tbuckley/cabot-search huggingface dataset:
Acute Brain Lesions on Magnetic Resonance Imaging and Delayed Neurological Sequelae in Carbon Monoxide Poisoning
Authors: Sang-Beom Jeon, Chang Hwan Sohn, Dong-Woo Seo, Bum Jin Oh, Kyoung Soo Lim, Dong-Wha Kang, Won Young Kim
Journal: JAMA Neurology (2018)

Preventing delayed neurological sequelae is a major goal of treating acute carbon monoxide poisoning, but to our knowledge there are no reliable tools for assessing the probability of these sequelae.To determine whether acute brain lesions on diffusion-weighted imaging are related to subsequent development of delayed neurological sequelae after acute carbon monoxide poisoning.This registry-based observational study was conducted at a university hospital in Seoul, Korea, between April 1, 2011, and December 31, 2015. Of 700 patients (aged ≥18 years) with acute carbon monoxide poisoning, 433 patients (61.9%) who underwent diffusion-weighted imaging at an emergency department were considered for the study. Patients who developed cardiac arrest before diffusion-weighted imaging (n = 3), had persistent neurological symptoms at discharge (n = 8), committed suicide soon after discharge (n = 1), and were lost to follow-up (n = 34) were excluded.The presence of unambiguous, high-signal-intensity, acute brain lesions on diffusion-weighted imaging (b = 1000 s/mm2).Development of delayed neurological sequelae defined as any neurological symptoms or signs that newly developed within 6 weeks of discharge.Of the 387 included patients (143 women [37.0%]; median age, 42.0 years [interquartile range, 32.0-56.0 years]), acute brain lesions on diffusion-weighted imaging were observed in 104 patients (26.9%). Among these, 77 patients (19.9%) had globus pallidus lesions, 13 (3.4%) had diffuse lesions, and 57 (14.7%) had focal lesions (37 patients [9.6%] had >1 pattern concurrently). Lesions were supratentorial and infratentorial in 101 and 23 patients, respectively. Delayed neurological sequelae occurred in 101 patients (26.1%). Multivariable logistic regression analysis indicated that the presence of acute brain lesions was independently associated with development of delayed neurological sequelae (adjusted odds ratio, 13.93; 95% CI, 7.16-27.11; P < .001). The sensitivity and specificity of acute brain lesions to assess the probability of delayed neurological sequelae were 75.2% (95% CI, 66.8%-83.7%) and 90.2% (95% CI, 86.8%-93.7%), respectively. In addition, the positive and negative predictive values were 73.1% (95% CI, 64.6%-81.6%) and 91.2% (95% CI, 87.9%-94.5%), respectively.The presence of acute brain lesions was significantly associated with the development of delayed neurological sequelae. Diffusion-weighted imaging during the acute phase of carbon monoxide poisoning may therefore help identify patients at risk of developing these debilitating sequelae.
The lure of the remote
Authors: Declan Fox
Journal: BMJ (2005)

EDITOR—I enjoyed the article on Scotland.1 I do general practitioner (GP) locums in the wilder bits from choice, and I have a few points to add to the discussion on recruitment and retention.

Firstly, work in the remote areas demands excellent clinical skills, people skills, some trauma/acute life support skills, and less tangible attributes such as …
Abstract 18: Can Schoolchildren provide Life Supporting First Aid sufficiently?
Authors: Roman Fleischhackl, Alexander Nuernberger, Christina Schoenberg, Tanja Urso, Tanja Habart, Martina Mittlboeck, Fritz Sterz
Journal: Circulation (2007)

