tbuckley/cabot-search huggingface dataset:
BMA guidance warns GPs to cut back on extra work to defend core services
Authors: Gareth Iacobucci
Journal: BMJ (2015)

GPs should decline unfunded additional work if it interferes with their ability to deliver safe and high quality core services to patients, the BMA’s General Practitioners Committee has advised.

This recommendation is contained in new guidance designed to help practices cope with an escalating workload that the BMA warns is threatening to damage patient care. The guidance, Managing Workload to Deliver Safe Patient Care ,1 offers detailed practical advice to general practices on how to work “within manageable limits” to deliver safe and high quality care.

The guidance urged GPs not to undertake clinical work that has been transferred from secondary or community care unless they receive adequate funding to do so. “If the clinical commissioning group (CCG) or commissioner does not fund workload shift, or an enhanced service, then the practice should decline to provide it, …
Functional Divergence of Delta and Mu Opioid Receptor Organization in CNS Pain Circuits
Authors: Dong Wang, Vivianne L. Tawfik, Gregory Corder, Sarah A. Low, Amaury François, Allan I. Basbaum, Grégory Scherrer
Journal: Neuron (2018)

Cellular interactions between delta and mu opioid receptors (DORs and MORs), including heteromerization, are thought to regulate opioid analgesia. However, the identity of the nociceptive neurons in which such interactions could occur in vivo remains elusive. Here we show that DOR-MOR co-expression is limited to small populations of excitatory interneurons and projection neurons in the spinal cord dorsal horn and unexpectedly predominates in ventral horn motor circuits. Similarly, DOR-MOR co-expression is rare in parabrachial, amygdalar, and cortical brain regions processing nociceptive information. We further demonstrate that in the discrete DOR-MOR co-expressing nociceptive neurons, the two receptors internalize and function independently. Finally, conditional knockout experiments revealed that DORs selectively regulate mechanical pain by controlling the excitability of somatostatin-positive dorsal horn interneurons. Collectively, our results illuminate the functional organization of DORs and MORs in CNS pain circuits and reappraise the importance of DOR-MOR cellular interactions for developing novel opioid analgesics.
Doctors offer tips to F1s for first day on job using #tipsfornewdocs
Authors: Sam Easton
Journal: BMJ (2015)

With over 7000 UK medical graduates set to start their first day as doctors on 5 August, experienced professionals are offering their advice on social media.

Doctors have been posting tips on Twitter for those beginning foundation year one (F1) posts using the hashtag #tipsfornewdocs.

Among those offering advice was Ranj Singh, an NHS doctor and presenter on ITV’s Good Morning Britain. Singh said, …
Polymer-based gadolinium oxide nanocomposites for FL/MR/PA imaging guided and photothermal/photodynamic combined anti-tumor therapy
Authors: Yu Cheng, Xiaoxiao Tan, Jinping Wang, Yidan Wang, Yilin Song, Qing You, Qi Sun, Li Liu, Siyu Wang, Fengping Tan, Jiao Li, Nan Li
Journal: Journal of Controlled Release (2018)
Acute Amnestic Syndrome Associated with Fentanyl Overdose
Authors: Jed A Barash, Michael Ganetsky, Katherine L Boyle, Vinod Raman, Michael S Toce, Scott Kaplan, Michael H Lev, Jonathan L Worth, Alfred DeMaria
Journal: New England Journal of Medicine (2018)

Fentanyl Overdose and Acute Amnestic Syndrome A syndrome of severe amnesia and medial temporal changes on magnetic resonance imaging after drug overdose has been reported with increasing frequency. Four additional cases are now reported in patients from Massachusetts who tested positive for fentanyl.
Targeted Therapies for Targeted Populations: Anti-EGFR Treatment for <i>EGFR</i>-Amplified Gastroesophageal Adenocarcinoma
Authors: Steven B. Maron, Lindsay Alpert, Heewon A. Kwak, Samantha Lomnicki, Leah Chase, David Xu, Emily O'Day, Rebecca J. Nagy, Richard B. Lanman, Fabiola Cecchi, Todd Hembrough, Alexa Schrock, John Hart, Shu-Yuan Xiao, Namrata Setia, Daniel V.T. Catenacci
Journal: Cancer Discovery (2018)

