tbuckley/cabot-search huggingface dataset:
Doctors can withdraw treatment from child on life support, says judge
Authors: Clare Dyer
Journal: BMJ (2018)

The parents of a 21 month old boy with an undiagnosed illness that is progressively destroying his brain have lost their High Court battle to try to keep him alive on life support.1

Mr Justice Hayden declared that continuing to provide ventilation for Alfie Evans would be “futile.” The treatment “now compromises Alfie’s future dignity and fails to respect his autonomy” and was no longer in his best interests, the judge said.

Alder Hey Children’s NHS Foundation Trust applied for the declaration after Alfie’s parents, Tom Evans and Kate James, refused to accept that nothing …
A Large-Scale, Exome-Wide Association Study of Han Chinese Women Identifies Three Novel Loci Predisposing to Breast Cancer
Authors: Bo Zhang, Men-Yun Chen, Yu-Jun Shen, Xian-Bo Zhuo, Ping Gao, Fu-Sheng Zhou, Bo Liang, Jun Zu, Qin Zhang, Sufyan Suleman, Yi-Hui Xu, Min-Gui Xu, Jin-Kai Xu, Chen-Cheng Liu, Nikolaos Giannareas, Ji-Han Xia, Yuan Zhao, Zhong-Lian Huang, Zhen Yang, Huai-Dong Cheng, Na Li, Yan-Yan Hong, Wei Li, Min-Jun Zhang, Ke-Da Yu, Guoliang Li, Meng-Hong Sun, Zhen-Dong Chen, Gong-Hong Wei, Zhi-Min Shao
Journal: Cancer Research (2018)

Genome-wide association studies have identified more than 90 susceptibility loci for breast cancer. However, the missing heritability is evident, and the contributions of coding variants to breast cancer susceptibility have not yet been systematically evaluated. Here, we present a large-scale whole-exome association study for breast cancer consisting of 24,162 individuals (10,055 cases and 14,107 controls). In addition to replicating known susceptibility loci (e.g., ESR1, FGFR2, and TOX3), we identify two novel missense variants in C21orf58 (rs13047478, Pmeta = 4.52 × 10-8) and ZNF526 (rs3810151, Pmeta = 7.60 × 10-9) and one new noncoding variant at 7q21.11 (P < 5 × 10-8). C21orf58 and ZNF526 possessed functional roles in the control of breast cancer cell growth, and the two coding variants were found to be the eQTL for several nearby genes. rs13047478 was significantly (P < 5.00 × 10-8) associated with the expression of genes MCM3AP and YBEY in breast mammary tissues. rs3810151 was found to be significantly associated with the expression of genes PAFAH1B3 (P = 8.39 × 10-8) and CNFN (P = 3.77 × 10-4) in human blood samples. C21orf58 and ZNF526, together with these eQTL genes, were differentially expressed in breast tumors versus normal breast. Our study reveals additional loci and novel genes for genetic predisposition to breast cancer and highlights a polygenic basis of disease development.Significance: Large-scale genetic screening identifies novel missense variants and a noncoding variant as predisposing factors for breast cancer. Cancer Res; 78(11); 3087-97. ©2018 AACR.
Is endocrinology a good choice of specialty for a doctor who has insulin dependent diabetes mellitus?
Authors: Tony Woolfson
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>
Current practice patterns surrounding fertility concerns in stage I seminoma patients: Survey of United States radiation oncologists.
Authors: Carl M Post, Aditya Jain, Catherine Degnin, Yiyi Chen, Michael Ellis Craycraft, Arthur Hung, Jerry Jeff Jaboin, Charles R. Thomas, Timur Mitin
Journal: Journal of Clinical Oncology (2018)

