Statement’s themes across sporting codes is likely to facilitate superior and uniform diagnosis and management, improve concussion education and highlight collaborative research opportunities. This document summarises the approaches discussed by medical representatives from the governing bodies of 10 different contact and collision sports in Dublin, Ireland in July 2017. Those sports are: American football, Australian football, basketball, cricket, equestrian sports, football/soccer, ice hockey, rugby league, rugby union and skiing. This document had been endorsed by 11 sport governing bodies/national federations at the time of being published.
Postgraduate diploma in cognitive behaviour therapy (PGDipCBT)
Authors: M S Krishnan
Journal: BMJ (2005)

Who's it for? Mental health professionals concerned with inpatient care—that is, psychiatrists (specialist registrars and consultants), general practitioners, nurses, psychologists, and occupational therapists.

When did you do it? 2002.

Why did you do it? I wanted to get formal training and supervision in practising cognitive behaviour therapy (CBT) and to use it in my day to day practice. I also wanted to get involved in training.

How much effort did it entail? It is a one year part time diploma course, and you need to attend one day a week for workshops and supervision. The work and preparation depend on prior knowledge in the …
What sort of specialist doctors work in intensive care units in the United Kingdom?
Authors: Gavin Perkins
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.
NHS trusts should learn from John Lewis and consider benefits of mutual status, King’s Fund says
Authors: Matthew Limb
Journal: BMJ (2014)

More NHS organisations should be encouraged to become staff owned and staff led “mutuals” as a way of accelerating improvements in patient care, the King’s Fund has said.

Changing the law could allow hospital trusts to adopt mutual status instead of becoming a foundation trust, said the fund’s review of staff engagement and empowerment in the NHS.1 Other new mutuals could be formed from partnerships providing more integrated health and social care and services such as urgent, maternity, or mental healthcare, the review said.

The King’s Fund noted emerging evidence that mutuals delivered high levels of staff engagement and encouraged initiative and innovation, leading to better organisational performance. “We should be clearer about the scope for giving staff a stronger staff voice within the existing foundation trust model,” the review said. “This might include learning from the John Lewis Partnership and other successful mutuals on the mechanisms for recruiting staff representatives and supporting them in delivering their roles effectively.”

Chris Ham, chief executive of the fund, said that a variety of …
Are there any MSc courses in biostatistics?
Authors: Howard Clark
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>
Abstract 20716: Can Long-Term Endurance Exercise Change MicroRNA Profiles and Prevent Cardiovascular Disease?
Authors: Priscilla R Prestes, Brendan J O’Brien, Fadi J Charchar
Journal: Circulation (2016)

Introduction: Exercise improves cardiovascular fitness and reduces the incidence of cardiovascular disease (CVD). MicroRNAs (miR) are small non-coding RNA molecules that regulate gene expression and cardiovascular physiology. We investigated the effects of long-term endurance exercise on microRNA signatures in leukocytes. Methods: We sequenced total microRNAs from leukocytes of six athletes and six healthy age-matched controls using the Illumina TruSeq Small RNA library prep on MiSeq. Results: We found eight microRNAs (miR-17, 25, 27, 140, 142, 148, 191 and 423) differentially expressed between athletes and controls (-0.44<FC<1.17; FDR<0.1). miR-17 which is downregulated in patients with CVD was found to be upregulated (FC=0.48; P<0.01) in our athlete group. miR-27 known to induce hypertrophic cell growth was found to be downregulated (FC=-0.57; P<0.01) in athletes. Changes in these microRNAs could be a cause of cardioprotection caused by exercise. Furthermore, we found 7 novel microRNAs. Three novel micr...
THE EARLY EVALUATION OF HEART RATE VARIATION AFTER CATHETER ABLATION PREDICTS THE RECURRENCE ON CHRONIC PHASE IN PATIENTS WITH ATRIAL FIBRILLATION
Authors: Kenki Ashida, Takanao Mine, Hideyuki Kishima, Satoshi Takahashi, Masaharu Ishihara, Tohru Masuyama
Journal: Journal of the American College of Cardiology (2018)
PROGNOSTIC VALUE OF VASODILATOR-INDUCED ST SEGMENT CHANGES IN PATIENTS WITH NORMAL RBUDIUM-82 MYOCARDIAL PERFUSION IMAGING
Authors: Ahmed Hamad Aljizeeri, Dalia Ahmed, Mousa Alali Alfaris, Jabir Farea, Ihab Suliman, Awadelkarim A. Elneama, Misfer Aldosari, Henry Fielding, Amjad Ahmed, Ahmed Alsaileek, Mohsen Alharthi, Mouaz H. Al-Mallah
Journal: Journal of the American College of Cardiology (2018)
Half of foundation trainees now choose not to progress straight to specialty training
Authors: Abi Rimmer
Journal: BMJ (2017)

Half of those doctors who have successfully completed the foundation training programme chose not to go straight into specialty training in 2016.

