tbuckley/cabot-search huggingface dataset:
Looking for improvement
Authors: Rhona MacDonald
Journal: BMJ (2004)

“The world of work has moved on,” according to Ray Clarke, consultant, trainer, and author of our series “Trainer taming.” I was struck by some of his comments in the final article (p 170), which is addressed to trainees: “You all have lives outside medicine and should not be blamed for the fact that doctors now do fewer hours, work shifts, are paid more, no longer learn anatomy …
Imaging, myeloid precursor immortalization, and genome editing for defining mechanisms of leukocyte recruitment <i>in vivo</i>
Authors: Sandra Gran, Lisa Honold, Olesja Fehler, Stefanie Zenker, Sarah Eligehausen, Michael T. Kuhlmann, Edwin Geven, Martijn van den Bosch, Peter van Lent, Christoph Spiekermann, Sven Hermann, Thomas Vogl, Michael Schäfers, Johannes Roth
Journal: Theranostics (2018)

Recruitment of leukocytes from the blood to sites of inflammation poses a promising target for new diagnostic and therapeutic approaches.We aimed to develop a novel method to non-invasively analyze molecular mechanisms of leukocyte migration in pre-clinical models of inflammation in vivo.Methods: We used the ER-HoxB8 system to transiently immortalize murine myeloid precursors from wildtype and CD18-as well as MRP14-deficient mice.A VLA4α-/-cell line was generated by CRISPR/Cas9-mediated gene editing.We analyzed the migration of wildtype and knockout leukocytes in vivo by optical and nuclear imaging in mice with irritant contact dermatitis, cutaneous granuloma, experimental arthritis and myocardial infarction.Results: Transient immortalization, gene editing and in vivo imaging can be combined to analyze migratory mechanisms of murine leukocytes, even for gene deletions resulting in lethal phenotypes in mice.We reliably confirmed known migratory defects of leukocytes deficient for the adhesion molecules CD18 or VLA4α.Also, using our new method we identified a new role of the most abundant calcium-binding proteins in phagocytes and major alarmins in many inflammatory diseases, MRP8 and MRP14, for transmigration in vivo. Conclusion:We provide a combinatorial approach to rapidly characterize molecular mechanisms of leukocyte recruitment in vivo, with the potential to aid in identification of diagnostic and therapeutic targets in inflammatory pathologies.
MANAGEMENT OF SUBMASSIVE PULMONARY EMBOLISM COMPLICATED BY PARADOXICAL THROMBUS-IN-TRANSIT
Authors: Fisayomi Shobayo, Ankit Upadhyay, Salman Arain, Igor Gregoric, Biswajit Kar, Ismael A. Salas De Armas
Journal: Journal of the American College of Cardiology (2018)
The first-in-class alkylating deacetylase inhibitor molecule tinostamustine shows antitumor effects and is synergistic with radiotherapy in preclinical models of glioblastoma
Authors: Claudio Festuccia, Andrea Mancini, Alessandro Colapietro, Giovanni Luca Gravina, Flora Vitale, Francesco Marampon, Simona Delle Monache, Simona Pompili, Loredana Cristiano, Antonella Vetuschi, Vincenzo Tombolini, Yi Chen, Thomas Mehrling
Journal: Journal of Hematology & Oncology (2018)

