tbuckley/cabot-search huggingface dataset:
An introduction to prescribing
Authors: Daniel R Burrage
Journal: BMJ (2014)

Writing a safe, effective, and legal prescription Prescribing is an essential skill that medical students must learn. It has the potential to improve health, but is associated with risk to patients. The EQUIP study reported that newly qualified doctors had a prescribing error rate of 8.4%, and drug errors account for more than 10% of incident reports a year.12 The most frequent errors are caused by incorrect dosage; common drug classes involved are analgesics, antibiotics, bronchodilators, and antianginals, with most errors being made on acute admissions.1 Undergraduate training should prepare students for their responsibilities as newly qualified doctors, but around half of graduates feel unprepared,345 particularly in areas of practice that are based on experiential learning such as prescribing.6 The General Medical Council (GMC) outlines eight key prescribing skills (box 1).3 These form the basis of the national Prescribing Safety Assessment (PSA) (box 2), which aims to ensure that all students obtain core prescribing competences by the point of graduation.7 The PSA is compulsory in several medical schools, where it is used as part of finals exams, and it is likely that the number of medical schools using it in this way will increase. This article will help you with the first component of the assessment by demonstrating how to plan appropriate drug treatment and provide a safe and legal prescription. It will provide a starting point for how to identify the most important drugs you need to be familiar with, what you need to consider when deciding what to prescribe, and how to prescribe it. #### Box 1: Key prescribing skills
Histologic Features Associated With an Invasive Component in Lentigo Maligna Lesions
Authors: Angela Moreno, Esperanza Manrique-Silva, Amaya Virós, Celia Requena, Onofre Sanmartín, Víctor Traves, Eduardo Nagore
Journal: JAMA Dermatology (2019)

Lentigo maligna (LM) presents an invasive component in up to 20% of biopsied cases, but to date the histologic features useful in detecting this invasive component have not been described. Some histologic characteristics are hypothesized to contribute to the progression of LM invasion.To identify the histologic characteristics associated with lentigo maligna melanoma (LMM) in patients with LM diagnosed by a partial diagnostic biopsy.A retrospective cross-sectional study of patients treated between January 1, 2000, and December 31, 2017, was conducted in a referral oncology center in València, Spain. Data and specimens of patients (n = 96) with a diagnosis of primary cutaneous melanoma in the form of either LM or LMM who had undergone surgical treatment, a complete histologic examination of the whole tumor, and an initial diagnostic partial biopsy of LM were included in the study. Histologic assessment was blinded to the presence of an invasive component.All biopsy specimens were evaluated for the presence of certain histologic characteristics.Comparisons between invasive samples and samples without an invasive component were performed. The differences in the distribution of variables between the groups were assessed using the χ2 and Fisher exact tests, and the degree of association of the relevant variables was quantified by logistic regression models. A classification and regression tree analysis was performed to rank the variables by importance.In total, 96 patients had sufficient histologic material that could be evaluated. The patients were predominantly male (56 [58.3%]) and had a mean (SD) age at diagnosis of 72 (12) years. Of these patients, 63 (65.6%) had an LM diagnosis and 33 (34.4%) had an LMM diagnosis (an invasive component). The histologic variables associated with the presence of an invasive component were melanocytes forming rows (odds ratio [OR], 11.5; 95% CI, 1.4-94.1; P = .02), subepidermal clefts (OR, 2.8; 95% CI, 1.0-7.9; P = .049), nests (OR, 3.0; 95% CI, 1.1-8.6; P = .04), and a lesser degree of solar elastosis (OR, 0.4; 95% CI, 0.1-1.1; P = .07). A classification and regression tree analysis of the relevant histologic features was able to accurately identify lentigo maligna with an invasive component (LMM) in more than 60% of patients.These findings may be useful in classifying early LM specimens at higher risk of invasion, which may eventually be relevant in identifying the most appropriate management for LM.
Nancy Index Scores of Chronic Inflammatory Bowel Disease Activity Associate With Development of Colorectal Neoplasia
Authors: Julien Kirchgesner, Magali Svrcek, Guillaume Le Gall, Cécilia Landman, Xavier Dray, Anne Bourrier, Isabelle Nion-Larmurier, Nadia Hoyeau, Harry Sokol, Philippe Seksik, Jacques Cosnes, Jean-François Fléjou, Laurent Beaugerie
Journal: Clinical Gastroenterology and Hepatology (2019)
Alcoholic and Nonalcoholic Fatty Liver Disease and Incident Hospitalization for Liver and Cardiovascular Diseases
Authors: Yoosoo Chang, Juhee Cho, Yong Kyun Cho, Ara Cho, Yun Soo Hong, Di Zhao, Jiin Ahn, Chong Il Sohn, Hocheol Shin, Eliseo Guallar, Seungho Ryu
Journal: Clinical Gastroenterology and Hepatology (2019)
Abstract ES2-3: Exosome-mediated stimulation of metastasis
Authors: A Minn
Journal: Cancer Research (2019)