Abstract Previous anti-EGFR trials in unselected patients with gastroesophageal adenocarcinoma (GEA) were resoundingly negative. We identified EGFR amplification in 5% (19/363) of patients at the University of Chicago, including 6% (8/140) who were prospectively screened with intention-to-treat using anti-EGFR therapy. Seven patients received ≥1 dose of treatment: three first-line FOLFOX plus ABT-806, one second-line FOLFIRI plus cetuximab, and three third/fourth-line cetuximab alone. Treatment achieved objective response in 58% (4/7) and disease control in 100% (7/7) with a median progression-free survival of 10 months. Pretreatment and posttreatment tumor next-generation sequencing (NGS), serial plasma circulating tumor DNA (ctDNA) NGS, and tumor IHC/FISH for EGFR revealed preexisting and/or acquired genomic events, including EGFR-negative clones, PTEN deletion, KRAS amplification/mutation, NRAS, MYC, and HER2 amplification, and GNAS mutations serving as mechanisms of resistance. Two evaluable patients demonstrated interval increase of CD3+ infiltrate, including one who demonstrated increased NKp46+, and PD-L1 IHC expression from baseline, suggesting an immune therapeutic mechanism of action. EGFR amplification predicted benefit from anti-EGFR therapy, albeit until various resistance mechanisms emerged. Significance: This paper highlights the role of EGFR inhibitors in EGFR-amplified GEA—despite negative results in prior unselected phase III trials. Using serial ctDNA and tissue NGS, we identified mechanisms of primary and acquired resistance in all patients, as well as potential contribution of antibody-dependent cell-mediated cytotoxicity to their clinical benefit. Cancer Discov; 8(6); 696–713. ©2018 AACR. See related commentary by Strickler, p. 679. This article is highlighted in the In This Issue feature, p. 663
How can a GP participate in public health?
Authors: Joyce Carter
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>
Antibody‐Based Therapeutics: Ultrasensitive NIR‐SERRS Probes with Multiplexed Ratiometric Quantification for In Vivo Antibody Leads Validation (Adv. Healthcare Mater. 4/2018)
Authors: Homan Kang, Sinyoung Jeong, Ahla Jo, Hyejin Chang, Jin‐Kyoung Yang, Cheolhwan Jeong, San Kyeong, Youn Woo Lee, Animesh Samanta, Kaustabh Kumar Maiti, Myeong Geun Cha, Taek‐Keun Kim, Sukmook Lee, Bong‐Hyun Jun, Young‐Tae Chang, Junho Chung, Ho‐Young Lee, Dae Hong Jeong, Yoon‐Sik Lee
Journal: Advanced Healthcare Materials (2018)

In article number 1700870, Yoon-Sik Lee and co-workers demonstrate in vivo validation process of candidate antibodies against human colon cancer, using a ratiometric quantification method. The validation is performed on a single mouse and analyzed by multiplexed surface-enhanced resonance Raman scattering (SERRS) with ultrasensitive and near-infrared (NIR)-active SERRS nanoprobes (NIR-SERRS dots).
Rho GTPase signaling and role of the Rac1 exchange factor DOCK4 in GBM invasion and vascular growth
Authors: Teklu Egnuni, Valerie Speirs, Aruna Chakrabarty, Heiko Wurdak, Susan Short, Georgia Mavria
Journal: Neuro-Oncology (2018)