Aims: We investigated possible relationships between body constitution, age and sex of school children and their intellectual and physical abilities to provide effective life supporting first aid. Methods: Our observational study was carried out at the end of a school year, after first aid training had been provided by local teachers. As primary outcomes we measured CPR effectiveness parameters (depth of chest-compressions, number of chest-compressions, ventilation volume). As secondary outcomes we rated emergency calls, guideline adherence when checking signs of life and recovery position according to predefined checklists. Possible inter-dependencies between age, sex, body mass index (BMI) and physical or intellectual performance were calculated. Correlations between continuous data were assessed by Spearman rank correlation coefficient and differences between groups were tested by Wilcoxon’s rank-sum test. A p-value &lt; 0.05 was considered significant. Results: We included 147 pupils at the age from 9 to 18 years. The median depth of chest-compressions was calculated at 35 mm (IQR 31– 41 mm), median number of compressions per minute was 129 bpm (IQR 108 ndash;143 bpm). Median volume applicated during mouth-to-mouth ventilation was 540 ml (IQR 0 –750 ml). Secondary outcomes are displayed in table 1 . BMI (r=0.35; p&lt;0.0001), body weight (r=0.38; p=&lt;0.0001) and body height (0.31; p=0.0002) showed statistically highly significant dependencies with chest-compression depth and ventilation volume. All other outcomes were not related to sex, age or body constitution. Conclusions: Children above the age of 9 years showed high quality overall performance after beeing trained in life supporting techniques. Effectivness parameters obtained from adults previously seem to be comparable. Even if physical strength could limit CPR effectiveness, children should not be withheld from first aid education. Sec. Outcomes: Check f. vital signs, recovery position, emergency call, chestcompr/ventilation ratio
Abstract GS4-06: Cancer risks and response to targeted therapy associated with <i>BRCA2</i> variants of uncertain significance
Authors: FJ Couch, H Shimelis, SN Hart, RM Moore, A Thomas, GB Lipton, E Iversen
Journal: Cancer Research (2018)

Abstract Background: Germline genetic testing of individuals with a diagnosis of triple negative breast cancer, young age at diagnosis, or a family history of breast and/or ovarian cancer has led to the identification of many unique BRCA2 missense variants of uncertain significance (VUS). VUS in BRCA2 are predominantly missense mutations that have unclear relevance to breast, ovarian, and other cancers. Thus, patients found to have a germline BRCA2 VUS do not know if the variant is associated with high risks of these cancers similar to truncating mutations, intermediate risks more similar to CHEK2 mutations, or low risks of no clinical significance. Furthermore, it is unclear if germline BRCA2 VUS, or somatic VUS identified by tumor sequencing, are associated with hypersensitivity to selected DNA damaging and cross-linking agents. Methods: We have used a homology directed repair (HDR) cell-based assay to characterize missense variants in the DNA binding domain (DBD) of BRCA2. The method has been validated using known pathogenic and known non-pathogenic BRCA2 missense variants and has 100% sensitivity (95% confidence interval (CI): 75.3%–100%) and 100% specificity (95% CI: 81.5%–100%) for pathogenic BRCA2 variants. A classifier of variant pathogenicity based on the mean and variances of the distributions of the HDR results of the known pathogenic and neutral variants has been established. We have also developed PARP inhibitor and cisplatin drug response assays for BRCA2 missense variants. Results: Assessment of 207 BRCA2 missense variants, identified in public databases such as BRCA exchange and ClinVar, by the HDR assay identified 71 deleterious variants with &amp;gt;99% probability of pathogenicity, 116 neutral variants with &amp;gt;99% probability of neutrality, and 20 with hypomorphic activity and potentially intermediate risk. A combination of the functional data and sequence-based predictors of protein activity in a Bayesian prediction model resulted in classification of the deleterious variants as pathogenic cancer predisposing variants and the neutral variants as non-pathogenic with low clinical significance. The influence of the deleterious/pathogenic variants on PARPi and cisplatin response was also assessed. Conclusion: The HDR assay is effective for characterization of BRCA2 VUS. The combination of functional data and in silico prediction models provides a robust tool for clinical annotation of BRCA2 VUS. HDR function of BRCA2 missense variants is strongly correlated with response to targeted therapy. Citation Format: Couch FJ, Shimelis H, Hart SN, Moore RM, Thomas A, Lipton GB, Iversen E. Cancer risks and response to targeted therapy associated with BRCA2 variants of uncertain significance [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS4-06.
Data chart: Consultant numbers have doubled over the past 20 years
Authors: Tom Moberly
Journal: BMJ (2017)

Over the past two decades, the number of consultants working in the NHS has more than doubled, rising from 22 920 in 1996 to 54 539 in 2016.