553 Background: Patients with testicular seminoma may face fertility issues because of their underlying disease as well as treatments they undergo. The current patterns of practice among US radiation oncologists aimed at assessing and preserving fertility in patients with Stage I seminoma are unknown. Methods: We surveyed practicing US radiation oncologists via an IRB-approved online questionnaire. Respondents’ characteristics, and perceived patient infertility rates were analyzed for association with treatment recommendations. Results: We received 353 responses, of whom one quarter (23%) consider themselves experts. A vast majority (84%) recommend observation as a default strategy. 52% routinely advise fertility assessment for patients prior to observation or chemotherapy, and 74% routinely do so prior to adjuvant RT. Nearly two-fifths believe that 10% and 30% of patients are infertile following orchiectomy. Thirty-seven and 22% believe infertility rates following para-aortic RT to be 30 and 50%, respectively. 80% routinely use clamshell scrotal shielding. Responders with higher perceived infertility rates are more likely to recommend fertility assessment/sperm banking (Fisher’s exact p&lt;0.0001). Responders who routinely advised fertility assessment were more likely to use clamshell shielding (Cochran-Armitage trend test p = 0.0007). Clamshell use was positively correlated with higher perceived infertility rates following para-aortic RT (Spearman’s correlation coefficient = 0.006). Conclusions: Despite a clear knowledge of fertility issues in men diagnosed with seminoma, there is no universal adoption of fertility assessment among US radiation oncologists.
Epigenetic Dysregulation of the Dynamin-Related Protein 1 Binding Partners MiD49 and MiD51 Increases Mitotic Mitochondrial Fission and Promotes Pulmonary Arterial Hypertension
Authors: Kuang-Hueih Chen, Asish Dasgupta, Jianhui Lin, François Potus, Sébastien Bonnet, James Iremonger, Jennifer Fu, Jeffrey Mewburn, Danchen Wu, Kimberly Dunham-Snary, Anne L. Theilmann, Zhi-Cheng Jing, Charles Hindmarch, Mark L. Ormiston, Allan Lawrie, Stephen L. Archer
Journal: Circulation (2018)

Mitotic fission is increased in pulmonary arterial hypertension (PAH), a hyperproliferative, apoptosis-resistant disease. The fission mediator dynamin-related protein 1 (Drp1) must complex with adaptor proteins to cause fission. Drp1-induced fission has been therapeutically targeted in experimental PAH. Here, we examine the role of 2 recently discovered, poorly understood Drp1 adapter proteins, mitochondrial dynamics protein of 49 and 51 kDa (MiD49 and MiD51), in normal vascular cells and explore their dysregulation in PAH.Immunoblots of pulmonary artery smooth muscle cells (control, n=6; PAH, n=8) and immunohistochemistry of lung sections (control, n=6; PAH, n=6) were used to assess the expression of MiD49 and MiD51. The effects of manipulating MiDs on cell proliferation, cell cycle, and apoptosis were assessed in human and rodent PAH pulmonary artery smooth muscle cells with flow cytometry. Mitochondrial fission was studied by confocal imaging. A microRNA (miR) involved in the regulation of MiD expression was identified using microarray techniques and in silico analyses. The expression of circulatory miR was assessed with quantitative reverse transcription-polymerase chain reaction in healthy volunteers (HVs) versus patients with PAH from Sheffield, UK (plasma: HV, n=29, PAH, n=27; whole blood: HV, n=11, PAH, n=14) and then confirmed in a cohort from Beijing, China (plasma: HV, n=19, PAH, n=36; whole blood: HV, n=20, PAH, n=39). This work was replicated in monocrotaline and Sugen 5416-hypoxia, preclinical PAH models. Small interfering RNAs targeting MiDs or an miR mimic were nebulized to rats with monocrotaline-induced PAH (n=4-10).MiD expression is increased in PAH pulmonary artery smooth muscle cells, which accelerates Drp1-mediated mitotic fission, increases cell proliferation, and decreases apoptosis. Silencing MiDs (but not other Drp1 binding partners, fission 1 or mitochondrial fission factor) promotes mitochondrial fusion and causes G1-phase cell cycle arrest through extracellular signal-regulated kinases 1/2- and cyclin-dependent kinase 4-dependent mechanisms. Augmenting MiDs in normal cells causes fission and recapitulates the PAH phenotype. MiD upregulation results from decreased miR-34a-3p expression. Circulatory miR-34a-3p expression is decreased in both patients with PAH and preclinical models of PAH. Silencing MiDs or augmenting miR-34a-3p regresses experimental PAH.In health, MiDs regulate Drp1-mediated fission, whereas in disease, epigenetic upregulation of MiDs increases mitotic fission, which drives pathological proliferation and apoptosis resistance. The miR-34a-3p-MiD pathway offers new therapeutic targets for PAH.
Simulation training day
Authors: Yasmeen Khan
Journal: BMJ (2008)

Newly qualified doctors entering the hospital environment are scared and underprepared when facing acutely ill patients. I am a foundation year 1 (F1) doctor currently based on a medical assessment unit in the United Kingdom, where some of the sickest patients arrive from the accident and emergency department. I have often had to deal with acutely ill patients, both medical and surgical. Initially, the thought of managing a sick patient evoked great stress for my colleagues and myself as we were thrown into the deep end with limited senior support. Bovier et al recognised that physicians in training were the most anxious group due to uncertainty in medical care.1 As medical students, we were more concerned about passing exams than recognising sick patients. When patients do present as acute emergencies, the urgency of the situation is such that there is often no time for teaching and training.2