disseminates predominantly along white matter tracts in the invasive unresectable region.Multi-region sampling has revealed phylogenetic relationships amongst GBM subclones, highlighting the utility of this method for the study of these heterogeneous tumours.Here, we report on an invasive region expression profile obtained through a multi-region sampling approach.METHODS: Multi-region sampling during maximal surgical resection was performed on five adult GBM patients based on MRI scans and 5-aminolevulinic acid administration for fluorescent identification of the invasive region.RNA was extracted from each region of the GBM patient and hybridized with Affymetrix GeneChip Human Gene 2.0 ST arrays.RESULTS: Distinct expression profiles were observed for regions within a patient, indicating intra-tumor heterogeneity of GBM.The comparison of invasive region with other tumor regions using linear models for microarray data revealed 44 differentially expressed genes (adjusted P-value < 0.05).Remarkably, all 44 genes showed elevated expression in the invasive region and were enriched with biological processes such as myelination (KLK6, MAL, and MBP), cell adhesion (CNTNAP4, CTNNA3, EDIL3, HAPLN2, MAG, and MOG), and lipid metabolic process (APOD, LRP2, and PLCL1).In addition, the GBM invasive region was characterized by the expression of several genes associated with a GBM neural subtype.CONCLUSIONS: Isolating and characterising tumour cells infiltrating normal brain within the invasive region remains a bottleneck to the development of therapies tailored to GBM.Gene expression analysis of the invasive region revealed the overexpression of cancer-related genes with possible involvement in invasion along white matter tracts.Although several overexpressed genes likely represent the normal white matter brain component obtained during maximal surgical removal, the identification of cancer-related genes provides proofof-principle for -omics approaches utilising invasive region tumour tissue to identify biomarkers and targets for therapeutic evaluation.
Progenitor Cells and Clinical Outcomes in Patients With Acute Coronary Syndromes
Authors: Ayman Samman Tahhan, Muhammad Hammadah, Mohamad Raad, Zakaria Almwaqqat, Ayman Alkhoder, Pratik B. Sandesara, Heval Mohamed-Kelli, Salim S. Hayek, Jeong Hwan Kim, Wesley T. O’Neal, Matthew L. Topel, Aubrey J. Grant, Nabil Sabbak, Robert E. Heinl, Mohamad Mazen Gafeer, Malik Obideen, Belal Kaseer, Nasser Abdelhadi, Yi-An Ko, Chang Liu, Iraj Hesaroieh, Ernestine A. Mahar, Viola Vaccarino, Edmund K. Waller, Arshed A. Quyyumi
Journal: Circulation Research (2018)

Rationale: Circulating progenitor cells (CPCs) mobilize in response to ischemic injury, but their predictive value remains unknown in acute coronary syndrome (ACS). Objective: We aimed to investigate the number of CPCs in ACS compared with those with stable coronary artery disease (CAD), relationship between bone marrow PCs and CPCs, and whether CPC counts predict mortality in patients with ACS. Methods and Results: In 2028 patients, 346 had unstable angina, 183 had an acute myocardial infarction (AMI), and the remaining 1499 patients had stable CAD. Patients with ACS were followed for the primary end point of all-cause death. CPCs were enumerated by flow cytometry as mononuclear cells expressing a combination of CD34+, CD133+, vascular endothelial growth factor receptor 2+, or chemokine (C-X-C motif) receptor 4+. CPC counts were higher in subjects with AMI compared those with stable CAD even after adjustment for age, sex, race, body mass index, renal function, hypertension, diabetes mellitus, hyperlipidemia, and smoking; CD34+, CD34+/CD133+, CD34+/CXCR4+, and CD34+/VEGFR2+ CPC counts were 19%, 25%, 28%, and 142% higher in those with AMI, respectively, compared with stable CAD. There were strong correlations between the concentrations of CPCs and the PC counts in bone marrow aspirates in 20 patients with AMI. During a 2 (interquartile range, 1.31–2.86)-year follow-up period of 529 patients with ACS, 12.4% died. In Cox regression models adjusted for age, sex, body mass index, heart failure history, estimated glomerular filtration rate, and AMI, subjects with low CD34+ cell counts had a 2.46-fold (95% confidence interval, 1.18–5.13) increase in all-cause mortality, P =0.01. CD34+/CD133+ and CD34+/CXCR4+, but not CD34+/VEGFR2+ PC counts, had similar associations with mortality. Results were validated in a separate cohort of 238 patients with ACS. Conclusions: CPC levels are significantly higher in patients after an AMI compared with those with stable CAD and reflect bone marrow PC content. Among patients with ACS, a lower number of hematopoietic-enriched CPCs are associated with a higher mortality.
Characterization of Coding/Noncoding Variants for SHROOM3 in Patients with CKD
Authors: Jeremy W. Prokop, Nan Cher Yeo, Christian Ottmann, Surya B. Chhetri, Kacie L. Florus, Emily J. Ross, Nadiya Sosonkina, Brian A. Link, Barry I. Freedman, Candice J. Coppola, Chris McDermott-Roe, Seppe Leysen, Lech-Gustav Milroy, Femke A. Meijer, Aron M. Geurts, Frank J. Rauscher, Ryne Ramaker, Michael J. Flister, Howard J. Jacob, Eric M. Mendenhall, Jozef Lazar
Journal: Journal of the American Society of Nephrology (2018)