The use of alkylating agents such as temozolomide in association with radiotherapy (RT) is the therapeutic standard of glioblastoma (GBM). This regimen modestly prolongs overall survival, also if, in light of the still dismal prognosis, further improvements are desperately needed, especially in the patients with O6-methylguanine-DNA-methyltransferase (MGMT) unmethylated tumors, in which the benefit of standard treatment is less. Tinostamustine (EDO-S101) is a first-in-class alkylating deacetylase inhibitor (AK-DACi) molecule that fuses the DNA damaging effect of bendamustine with the fully functional pan-histone deacetylase (HDAC) inhibitor, vorinostat, in a completely new chemical entity. Tinostamustine has been tested in models of GBM by using 13 GBM cell lines and seven patient-derived GBM proliferating/stem cell lines in vitro. U87MG and U251MG (MGMT negative), as well as T98G (MGMT positive), were subcutaneously injected in nude mice, whereas luciferase positive U251MG cells and patient-derived GBM stem cell line (CSCs-5) were evaluated the orthotopic intra-brain in vivo experiments. We demonstrated that tinostamustine possesses stronger antiproliferative and pro-apoptotic effects than those observed for vorinostat and bendamustine alone and similar to their combination and irrespective of MGMT expression. In addition, we observed a stronger radio-sensitization of single treatment and temozolomide used as control due to reduced expression and increased time of disappearance of γH2AX indicative of reduced signal and DNA repair. This was associated with higher caspase-3 activation and reduction of RT-mediated autophagy. In vivo, tinostamustine increased time-to-progression (TTP) and this was additive/synergistic to RT. Tinostamustine had significant therapeutic activity with suppression of tumor growth and prolongation of DFS (disease-free survival) and OS (overall survival) in orthotopic intra-brain models that was superior to bendamustine, RT and temozolomide and showing stronger radio sensitivity. Our data suggest that tinostamustine deserves further investigation in patients with glioblastoma.
IMPLEMENTATION OF THE FIRST REPORTED ROUTINE ONE-DAY TRANSCATHETER AORTIC VALVE REPLACEMENT (TAVR) PATIENT EVALUATION
Authors: Benjamin Zev Galper, Ameya Kulkarni, John Rhee, Sudip Saha, John Garrett, Robyn Moseley, Virginia Seay, John Golden
Journal: Journal of the American College of Cardiology (2018)
Interim 2017/18 influenza seasonal vaccine effectiveness: combined results from five European studies
Authors: Marc Rondy, Esther Kissling, Hanne-Dorthe Emborg, Alin Gherasim, Richard Pebody, Ramona Trebbien, Francisco Pozo, Amparo Larrauri, Jim McMenamin, Marta Valenciano
Journal: Eurosurveillance (2018)

Between September 2017 and February 2018, influenza A(H1N1)pdm09, A(H3N2) and B viruses (mainly B/Yamagata, not included in 2017/18 trivalent vaccines) co-circulated in Europe. Interim results from five European studies indicate that, in all age groups, 2017/18 influenza vaccine effectiveness was 25 to 52% against any influenza, 55 to 68% against influenza A(H1N1)pdm09, -42 to 7% against influenza A(H3N2) and 36 to 54% against influenza B. 2017/18 influenza vaccine should be promoted where influenza still circulates.
What does the brain tumour community want to know about the behaviour and personality changes following a brain tumour diagnosis?
Authors: Helen Bulbeck
Journal: Neuro-Oncology (2018)

BPC are a major comorbidity for patients/caregivers living with a brain tumour, with prevalence rates of up to 20% for clinical depression[1] and up to 60% for personality change[2]. The objective was to find out what people living with a brain tumour want to know about BPC, so that supportive guidance can be developed. The question ‘What do you want to know about BPC following a brain tumour diagnosis?” was posted on social media to a closed group (patients/caregivers). The question ran for one month (2015), generating 103 posts. Two responses resonated: 1. Why do we hurt those closest to us when anger/frustration builds up, more often than previously?2. Why don’t we receive support/information from clinicians?Key themes emerged: Threat to way of life Lack of behaviour control Impact of BPC on relationships Systemic problems leading to isolation Access to support These resonate with the brainstrust report[3] where the two key sentiments are:a desire to know what to expectcalls for better personal support, including a more equal relationship with clinicians. Fundamental is the theme of relationships, with a close person, with a healthcare practitioner, and with the patient themselves. When illness strikes, structural and emotional skews follow. Belief systems are challenged, roles are upended, and identities shift. The onset of a brain tumour diagnosis forcefully challenges the emotional and physical boundaries that we have spent a lifetime building. There is an immediate need to develop resources that enable everyone to be more resilient when faced with the challenges of BPC. brainstrust is well placed to meet this agenda with its coaching led approach. [1] Rooney AG, McNamara S, Mackinnon M, et al. J Clin Oncol 2011; 29:4307–12. [2] Gofton TE, Graber J, Carver A. J Neurooncol 2012; 108:527–34 [3] brainstrust 2014
<i>E. coli</i> Nissle 1917-Derived Minicells for Targeted Delivery of Chemotherapeutic Drug to Hypoxic Regions for Cancer Therapy
Authors: Yunlei Zhang, Wei Ji, Lian He, Yiyan Chen, Xuezhi Ding, Yunjun Sun, Shengbiao Hu, Huijun Yang, Weitao Huang, Youming Zhang, Fei Liu, Liqiu Xia
Journal: Theranostics (2018)