Rise in the number of consultant between 1955 and 2016

The rate of growth during this period was faster than in the four decades beforehand. Between 1955 and 1975, the number rose from 5210 to …
Type 1 Diabetes TrialNet: A Multifaceted Approach to Bringing Disease-Modifying Therapy to Clinical Use in Type 1 Diabetes
Authors: Polly J. Bingley, Diane K. Wherrett, Ann Shultz, Lisa E. Rafkin, Mark A. Atkinson, Carla J. Greenbaum
Journal: Diabetes Care (2018)

What will it take to bring disease-modifying therapy to clinical use in type 1 diabetes? Coordinated efforts of investigators involved in discovery, translational, and clinical research operating in partnership with funders and industry and in sync with regulatory agencies are needed. This Perspective describes one such effort, Type 1 Diabetes TrialNet, a National Institutes of Health–funded and JDRF-supported international clinical trials network that emerged from the Diabetes Prevention Trial–Type 1 (DPT-1). Through longitudinal natural history studies, as well as trials before and after clinical onset of disease combined with mechanistic and ancillary investigations to enhance scientific understanding and translation to clinical use, TrialNet is working to bring disease-modifying therapies to individuals with type 1 diabetes. Moreover, TrialNet uses its expertise and experience in clinical studies to increase efficiencies in the conduct of trials and to reduce the burden of participation on individuals and families. Herein, we highlight key contributions made by TrialNet toward a revised understanding of the natural history of disease and approaches to alter disease course and outline the consortium’s plans for the future.
P100 The link between angiogenesis and osteogenesis in spondyloarthritis
Authors: MH Kaaij, JP van Hamburg, G Kollias, D Baeten, L van Duivenvoorde
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Spondyloarthritis is characterised by inflammation, extensive angiogenesis and pathological osteogenesis. Transmembrane (tm) TNF transgenic (tg) mice<sup>1</sup> that overexpress tmTNF exhibit features of SpA, including chronic inflammation and pathological osteogenesis. tmTNF ligation to TNF receptor 2 in endothelial cells (ECs) can induce signal transduction pathways, that may promote these processes. Of note, angiogenesis and osteogenesis are coupled by EC differentiation towards a type H (CD31<sup>hi</sup>endomucin<sup>hi</sup>) phenotype.<sup>2</sup> <h3>Objectives</h3> To investigate the link between pathological angiogenesis and osteogenesis in tmTNF tg mice and the potential contribution of noncanonical NF-κB signalling in ECs to this process and infiltration of immune cells into the bone marrow (BM). <h3>Methods</h3> Vertebrae and ankles from 6 and 12 weeks and 8 months old tmTNF tg mice or sex-matched non-tg littermates (n=18) were prepared by cutting 60 µm thick cryosections for confocal imaging. <h3>Results</h3> tmTNF tg mice exhibited ectopic osteogenesis which was not observed in non-tg littermates. Immunostainings showed that type H vessels are in the vicinity of the ectopic osteogenesis and osterix<sup>+</sup> osteoprogenitors. At six weeks of age, osterix<sup>+</sup> cells are located throughout the ectopic lesion, while at eight months, osterix<sup>+</sup> cells are only present at the border of the lesion. Furthermore, there is increased osteogenesis and a different vessel architecture within the vertebrae of tmTNF tg mice compared to non-tg littermates that progresses with age. Non-tg littermate vertebrae only have physiological osteogenesis, which is in the metaphysis and periosteum. In addition, tmTNF tg mice also exhibit altered bone marrow (BM) architecture containing extensive lymphoid aggregates, which predominantly consisted of B220<sup>+</sup> B cells. <h3>Conclusions</h3> tmTNF overexpression in mice leads to development of type H vessels associated with ectopic osteogenesis. In addition, extensive lymphoid aggregates develop in the BM. Current studies are aimed at identification of signalling pathways in ECs that contribute to these processes. <h3>References</h3> . Alexopoulou L, et al. Eur J Immunol1997;27(10):2588–92. . Kusumbe AP, et al. Nature2014;507(7492):323–328. <h3>Disclosure of interest</h3> None declared
What is the accuracy of multi-parametric magnetic resonance imaging in predicting adverse pathology in patients undergoing radical prostatectomy?
Authors: Samarpit Rai, Adnan Dervishi, Brittany Ewing O'Bryan, Thomas Michael FitzGibbon, Paul Knoll, Kristy Doan Nguyen, Murali Ankem, Jamie Christopher Messer
Journal: Journal of Clinical Oncology (2018)