Background Interpreting genetic variants is one of the greatest challenges impeding analysis of rapidly increasing volumes of genomic data from patients. For example, SHROOM3 is an associated risk gene for CKD, yet causative mechanism(s) of SHROOM3 allele(s) are unknown. Methods We used our analytic pipeline that integrates genetic, computational, biochemical, CRISPR/Cas9 editing, molecular, and physiologic data to characterize coding and noncoding variants to study the human SHROOM3 risk locus for CKD. Results We identified a novel SHROOM3 transcriptional start site, which results in a shorter isoform lacking the PDZ domain and is regulated by a common noncoding sequence variant associated with CKD (rs17319721, allele frequency: 0.35). This variant disrupted allele binding to the transcription factor TCF7L2 in podocyte cell nuclear extracts and altered transcription levels of SHROOM3 in cultured cells, potentially through the loss of repressive looping between rs17319721 and the novel start site. Although common variant mechanisms are of high utility, sequencing is beginning to identify rare variants involved in disease; therefore, we used our biophysical tools to analyze an average of 112,849 individual human genome sequences for rare SHROOM3 missense variants, revealing 35 high-effect variants. The high-effect alleles include a coding variant (P1244L) previously associated with CKD ( P =0.01, odds ratio=7.95; 95% CI, 1.53 to 41.46) that we find to be present in East Asian individuals at an allele frequency of 0.0027. We determined that P1244L attenuates the interaction of SHROOM3 with 14–3-3, suggesting alterations to the Hippo pathway, a known mediator of CKD. Conclusions These data demonstrate multiple new SHROOM3 -dependent genetic/molecular mechanisms that likely affect CKD.
Re: Zhangqun Ye, Guohua Zeng, Huan Yang, et al. Efficacy and Safety of Tamsulosin in Medical Expulsive Therapy for Distal Ureteral Stones with Renal Colic: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial. Eur Urol 2018;73:385–91
Authors: Taimur T. Shah, Graeme MacLennan, Rob Pickard, Samuel McClinton, Veeru Kasivisvanathan
Journal: European Urology (2018)
Genital inflammation undermines the effectiveness of tenofovir gel in preventing HIV acquisition in women
Authors: Lyle R McKinnon, Lenine J Liebenberg, Nonhlanhla Yende-Zuma, Derseree Archary, Sinaye Ngcapu, Aida Sivro, Nico Nagelkerke, Jose Gerardo Garcia Lerma, Angela D Kashuba, Lindi Masson, Leila E Mansoor, Quarraisha Abdool Karim, Salim S Abdool Karim, Jo-Ann S Passmore
Journal: Nature Medicine (2018)
Postgraduate Diploma in Aviation Medicine (PGDipAvMed)
Authors: Nomy Ahmed
Journal: BMJ (2007)

Credit: THE KOBAL COLLECTION



FURTHER INFORMATION 

The courses being offered are via the University of Otago, New Zealand: www.otago.ac.nz/aviation_medicine/ Contact: Dr Rob Griffiths, academic coordinator (rfgriffiths@wnmeds.ac.nz)

Anyone currently working or wanting to work in aviation medicine. This includes those wanting to join airline medical departments, doing pilot medicals and aeromedical retrievals. It is open even to those not wanting to do the full diploma but wanting courses in certain subjects such as aeromedical emergencies. Papers in occupational medicine are also offered.