Purpose: Systemic administration of free chemotherapeutic drugs leads to severe toxic effects, and physiological characteristics of solid tumors restrain the drugs from reaching the hypoxic regions.E. coli Nissle 1917 (EcN) has been known to penetrate the barrier and proliferate in the interface between the viable and necrotic regions of tumors.This study aimed to fabricate a nanoscale minicell via genetic engineering of EcN for targeted delivery of chemotherapeutic drugs to the hypoxic regions of tumors for cancer therapy.Methods: A large number of minicells were produced by knocking out the minCD gene and enhancing the minE expression in EcN.Then, a pH (low) insertion peptide (pHLIP) was displayed on the membrane surface through protein display technology to endow the cells with the ability to target the acidic microenvironments of tumors.The acidic-microenvironment targeting ability and therapeutic effect of the engineered minicells with chemotherapeutic drugs was thoroughly evaluated by using breast cancer cells and an orthotopic model of breast tumor. Results:The EcN-derived minicells displaying pHLIP could be directly extracted from the fermentation broth and used for delivering chemotherapeutic drugs without any further modification.Targeting of doxorubicin (DOX)-loaded minicells to cancer cells via pHLIP resulted in rapid internalization and drug release in acidic media.Importantly, the pHLIP-mosaic minicells successfully invaded the necrotic and hypoxic regions of orthotopic breast cancers where free chemotherapeutic drugs could never get to because of vascular insufficiency and high interstitial fluid pressure.This invasion resulted in significant regression of an orthotopic breast tumor in a mouse model, while no seriously pathogenic effects were observed during the animal experiments.Conclusions: This study provides a novel strategy for the fabrication of tumor-targeting carriers via genetic engineering based on biomaterials with the ability to penetrate hypoxic regions of tumors, high biocompatibility and low toxicity.
Teaching and Learning in Primary Care
Authors: Bill Irish
Journal: BMJ (2006)

Richard Hays

Radcliffe, 2005, £21.95, 144 pages ISBN: 1 85775 756 4 Rating: ⋆⋆⋆⋆⋆/5



Iwork with a bunch of fantastic GP trainers. They are committed medical teachers, each with an infectious, bubbling passion for the intricacies of primary care medicine. All act as superb role models for the medical students and junior doctors we send them.

Trainers make the whole of UK primary care tick. They inject a steady stream of young capable GPs into the system, each delivering high quality patient care, enthusiasm and energy to the …
Microvesicles as Emerging Biomarkers and Therapeutic Targets in Cardiometabolic Diseases
Authors: Yan Chen, Guangping Li, Ming-Lin Liu
Journal: Genomics Proteomics & Bioinformatics (2018)

Microvesicles (MVs, also known as microparticles) are small vesicles that originate from plasma membrane of almost all eukaryotic cells during apoptosis or activation. MVs can serve as extracellular vehicles to transport bioactive molecules from their parental cells to recipient target cells, thereby serving as novel mediators for intercellular communication. Importantly, more and more evidence indicates that MVs could play important roles in early pathogenesis and subsequent progression of cardiovascular and metabolic diseases. Elevated plasma concentrations of MVs, originating from red blood cells, leukocytes, platelets, or other organs and tissues, have been reported in various cardiometabolic diseases. Circulating MVs could serve as potential biomarkers for disease diagnosis or therapeutic monitoring. In this review, we summarized recently-published studies in the field and discussed the role of MVs in the pathogenesis of cardiometabolic diseases. The emerging values of MVs that serve as biomarker for non-invasive diagnosis and prognosis, as well as their roles as novel therapeutic targets in cardiometabolic diseases, were also described.
Peter Alexander Murray Weston
Authors: Theo Weston
Journal: BMJ (2018)