139 Background: Few studies have examined the accuracy of preoperative multi-parametric magnetic resonance imaging (MP-MRI) in predicting adverse pathological features in patients undergoing radical prostatectomy (RP) for localized prostate cancer (PCa). Methods: We retrospectively analyzed the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of preoperative MP-MRI for adverse pathologic features [extracapsular extension (ECE), seminal vesicle invasion (SVI), lymph node involvement (LNI) and high Gleason score) on postoperative pathologic staging after RP in 30 patients with localized PCa . Results: The median age and preoperative PSA were 62.5 years and 8.5 ng/mL, respectively.17 patients had ECE, 5 had SVI, 5 had LNI, and 15 had high risk Gleason score (4+3, tertiary pattern 5, 4+4 or higher). The sensitivity, specificity, PPV and NPV of MP-MRI for ECE was 64.71% (95%CI 38.33 - 65.79), 92.31% (95% CI 63.97 - 99.81), 91.67% (95% CI 61.52 - 99.79), and 66.67% (95% CI 40.89 - 86.96) respectively. For the detection of SVI on MP-MRI, the sensitivity, specificity, PPV, and NPV were 60% (95% CI 14.66 - 94.73), 96% (95% CI 76.95 - 99.90), 75% (95% CI 19.41 - 99.37), and 92.31% (95% CI 74.87 - 99.05) respectively. For the detection of LNI, the sensitivity of MP-MRI was 100% (95% CI 47.82 - 100), specificity was 96% (95% CI 79.65 - 99.90), PPV was 83.33% (95% CI 35.88 - 99.58), NPV was 100% (95% CI 85.75 - 100). For detection of of high risk Gleason score the sensitivity of MP-MRI was 94.44% (95% CI 72.71 - 99.86), specificity was 66.67% (95% CI 34.89 - 90.08), PPV was 80.95% (95% CI 58.09 - 94.55), and NPV was 88.89% (95% CI 51.75 - 99.72). Conclusions: MP-MRI has a reasonable sensitivity, specificity, and NPV for the preoperative detection of adverse pathologic features at prostatectomy. This could provide assistance in the selection of patients appropriate for Active Surveillance as well as in the preoperative counseling regarding multimodality treatment for PCa.
Abstract P6-11-20: Not presented
Authors: JE Bargallo-Rocha, LM Gutierrez-Zacarias, LN Gallardo-Alvarado, N Esparza-Arias, RJ Shaw-Dulin, R Vazquez-Romo, CD Robles-Vidal, DF Cantu-De Leon
Journal: Cancer Research (2018)

Abstract This abstract was not presented at the symposium.
Test for overseas doctors will be strengthened, says GMC
Authors: Abi Rimmer
Journal: BMJ (2016)

The General Medical Council (GMC) has said that it will strengthen its test for international doctors who want to work in the UK.

Changes are being made to the Professional and Linguistic Assessments Board (PLAB) test after recommendations from an independent review commissioned by the GMC.1

The test is taken by international medical graduates to assess whether they have the knowledge and skills to practise in the UK. It consists of a written knowledge test and …
Neoadjuvant enzalutamide and androgen deprivation therapy for high-risk prostate cancer: Early results from a feasibility trial.
Authors: David James VanderWeele, Baris Turkbey, Fatima Karzai, Stephanie Harmon, Adam G. Sowalsky, Huihui Ye, Scott Wilkinson, Guinevere Chun, Samuel Gold, Peter A. Pinto, Peter L. Choyke, William L. Dahut
Journal: Journal of Clinical Oncology (2018)