For three main reasons. Firstly, to gain knowledge to impart to my travelling patients who all seemed to …
Abstract P1-02-02: FASN inhibition by TVB-3166 associates with breast cancer subtype
Authors: AB Gruslova, C-L Chen, C-M Wang, RM Elledge, VG Kaklamani, K Lathrop, TH Huang, A Brenner
Journal: Cancer Research (2018)

Abstract Fatty acid synthase (FASN) is overexpressed in numerous tumor types, including breast carcinomas, and promotes changes in the genetic program controlling lipid biosynthesis. While inhibiting FASN appears to be an attractive therapeutic approach under development, the success of this approach may depend on the identification of tumor subtypes with specific metabolic requirements. Applying a comprehensive profile of circulating tumor cells (CTC) using canonical pathway gene sets, we identified a correlation of metabolic subtypes with breast tumor subtype. A lipogenic subtype is strongly associated with Luminal A subtype, whereas the glycolytic subtype associated with Luminal B tumors. The triple negative subtype was more heterogeneous and had the expression of both sets of gene. Such a difference in the metabolic profile may dictate differential sensitivity to inhibitors targeting de novo lipid synthesis, including FASN. This was supported by in vitro studies using selective FASN inhibitor, TVB-3166. Exposure to TVB-3166 over 14 days incubation in Advanced MEM with 1% charcoal-stripped FBS selectively inhibited growth and viability of Luminal A breast cancer cells, but had no effect on Luminal B subtype. This was further confirmed in short-term patient derived cultures. Mechanistic studies suggest that TVB-3166 quickly disrupts FA synthesis leading to the disruption of the lipid raft architecture and tumor cell death through an apoptotic mechanism. In conclusion, our findings highlight that success of targeting cancer metabolism directly may depend on identification of tumor subtypes with specific metabolic requirements. Citation Format: Gruslova AB, Chen C-L, Wang C-M, Elledge RM, Kaklamani VG, Lathrop K, Huang TH, Brenner A. FASN inhibition by TVB-3166 associates with breast cancer subtype [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 P1-02-02.
Angiogenesis and vascular remodeling of vasa nervorum in locally advanced prostate cancer.
Authors: Nicolae Ghinea
Journal: Journal of Clinical Oncology (2018)