The UK Foundation Programme Office carried out a survey of the career destinations of foundation year 2 (FY2) doctors who did their foundation training in August 2016.1 The UKFPO’s survey found that 50.4% of those who responded planned to go directly into specialty training.

The number of successful FY2s …
HEMODYNAMIC EFFICACY OF A NOVEL CATHETER-DEPLOYED INTRA-AORTIC MICRO-AXIAL ENTRAINMENT PUMP IN A PORCINE ACUTE HF MODEL
Authors: Farshad Raissi, Joggy George, Michael Cuchiara, Jason Heuring, Benjamin Hertzog, Reynolds Delgado
Journal: Journal of the American College of Cardiology (2012)
A cardiothoracic surgeon
Authors: Menaka Jegatheesan, Steven Gresham
Journal: BMJ (2007)

Michael Chester was recently awarded the Henley Customer Experience Leadership award for his patient focused approach.

Who's in charge, and in my opinion it ought to be the patient. Paternalism lies at the root of the problem with health care, and if you treat people like grown-ups and let them participate in decision making, giving them the information they need, they just take control. You're there to help them make good decisions because you provide them with the right information. If you take a paternalistic approach you make them feel insecure and impotent, and they become more dependent. I've learnt over the years to bend over backwards to educate patients to a level where they can make decisions themselves.

There is a constituency of doctors, especially in general practices, who understand the principle but don't have the time to do it. Young doctors in many …
Plagiarism: the thin grey line
Authors: Lynn Eaton
Journal: BMJ (2004)

<i>The internet makes it easier to copy other people9s work and pass it off as your own but it9s also easier to get caught. Punishments for plagiarism can be severe, including stopping a career before it has even started. Yet students are often given little advice.</i> Lynn Eaton <i>finds out more</i>
Access to medicine has widened, but there is more to do, two reports conclude
Authors: Caroline White
Journal: BMJ (2013)

Medicine has made great strides towards widening access to the profession, but higher education bodies must do more to ensure fair access, two reports have concluded.

The reports from the Social Mobility and Child Poverty Commission and the Supporting Professionalism in Admissions Programme said that socioeconomic disadvantage remains the greatest barrier to equitable access.

“The past 18 months have seen a notable increase in the commitment and activity in medicine,” notes the latest report from the Social Mobility and Child Poverty Commission.1 “Medicine has taken the first vital steps in tackling social mobility and is now showing leadership on the issue of fair access.”

This year the Medical Schools Council set up the Selecting for Excellence group, in a bid to widen participation,2 and the GMC included questions …
Repeat Transurethral Resection in Non–muscle-invasive Bladder Cancer: A Systematic Review
Authors: Marcus G.K. Cumberbatch, Beat Foerster, James W.F. Catto, Ashish M. Kamat, Wassim Kassouf, Ibrahim Jubber, Shahrokh F. Shariat, Richard J. Sylvester, Paolo Gontero
Journal: European Urology (2018)
Branchial-Cleft Sinus Manifesting as Recurrent Neck Abscess
Authors: Chin-Yee Lau, Hui-Tong Wong
Journal: New England Journal of Medicine (2018)