Educational tools that help build this skill are invaluable, particularly now that junior doctors gain …
P080 C-reactive protein: not only a marker, but also a cause of inflammation through metabolic reprogramming of human macrophages
Authors: M Newling, L Sritharan, D Baeten, J Den Dunnen
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> C-reactive protein (CRP) is an acute-phase protein produced in high quantities by the liver in response to infection and during chronic inflammatory disorders such as rheumatoid arthritis (RA). As a consequence, CRP is in widespread clinical use as a general marker of inflammation. Although CRP is known to facilitate clearance of cell debris by phagocytic cells by binding to its ligand phosphocholine on dead cells, it is still unclear whether CRP displays additional immunological functions. <h3>Objectives</h3> Here, we set out to investigate whether CRP, which is present in high concentrations in synovial fluid of active RA patients, also plays a role in the orchestration of inflammation in the inflamed joint. <h3>Methods</h3> Human macrophages were differentiated from blood monocytes of healthy volunteers, or sorted from synovial fluid of RA patients. Cells were stimulated with complexed CRP (c-CRP) and/or ligands for Toll-like receptors (TLRs) and NOD-like receptors (NLRs), mimicking the stimuli in the inflamed joint. Responsible signalling pathways were identified using small molecule inhibitors and RNA interference. Metabolic pathways were identified using specific inhibitors and the Seahorse metabolic analyzer. <h3>Results</h3> Strikingly, we here provide evidence that CRP is not only a marker, but also a cause of inflammation by strongly amplifying the production of RA-associated pro-inflammatory cytokines. We show that complex formation of CRP as a result of binding to its ligand phosphocholine selectively enhanced TNFα, IL-1β, and IL-23 production by human macrophages. While c-CRP did not induce cytokine production individually, c-CRP synergized with TLRs and NLRs to amplify cytokine gene translation. We identified Fc gamma receptor I and IIa (FcγRI and FcγRIIa) as the main receptors responsible. Moreover, we unravelled the responsible molecular mechanism of c-CRP-induced inflammation, which crucially depends on signalling through kinases Syk and PI3K, resulting in enhanced gene translation of pro-inflammatory cytokines through metabolic reprogramming, particularly through amplified glycolysis and fatty acid synthesis. <h3>Conclusions</h3> These data indicate that CRP is not only a marker, but also a cause of inflammation in RA patients by selectively promoting RA-associated pro-inflammatory cytokine production by human macrophages, thereby exacerbating pathology. From a therapeutic point of view, inhibition of c-CRP-induced immune activation, e.g. by targeting the identified molecular mechanisms, may be a valuable tool to suppress inflammation. <h3>Disclosure of interest</h3> M. Newling: None declared, L. Sritharan: None declared, D. Baeten Employee of: Part-time employee UCB, J. Den Dunnen: None declared
The AP-1-BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma
Authors: Nikolai Schleussner, Olaf Merkel, Mariantonia Costanza, Huan-Chang Liang, Franziska Hummel, Chiara Romagnani, Pawel Durek, Ioannis Anagnostopoulos, Michael Hummel, Korinna Jöhrens, Antonia Niedobitek, Patrick R. Griffin, Roberto Piva, Henrike L. Sczakiel, Wilhelm Woessmann, Christine Damm-Welk, Christian Hinze, Dagmar Stoiber, Bernd Gillissen, Suzanne D. Turner, Eva Kaergel, Linda von Hoff, Michael Grau, Georg Lenz, Bernd Dörken, Claus Scheidereit, Lukas Kenner, Martin Janz, Stephan Mathas
Journal: Leukemia (2018)