341 Background: Perineural invasion (PNI) is generally accepted as a major route of cancer dissemination encountered in malignancies associated with highly enervated organs. However, the effect of cancer cells on the blood vessels nourishing the nerves (i.e., vasa nervorum) remains unknown. Methods: We used immunohistochemistry involving three specific antibodies that recognize different endothelial markers (CD34, VEGF-R2 and FSHR), and standard histochemical methods (HES, PAS, TRICHROM) to detect changes in the vasa nervorum of nerves invaded by cancer cells in tissue samples from 85 patients diagnosed with locally advanced prostate cancer (LAPC). Genes known to be implicated in the process of angiogenesis and vascular remodeling have been also explored. NanoString nCounter Analysis covering 86 target genes was used for comparison of gene expression levels between LAPC (6 frozen samples) and normal prostate (NP; 2 frozen samples). Results: The percentage of the area occupied by CD34-positive vasa nervorum endothelial cells associated to nerves with PNI was significantly higher than that in nerves without PNI (6.93 ± 1.08 versus 1.76 ± 0.32; p = 0.003), suggesting a process of angiogenesis. In 18/85 (21%) of patients diagnosed with LAPC the vasa nervorum arterioles had a thick (25 ± 5 µm) tunica media consisting of collagen fibers. More than 75% of CD34-positive vasa nervorum of nerves with or without PNI expressed FSHR. In contrast, none of vasa nervorum expressed detectable VEGF-R2. A panel of 19 genes was found to be significantly (p &lt; 0.05), differentially expressed between LAPC and NP. Six of them (ANGPT1, ITGB3, PGGFB, VEGFC, FSHR, and SDC1) have previously been associated with tumor progression, angiogenesis, and metastasis. Other three genes (SELE, SELP, and ESAM) are known to be responsible for the accumulation of blood leukocytes at sites of inflammation by mediating the adhesion of cells to the vascular lining. Conclusions: Perineural invasion of cancer cells caused angiogenesis and vascular remodeling of vasa nervorum in locally advanced prostate cancer.
Anaplastic Lymphoma Kinase Mutation (<i>ALK</i> F1174C) in Small Cell Carcinoma of the Prostate and Molecular Response to Alectinib
Authors: Benedito A. Carneiro, Sahithi Pamarthy, Ami N. Shah, Vinay Sagar, Kenji Unno, HuiYing Han, Ximing J. Yang, Rubens B. Costa, Rebecca J. Nagy, Richard B. Lanman, Timothy M. Kuzel, Jeffrey S. Ross, Laurie Gay, Julia A. Elvin, Siraj M. Ali, Massimo Cristofanilli, Young K. Chae, Francis J. Giles, Sarki A. Abdulkadir
Journal: Clinical Cancer Research (2018)

Small cell carcinoma of the prostate (SCCP) is an aggressive disease that can arise
SUCCESSFUL IMPLEMENTATION OF VENO-ARTERIAL EXTRA-CORPOREAL MEMBRANE OXYGENATION (VA ECMO) AS RESCUE FOR REFRACTORY VENTRICULAR TACHYCARDIA (VT) IN FULMINANT MYOCARDITIS
Authors: Omer Mirza, Anurag Sahu, David Vega
Journal: Journal of the American College of Cardiology (2018)
Takotsubo Syndrome Associated With Structural Brain Alterations of the Limbic System
Authors: Thierry Hiestand, Jürgen Hänggi, Carina Klein, Marlene S. Topka, Milosz Jaguszewski, Jelena R. Ghadri, Thomas F. Lüscher, Lutz Jäncke, Christian Templin
Journal: Journal of the American College of Cardiology (2018)
Does physical fitness enhance lung function in children and young adults?
Authors: Robert J. Hancox, Finn Rasmussen
Journal: European Respiratory Journal (2018)

Although physical activity is important for lung health, it is unclear whether physical fitness influences lung function. We investigated associations between lung function and fitness in two population-based cohort studies of children and young adults. Aerobic fitness was measured using a maximal cycle ergometer test at ages 9, 15, 21 and 29 years in Odense, Denmark and using a submaximal cycle test at ages 15, 26, 32 and 38 years in Dunedin, New Zealand. Aerobic fitness was positively associated with forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) in cross-sectional analyses at all ages in both cohorts, independently of height, weight, sex, asthma and smoking. Each standard deviation difference in fitness was associated with 2–3% predicted higher values of FEV 1 and FVC. Improvements in fitness during childhood and adolescence were associated with growth in lung volumes in longitudinal analyses. These associations tended to be stronger in males than females. No longitudinal associations were found after peak adult lung function had been attained. Fitness was not significantly associated with FEV 1 /FVC ratios. Aerobic fitness is positively associated with lung volumes. Improving fitness during childhood and adolescence is associated with greater adult lung volumes, but not with airway calibre.
GP bashing is unacceptable, says Health Education England
Authors: Abi Rimmer
Journal: BMJ (2016)

The denigration of general practice by other medical specialties must be recognised as unacceptable, Health Education England (HEE) has said.

HEE published a report on students’ experiences of general practice while at medical school on Tuesday 8 November.1 The report was the work of a taskforce, chaired by Val Wass, emeritus professor of medical education at Keele University, which investigated how …