94 Background: Intensive androgen-targeted therapy improves survival for patients with androgen naive metastatic prostate cancer. Neoadjuvant androgen deprivation therapy (nADT) with abiraterone for localized disease leads to complete responses (pCR) rates of up to 10%. In this study we tested the efficacy of nADT with enzalutamide for patients with high risk, localized disease and the ability of post-treatment multiparametric MRI (mpMRI) to evaluate response. Methods: A single institution trial (NCT02430480) evaluated nADT and enzalutamide 160 mg daily in patients with high risk non-metastatic prostate cancer. Patients underwent MRI-TRUS-guided fusion biopsy at screening and repeat mpMRI followed by radical prostatectomy (RP) after completing six months of therapy. Results: Twenty patients have completed therapy and undergone radical prostatectomy. Clinical characteristics were typical of those with high risk disease: median PSA 8.96 ng/ml (range 2.07-985.9) and clinical stage by mpMRI cT2 (one patient), cT3 (17 patients), or cT4 (2 patients); 7 patients had enlarged pelvic lymph nodes. Following 6 months of therapy, median pre-RP PSA was &lt; 0.02 ng/ml (range &lt; 0.02 – 0.35). On final pathology, 0 patients were upstaged, 5 (25%) were unchanged, and 15 (75%) were downstaged, including 3 (16%) pCR. Four patients were downstaged from N1 to N0. There was little correlation between post-treatment mpMRI tumor volume and pathologic tumor volume. Two patients had radiographic complete responses, one of whom had extensive residual disease. Conclusions: Six months of nADT with enzalutamide has activity in high risk, localized prostate cancer, with a small number of patients having exceptional responses. Standard analysis of mpMRI does not reliably characterize depth of response. Evaluation of molecular characteristics that predict exceptional response or intrinsic resistance is on-going. Patients are being followed for recurrence. Clinical trial information: NCT02430480.
Photoacoustic Imaging as an Early Biomarker of Radio Therapeutic Efficacy in Head and Neck Cancer
Authors: Laurie J Rich, Austin Miller, Anurag K Singh, Mukund Seshadri
Journal: Theranostics (2018)

The negative impact of tumor hypoxia on radiotherapeutic efficacy is well recognized. However, an easy to use, reliable imaging method for assessment of tumor oxygenation in routine clinical practice remains elusive. Photoacoustic imaging (PAI) is a relatively new imaging technique that utilizes a combination of light and ultrasound (US) to enable functional imaging of tumor hemodynamic characteristics in vivo. Several clinical trials are currently evaluating the utility of PAI in cancer detection for breast, thyroid, and prostate cancer. Here, we evaluated the potential of PAI for rapid, label-free, non-invasive quantification of tumor oxygenation as a biomarker of radiation response in head and neck cancer. Methods: Studies were performed human papilloma virus- positive (HPV+) and -negative (HPV-) patient-derived xenograft (PDX) models of head and neck squamous cell carcinoma (HNSCC). PAI was utilized for longitudinal assessment of tumor hemodynamics (oxygenation saturation and hemoglobin concentration) before, during and after fractionated radiation therapy (fRT). Imaging datasets were correlated with histologic measures of vascularity (CD31), DNA damage (phosphorylated γH2AX) and statistical modeling of tumor growth. Results: A differential response to fRT was observed between HPV+ and HPV- xenografts. Temporal changes in tumor hemodynamics (oxygen saturation and hemoglobin concentration) measured by PAI showed significant association with treatment outcomes. PAI-based changes in oxygen saturation were detected within days after initiation of fRT prior to detectable change in tumor volume, highlighting the potential of PAI to serve as an early biomarker of therapeutic efficacy. Consistent with PAI results, immunohistochemical staining of vascularity (CD31) and DNA damage (phosphorylated γH2AX) revealed distinct patterns of response in HPV+ and HPV- xenografts. Conclusion: Collectively, our observations demonstrate the utility of PAI for temporal mapping of tumor hemodynamics and the value of PAI read-outs as surrogate measures of radiation response in HNSCC.
MEK-1 inhibitor PDO8059 potentiates apoptosis and growth inhibition induced by intereferon alpha (IFN alpha) in human epidermoid cancer cells.
Authors: M. Caraglia, P. Tagliaferri, P. Tassone, G. Giuberti, M. Marra, S. Pepe, A. Budillon, E. Di Gennaro, A. R. Bianco, A. Abbruzzese, S. Venuta.
Journal: Clinical Cancer Research (2000)
Heavy workloads and poor supervision are deterring doctors from emergency medicine
Authors: Caroline White
Journal: BMJ (2013)

Heavy workloads and inconsistent and inadequate supervision are deterring doctors from training in emergency medicine, concludes a review from the General Medical Council.

The GMC carried out checks on the quality of doctors’ training at seven emergency medicine departments in England and Jersey between December 2012 and February 2013.1

The checks were prompted by the rising number of reports of concerns to the GMC about education and training in emergency medicine—and particularly about very junior trainees working unsupervised at night.

Figures from the College of Emergency Medicine show that in 2012 only 61 of the 115 foundation doctors offered a place to start training in emergency medicine accepted the offer. This is the second lowest acceptance rate of any specialty.

The seven sites used by the GMC were selected on the basis of evidence from the …