Peter Alexander Murray Weston was born in Oswestry but spent his early years in Eastbourne, where among other things he taught himself to sail and developed his love of the sea. He went to Chelmsford Hall Preparatory School and then was awarded a Kitchener scholarship to board at Bradfield College, Berkshire. Following in his father’s and grandfather’s footsteps (his dad had been an army medical officer for many years before leaving to work as a surgeon and GP in Oswestry and Eastbourne; his grandfather had been a GP), he started his medical training at St Bartholomew’s medical school in London in 1942. After qualifying in 1947, he spent a short time in the army, doing his national service (based at Millbank during the Korean war, treating returning casualties) while also studying for his FRCS from 1949 to 1951. During this time, he was a demonstrator in anatomy, before qualifying as a surgeon in 1950. He then worked in the Children’s Hospital, Toronto, from 1953. This included being the doctor in charge of the Grenfell Mission Hospital, St Anthony, Newfoundland, during the winter of 1953-54. He had many adventures including rescuing casualties by dog sled and sea plane. He spent a year as registrar at the Farnborough Hospital from 1954 to 1955 before …
Interferon-free treatment for hepatitis C virus infection induces normalization of extrahepatic type I interferon signaling
Authors: Pil Soo Sung, Eun Byul Lee, Dong Jun Park, Angelo Lozada, Jeong Won Jang, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon
Journal: Clinical and Molecular Hepatology (2018)

Hepatitis C virus (HCV) replicates in the peripheral blood mononuclear cells (PBMCs), leading to the production of type I interferons (IFNs). It is well known that the gene expression profile of PBMC is similar to that of the liver. The present study explored the dynamic gene expression profile of PBMCs collected from HCV-infected patients undergoing direct-acting antiviral (DAA) therapy.A prospective cohort comprising 27 patients under DAA therapy was formed. Expression level of IFN-β and its downstream interferon-stimulated genes (ISGs) was measured in PBMCs before and after DAA treatment. Furthermore, immunoblotting was performed to identify the signaling molecules involved in the expression of ISGs.The pretreatment expression level of interferon-induced protein 44 (IFI44) and C-X-C motif chemokine ligand 10 (CXCL10) correlated with the pretreatment expression level of IFN-β. After DAA treatment, a significant decrease in the expression levels of IFN-β, IFI44, and CXCL10 was observed in the PBMCs. Furthermore, the pretreatment expression level of IFN-β and ISGs correlated with the level of signal transducer and activator of transcription 1 (STAT1) phosphorylation, and DAA treatment abrogated STAT1 phosphorylation.Pretreatment activation of IFN-β response is rapidly normalized after DAA treatment. The present study suggests that the decreased type I IFN response by the clearance of HCV might contribute to DAA-induced alleviation of extrahepatic manifestation of chronic HCV infection.
SIGNIFICANCE OF 6-MINUTE WALK STRESS ECHOCARDIOGRAPHY FOR PATIENTS WITH AORTIC STENOSIS
Authors: Kentaro Shibayama, Nahoko Kato, Masahiko Noguchi, Yu Makihara, Hiroshi Okumura, Kotaro Obunai, Hiroyuki Watanabe
Journal: Journal of the American College of Cardiology (2018)
WALKING DISABILITIES AS PREDICTORS OF NON-INDICATION OF ORAL ANTICOAGULANTS FOR ATRIAL FIBRILLATION IN ARGENTINA: INSIGHTS FROM CONAREC XIX REGISTRY
Authors: Ignacio Manuel Cigalini, Ezequiel J. Zaidel, Juan Moukarzel, Walter Da Rosa, Emmanuel Scatularo, Maico I. Bernal, Valentín Roel, Rodolfo Leiva, Carolina Cicero, Dario Ben Igolnikof, Jorge Thierer
Journal: Journal of the American College of Cardiology (2018)
Correlative analysis of circulating tumor (ct) DNA and tumor mutational analysis (TMA) in patients with advanced pancreatobilliary malignancies (PBM).
Authors: Hani M. Babiker, Alex John Liu, Alejandro Recio Boiles, Kathylynn Saboda, Joy Liau, Aaron James Scott, Emad Elquza, Daruka Mahadevan
Journal: Journal of Clinical Oncology (2018)