Transcription factor AP-1 is constitutively activated and IRF4 drives growth and survival in ALK+ and ALK– anaplastic large cell lymphoma (ALCL). Here we demonstrate high-level BATF and BATF3 expression in ALCL. Both BATFs bind classical AP-1 motifs and interact with in ALCL deregulated AP-1 factors. Together with IRF4, they co-occupy AP-1-IRF composite elements, differentiating ALCL from non-ALCL. Gene-specific inactivation of BATFs, or global AP-1 inhibition results in ALCL growth retardation and/or cell death in vitro and in vivo. Furthermore, the AP-1-BATF module establishes TH17/group 3 innate lymphoid cells (ILC3)-associated gene expression in ALCL cells, including marker genes such as AHR, IL17F, IL22, IL26, IL23R and RORγt. Elevated IL-17A and IL-17F levels were detected in a subset of children and adolescents with ALK+ ALCL. Furthermore, a comprehensive analysis of primary lymphoma data confirms TH17–, and in particular ILC3-skewing in ALCL compared with PTCL. Finally, pharmacological inhibition of RORC as single treatment leads to cell death in ALCL cell lines and, in combination with the ALK inhibitor crizotinib, enforces death induction in ALK+ ALCL. Our data highlight the crucial role of AP-1/BATFs in ALCL and lead to the concept that some ALCL might originate from ILC3.
KINEMATIC MODELING OF DIASTOLIC FILLING IDENTIFIES DISTINCT DIASTOLIC FUNCTION PATTERNS IN HEART FAILURE WITH PRESERVED AND REDUCED EJECTION FRACTION
Authors: Julio A. Chirinos, Swetha Gaddam, Bilal Ansari, Jonathan Lee, Yueya Ge, Jessica Kim, Rachana Miller, Izzah Arfa, Rushik Bhuva, Scott Akers
Journal: Journal of the American College of Cardiology (2018)
Abstract 18893: Poly-L-Lactide Bioresorbable Vascular Scaffold Disruption as Assessed in vivo by Three-Dimensional ECG-Triggered Ultrahigh-Speed OCT and Its Detrimental Effects on Arterial Healing
Authors: Sun Won Kim, Hyun-Sang Park, Min Woo Lee, Tae Shik Kim, Woo Hyun Kim, Hyeong Soo Nam, Joon Woo Song, Dong Joo Oh, Kyeongsoon Park, Hongki Yoo, Wang-Yuhl Oh, Jin Won Kim
Journal: Circulation (2016)

Background: While bioresorbable vascular scaffold (BVS) disruption is known to predispose to thrombosis, current 2 dimensional-optical coherence tomography (2D-OCT) may not fully characterize scaff...
Efficacy of PD-1/PD-L1 therapy: Do proton pump inhibitors affect the outcome?
Authors: Sarbajit Mukherjee, Bilal Khalid, Sami Ibrahimi, Jordan Malie Morton, Darwin Roman, Yan D Zhao, Raid Aljumaily
Journal: Journal of Clinical Oncology (2018)

208 Background: Recent studies have shown that manipulating the gut microbiome modulates the efficacy of anti-PD1/PD-L1 directed therapy leading to increase in the activity of CD8+ T-cells. Proton Pump inhibitors (PPIs) affect the gut microbiome. The objective of this study was to investigate the effects of PPIs use on agents that target the PD-1/PD-L1 pathway in patients treated with these agents. Methods: We looked at the outcomes of 158 patients aged 18 years or older, treated at the University of Oklahoma Health Sciences Center between 2014 and 2016. The primary aim of this study was to investigate whether survival of patients treated with agents that target PD-1/PD-L1 pathway was affected by PPI use. The secondary objective was to identify if there is any difference in the immune related side effect profile between PPI users and non-users. The overall survival (OS) and progression free survival (PFS) were compared between PPI users and nonusers using the log-rank tests. Survival curves were generated using the Kaplan-Meyer method. The proportions of Grade 3 or 4 colitis or pneumonitis were compared between PPI users and nonusers using the Fisher’s exact test. SAS 9.4 was used for the statistical analysis and a 0.05 significance level was used. Results: The majority of patients were females (57%). The median age was 63 years. Lung cancer was the most common diagnosis (20%) followed by melanoma (20%) and ovarian cancer (12%). Nivolumab was the most commonly used agent (47%) followed by Pembrolizumab (22%), other investigational agents (22%) and Atezolizumab (7%). The median follow-up time from the date of first PPI dose was 7 months. There was no statistically significant difference in OS or PFS between PPI users and nonusers (p = 0.77). There were no significant differences in proportions of Grade 3 or 4 colitis between PPI users and nonusers (5% vs. 5.26%, p &gt; .99). Similarly, there were no significant differences in proportions of Grade 3 or 4 pneumonitis between PPI users and nonusers (6.25% vs. 1.75%, p = 0.40). Conclusions: Use of PPI does not affect the outcome of patients receiving agents that target PD1/PD-L1 pathway. The incidence of important immune related side effects was similar between PPI users and non-users.
Using Microsoft Excel
Authors: Mohammad Al-Ubaydli
Journal: BMJ (2005)

In a busy hospital environment, getting access to the notes for your audit data can be a haphazard and temporary affair. Always carry a handheld computer. Most Palm compatible machines come with ExcelToGo while Pocket PCs come with Pocket Excel. Data you enter there will easily transfer to your desktop computer's Microsoft Excel.