A 24-year-old man presented to the otolaryngology clinic with a recurrent neck abscess. Imaging revealed that the abscess was due to a sinus created by a branchial-cleft remnant.
P083 Comorbid TNF-mediated heart valve disease and chronic polyarthritis share common mesenchymal aetiopathogenesis
Authors: L Ntari, M Sakkou, P Chouvardas, I Mourouzis, A Prados, MC Denis, N Karagianni, C Pantos, G Kollias
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> Rheumatoid arthritis (RA) is a chronic condition characterised by prolonged inflammation of the joints leading to bone and cartilage destruction. The key molecular and cellular regulators of RA pathology are the Tumour Necrosis Factor (TNF) and the mesenchymal-origin Synovial Fibroblasts (SFs), respectively. Apart from the joint pathology, RA patients also show higher morbidity rates, mainly due to the development of extraarticular conditions including cardiovascular, gut and skin disease manifestations. The Tg197 arthritis model develops TNF-driven and mesenchymal synovial fibroblasts (SFs)-dependent polyarthritis. Here, we investigate whether this model develops, similarly to human patients, co-morbid heart pathology and we explore cellular and molecular mechanisms linking arthritis to cardiovascular comorbidities. <h3>Methods</h3> The established human TNF-transgenic model of arthritis (Tg197) was used to evaluate possible arthritis-related cardiovascular disease. We further studied the role of Valve Interstitial Cells (VICs) in the pathology, using the <i>ColVI-Cre</i> mouse which specifically targets mesenchymal cells. Tg197<i> ColVI-Cre Tnfr1</i><sup>fl/fl</sup> and Tg197<i> ColVI-Cre Tnfr1</i><sup>cneo/cneo</sup> mice were used to explore the role of mesenchymal TNF signalling in the developing heart valve disease. Similarities of pathogenic VICs and SFs were analysed by RNA-sequencing. <h3>Results</h3> Tg197 mice develop left-sided heart valve disease, characterised by valvular fibrosis with minimal signs of inflammatory cell infiltration and thickened areas, consisting almost entirely of <i>ColVI</i>-expressing mesenchymal VICs, indicating proliferation of this cell type as a hallmark of the observed phenotype. Development of the pathology results in valve stenosis and left ventricular dysfunction, accompanied by arrhythmic episodes and, occasionally, valvular regurgitation. TNF-dependency of the pathology was indicated by the disease amelioration following pharmacological inhibition or genetic ablation of TNF-signalling. Interestingly, Tg197-derived VICs exhibited an activated phenotype <i>ex vivo</i>, resembling the activation of pathogenic Tg197-derived SFs. A significant functional correlation between these two mesenchymal cells was further supported by RNA-seq analysis, suggesting common pathogenic cellular mechanisms operating in arthritis and cardiovascular comorbidities. <h3>Conclusions</h3> TNF-mediated joint pathologies, commonly associated with comorbid heart valve disease, are efficiently modelled in Tg197 arthritis model and are commonly underlined by mesenchymal cell-specific pathogenic mechanisms. <h3>Disclosure of interest</h3> None declared
Phase 1, multicenter, open-label study of single-agent bispecific antibody T-cell engager GBR 1342 in relapsed/refractory multiple myeloma.
Authors: Joshua Ryan Richter, Martin Wermke, John S. Kauh, Jonathan Back, Yacine Salhi, Venkateshwar Reddy, Eliel Bayever, Carl Ola Landgren
Journal: Journal of Clinical Oncology (2018)

TPS81 Background: Available therapies have improved outcomes in multiple myeloma but patients eventually relapse, requiring treatment with agents that are active in refractory disease. CD38, a transmembrane glycoprotein, is upregulated on myeloma cells and is a validated disease target, evidenced by the anti-myeloma activity of daratumumab, an anti-CD38 human IgG1κ monoclonal antibody. GBR 1342 is a CD3xCD38 bispecific antibody engineered (using Glenmark’s BEAT ® platform) to direct T-cells to CD38-expressing myeloma cells. In preclinical studies, GBR 1342 redirected the cytotoxic potential of T-cells to human myeloma cell lines in vitro and in mouse xenograft models. This ongoing, 2-part, first-in-human study aims to: (1) evaluate the safety profile and maximum tolerable dose (MTD) of GBR 1342 monotherapy in subjects with relapsed/refractory multiple myeloma ( &gt; 3 prior therapies); and (2) further elucidate the safety, tolerability, and preliminary clinical activity of GBR 1342 at the MTD. The study is also evaluating the mechanisms by which GBR 1342 redirects T-cells to tumor and enhances cytolytic activity of cytotoxic T-cells. Methods: In Part 1, intravenous GBR 1342 is administered on Day 1 and Day 15 in 28-day treatment cycles at escalating dose levels (Table). The first 4 cohorts consist of a single subject. Subsequent cohorts will enroll using a 3+3 design. In Part 2, 65 evaluable subjects will be treated at the MTD identified in Part 1 until disease progression or unacceptable toxicity occurs. Primary endpoints include frequency and severity of AEs, number of dose-limiting toxicities during Cycle 1 (Part 1 only), and objective response to GBR 1342 (Part 2 only). Secondary endpoints include pharmacokinetics and anti-tumor activity of GBR 1342 (objective response, progression-free and overall survival). [Table: see text]