235 Background: Tumor archival tissue (TT) MA of PBM is challenging due to insufficient specimen acquired from fine needle aspirations. This is a barrier to analyzing specimens for targeted therapy (clinical trial enrollment). The correlation of cell free ctDNA and TMA has not been studied extensively. We hypothesize that somatic TMA correlates with ctDNA and will be a surrogate for enrollment to targeted trials. Methods: We retrospectively identified PBM patients evaluated in the Phase I Program and analyzed ctDNA and TT. ctDNA was extracted from plasma, genomic alterations were analyzed by parallel sequencing of amplified target genes (73 genes) using Illumina Hi Seq (Guardant360). Direct sequence analysis was performed on genomic DNA isolated from FFPE TT using the Illumina MiSeq platform, 592-whole gene targets (Caris MI/X). The primary objective was to correlate the mutation concordance rate (mCR, common mutations/all mutations) between ctDNA and TT. We utilized Stata 15 for descriptive analysis, Spearman correlation coefficient, and Wilcoxon Sign Rank test for statistical analysis. Results: Between 03/2016-08/2017, 28 patients (M:F 1:1) were identified, 89.2% had pancreatic adenocarcinoma, 54% were treatment naïve and age ranged from 52-83 years old. The mCR for ctDNA was 31% (21/67) and the mCR for TT was 38% (21/55). These mCRs were highly correlative with a Spearman’s Rho = 0.89, (p &lt; 0.0001). The mCR in ctDNA was compared to mCR in TT using Wilcoxon Sign Rank Test and was found to not be statistically different (p = 0.69). Adequate TT for MA occurred in 64 % (18/28) of patients. Percentage of DNA alterations found was 89.3% (25/28) in ctDNA and 94.4% (17/18) in TT. Moreover, 61% (11/18) of patients had at least 1 shared mutation. Percentages of driver mutations identified were 92% (23/25) in ctDNA and 100% (17/17) in TT. The most common driver mutations in ctDNA were TP53, KRAS, SMAD4, and NF1. The most common driver mutations in TT were KRAS, TP53, CDKN2A, and SMAD4. Conclusions: There was a statistically significant correlation between mCR of ctDNA and TMs in PBM (p &lt; 0.0001).
Oxford Handbook of Genitourinary Medicine, HIV, and AIDS
Authors: Patrick Wills
Journal: BMJ (2006)

Eds Richard Pattman, Michael Snow, Pauline Handy, K Nathan Sankar, Babiker Elawad

Oxford University Press, 2006, £24.95, 562 pages

ISBN 0 19 852077 8

Rating: ★★★★★/5



Sex sells anything, so this guide to the mysteries of the “special” clinic should do well. The guide takes a disease based view of the conditions seen in clinic and will be useful to anyone working in the specialty, from student to consultant. The book will also be useful for the growing number of nurses working autonomously within clinics, and to that species unique to genitourinary (GU) clinics—health advisers.