To add up all the cells in a column, click inside the …
Notes from the Field: Assessing Rabies Risk After a Mass Bat Exposure at a Research Facility in a National Park — Wyoming, 2017
Authors: Andrea Cote, Sarah Anne J. Guagliardo, Cuc H. Tran, Maria A. Said, Veronica Pickens, Karl Musgrave, Ryan Wallace
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

On August 2, 2017, the Wyoming Department of Health (WDH) was notified by local public health nursing of a group of 20 persons who had slept in a national park research facility and reported contact with bats and bat excrement.Four of the 20 persons had already received rabies postexposure prophylaxis (PEP)* when WDH notified the National Park Service (NPS) and requested assistance from CDC for a mass bat exposure investigation of the remaining 16 persons.Rabies is a fatal, viral zoonotic disease causing an estimated 59,000 human deaths annually worldwide.Transmission from animals to humans mainly occurs through bites; however, scratches or mucous membrane contact with saliva also present transmission risks (1-3).Although human rabies in the United States is rare, most human cases result from bat exposures; 75% of infected patients become ill within 3 months of exposure (3).Bat infestation of human habitations increases the risk for bat contact.Infestations can expose numerous persons to rabies and are referred to as mass bat exposures.Review of facility records identified 172 persons from 11 research groups who had slept at the research facility, with 73% of persons sleeping in one of two buildings possibly infested with bats since both buildings opened for the summer season on May 19, 2017, and closed August 2, 2017, to overnight guests.The facility director provided investigators with contact information for group leaders, who then provided contact information for potentially exposed persons.Persons resided in 29 states, the District of Columbia, one U.S. territory, and four non-U.S.residents were from four countries.Investigators from WDH, CDC, NPS, and public health professionals in other local, state, and international jurisdictions attempted to contact all potentially exposed persons by telephone, e-mail, and through social media.All persons who completed a risk assessment were contacted 1-2 weeks later to complete a follow-up assessment regarding receipt of PEP and to answer additional questions.Rabies risk assessments and follow-up assessments were conducted by telephone and e-mail.
Number of doctors facing medicolegal claims increases by 15%
Authors: Helen Jaques
Journal: BMJ (2013)

The number of doctors facing medicolegal claims increased by 15% in 2012, the Medical Defence Union (MDU) has reported. 

Total claims against doctors and dentists received by the union increased by 20% last year compared with an average increase of 8.6% for 2008-11. Claims against general practitioners and dentists saw a particularly sharp rise, the organisation said. 

Jill Harding, head of claims at …
Utilization and outcomes of chemoprophylaxis for the prevention of venous thromboembolism following radical cystectomy: A population-based study.
Authors: Stephen Reese, Matthew Mossanen, Dimitar V. Zlatev, Daniel Pucheril, Benjamin I. Chung, Steven Lee Chang
Journal: Journal of Clinical Oncology (2018)

491 Background: Venous thromboembolism (VTE), comprising deep venous thrombosis (DVT) and pulmonary embolism (PE), is a major preventable source of postoperative complications. The risk of VTE in patients undergoing radical cystectomy (RC) for bladder cancer has been estimated at 6%, and the American Society of Clinical Oncology, American Urological Association, and National Comprehensive Cancer Network all recommend perioperative chemoprophylaxis. We performed a population-based analysis to determine the utilization of chemoprophylaxis against VTE in patients undergoing RC. Methods: Using the Premier Hospital Database (Premier, Inc., Charlotte, NC), we retrospectively identified patients who underwent RC for bladder cancer in the US between 2006 and 2015. Administration of chemoprophylaxis within 24 hours of surgery was deemed consistent with recommendations. A subgroup analysis of higher volume hospitals (³10 RC annually) compared outcomes of DVT, PE, and bleeding between patients in hospitals with uniform use versus no use of chemoprophylaxis. Multivariate analysis was used to evaluate predictors of under-utilization of chemoprophylaxis. Results: Among the cohort of 9,133 patients (48,714 patients after weighting adjustment) undergoing RC, 35.1% were administered recommended chemoprophylaxis, with an increase in utilization from 20.7% in 2006 to 49.6% in 2015. Characteristics associated with decreased likelihood of chemoprophylaxis administration included patient age ≥65 years, Charlson Comorbidity Index score ≥2, rural hospital location, commercial insurance, and year of surgery prior to 2010. Patients who received recommended chemoprophylaxis had significantly lower rates of VTE (5.1% vs 6.0%) and PE (2.0% vs 3.1%), but elevated rates of bleeding (12.8% vs 7.7%). Conclusions: The recommended utilization of chemoprophylaxis in a contemporary nationwide cohort of patients undergoing RC is limited despite its notable increase over the course of the study period. Greater compliance with recommended use of chemoprophylaxis following RC may be associated with decreased risk of PE and VTE, but also with increased risk of bleeding.