Fifty five …
Prognostic impact of smoking status in non-small-cell lung cancer patients treated with immune checkpoint inhibitors.
Authors: Hyo Jung Kim, Jung Han Kim
Journal: Journal of Clinical Oncology (2018)

164 Background: Immune checkpoint inhibitors (ICIs) have emerged as a new treatment option for patients with advanced non-small-cell lung cancer (NSCLC). Some studies with ICIs in NSCLC suggested that smoking history was associated with improved survival outcomes. We conducted this meta-analysis to investigate if the survival benefits of ICIs in patients with advanced NSCLC are different according to smoking status. Methods: Electronic databases were searched for eligible studies. We included randomized controlled trials with the data of survival outcomes and extracted progression-free survival (PFS) or overall survival (OS) stratified by smoking status. Results: From 6 studies, 2,389 ever-smokers and 413 never-smokers were included in the meta-analysis. In first-line treatment setting, ICIs tended to improve PFS in patients with smoking history (HR = 0.85 [95% CI, 0.71-1.10], P = 0.07). For never-smokers with advanced NSCLC, chemotherapy, not ICIs, was significantly associated with improvement of PFS (HR = 2.30 [95% CI, 1.23-4.28], P = 0.009). In more than second-line setting, ICIs significantly prolonged OS over that with chemotherapy in ever-smokers (HR = 0.70 [95% CI, 0.63-0.79], P &lt; 0.00001). For never-smokers with NSCLC, however, ICIs failed to significantly improve OS (HR = 0.79 [95% CI, 0.59-1.06], P = 0.12). Conclusions: This meta-analysis indicates that ICIs can prolong survival over that with chemotherapy in ever-smokers with advanced NSCLC. However, ICIs failed to improve survival in never-smokers. These results suggest that smoking status may be a predictive marker for survival benefits to ICIs.
Frequency and Anatomic Distribution of Magnetic Resonance Imaging Features in the Sacroiliac Joints of Young Athletes
Authors: Ulrich Weber, Anne Grethe Jurik, Anna Zejden, Ejnar Larsen, Steen Hylgaard Jørgensen, Kaspar Rufibach, Christian Schioldan, Søren Schmidt‐Olsen
Journal: Arthritis & Rheumatology (2018)

Objective Low‐grade bone marrow edema ( BME ) has been reported in the sacroiliac ( SI ) joints of 25% of healthy individuals and patients with nonspecific mechanical back pain, thus challenging the specificity and predictive value of magnetic resonance imaging ( MRI ) for the discrimination of early spondyloarthritis (SpA). It is unknown whether stress injury in competition sports may trigger BME . This study sought to explore the frequency and anatomic distribution of SI joint MRI lesions in recreational and elite athletes. Methods After pretest calibration, semicoronal MRI scans of the SI joints of 20 recreational runners before and after running and 22 elite ice hockey players were assessed for BME and structural lesions. Three readers assessed the MRI scans in a blinded manner, using an SI joint quadrant–based module; scans from tumor necrosis factor inhibitor–treated patients with SpA served for masking. The readers recorded subjects who met the Assessment of SpondyloArthritis international Society ( ASAS ) definition of active sacroiliitis. For descriptive analysis, the frequency of SI joint quadrants exhibiting BME and structural lesions, as concordantly recorded by ≥2 of 3 readers, and their distribution in 8 anatomic SI joint regions (the upper and lower ilium and sacrum, subdivided in anterior and posterior slices) were determined. Results The proportions of recreational runners and elite ice hockey players fulfilling the ASAS definition of active sacroiliitis, as recorded concordantly by ≥2 of 3 readers, were 30–35% and 41%, respectively. In recreational runners before and after running, the mean ± SD number of SI joint quadrants showing BME was 3.1 ± 4.2 and 3.1 ± 4.5, respectively, while in elite ice hockey players, it was 3.6 ± 3.0. The posterior lower ilium was the single most affected SI joint region, followed by the anterior upper sacrum. Erosion was virtually absent. Conclusion In recreational and elite athletes, MRI revealed BME in an average of 3–4 SI joint quadrants, meeting the ASAS definition of active sacroiliitis in 30–41% of subjects. The posterior lower ilium was the single most affected SI joint region. These findings in athletes could help refine data‐driven thresholds for defining sacroiliitis in early SpA.