Abstract Although cancer cell intrinsic mechanisms are important in driving aggressive features of cancer, stromal cells in the tumor microenvironment also serve critical roles. In particular, heterotypic interaction between cancer cells and stromal fibroblasts can generate signals for cancer progression, therapy resistance, and inflammatory responses. Among the signals resulting from cellular cross-talk include anti-viral pathways that induce interferon-stimulated genes (ISGs). These observations suggest 1) the existence of signals in the tumor microenvironment that mimic a viral infection, 2) resulting activation of anti-viral signaling may contribute to how stromal cells promote aggressive features of cancer, and 3) mechanisms must exist to prevent this anti-viral signaling under non-pathological conditions. We have demonstrated that exosomes and their RNA produced by stromal fibroblasts represents one such “virus mimic” by engaging RNA pattern recognition receptors (PRRs) such as RIG-I. Triggering of stromal NOTCH-MYC by breast cancer cells results in a POL3-driven increase in RN7SL1, an endogenous non-coding RNA normally shielded from PRR recognition by RNA binding proteins SRP9/14. This increase in RN7SL1 alters its stoichiometry with SRP9/14 and generates unshielded RN7SL1 that is deployed in stromal exosomes. After these stromal exosomes are transferred to immune cells, the unshielded RN7SL1 can drive an inflammatory response. Upon exosome transfer to breast cancer cells, unshielded RN7SL1 activates the RIG-I to enhance tumor growth, metastasis, and therapy resistance. The significance of this “virus mimicry” and failure to shield endogenous RN7SL1 from PRR activation is corroborated by evidence from patient tumors and blood. In total, these results demonstrate how exosomes, unshielding of endogenous RNAs, and engagement of pattern recognition receptors couple stromal activation with aggressive features of breast cancer. Citation Format: Minn A. Exosome-mediated stimulation of metastasis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES2-3.
Oral vitamin B<sub>12</sub> supplement is delivered to the distal gut, altering the corrinoid profile and selectively depleting <i>Bacteroides</i> in C57BL/6 mice
Authors: Caleb J Kelly, Erica E Alexeev, Linda Farb, Thad W Vickery, Leon Zheng, Campbell Eric L, David A Kitzenberg, Kayla D Battista, Douglas J Kominsky, Charles E Robertson, Daniel N Frank, Sally P Stabler, Sean P Colgan
Journal: Gut Microbes (2019)

Vitamin B12 is a critical nutrient for humans as well as microbes. Due to saturable uptake, high dose oral B12 supplements are largely unabsorbed and reach the distal gut where they are available to interact with the microbiota. The aim of this study was to determine if oral B12 supplementation in mice alters 1) the concentration of B12 and related corrinoids in the distal gut, 2) the fecal microbiome, 3) short chain fatty acids (SCFA), and 4) susceptibility to experimental colitis. C57BL/6 mice (up to 24 animals/group) were supplemented with oral 3.94 µg/ml cyanocobalamin (B12), a dose selected to approximate a single 5 mg supplement for a human. Active vitamin B12 (cobalamin), and four B12-analogues ([ADE]CN-Cba, [2Me-ADE]CN-Cba, [2MeS-ADE]CN-Cba, CN-Cbi) were analyzed in cecal and fecal contents using liquid chromatography/mass spectrometry (LC/MS), in parallel with evaluation of fecal microbiota, cecal SCFA, and susceptibility to dextran sodium sulfate (DSS) colitis. At baseline, active B12 was a minor constituent of overall cecal (0.86%) and fecal (0.44%) corrinoid. Oral B12 supplementation increased active B12 at distal sites by >130-fold (cecal B12 increased from 0.08 to 10.60 ng/mg, fecal B12 increased from 0.06 to 7.81 ng/ml) and reduced microbe-derived fecal corrinoid analogues ([ADE]CN-Cba, [2Me-ADE]CN-Cba, [2MeS-ADE]CN-Cba). Oral B12 had no effect on cecal SCFA. Microbial diversity was unaffected by this intervention, however a selective decrease in Bacteroides was observed with B12 treatment. Lastly, no difference in markers of DSS-induced colitis were detected with B12 treatment.
Not enough jobs for medical students
Authors: Oliver Ellis
Journal: BMJ (2010)

Medical training is difficult, tiring, and sometimes unpleasant. During the day you deal with pompous consultants, stroppy juniors, and shouting nurses; then at night you settle down to read textbooks. Not much of a life, but in the UK at least you are guaranteed a job when you’ve graduated.

Not any more though. This year the UK might not have enough foundation year jobs so some medical graduates might be left out in the cold.

The UK Foundation Programme Office (UKFPO) have produced a contingency plan, …
The clinical application of cancer immunotherapy based on naturally circulating dendritic cells
Authors: Kalijn F. Bol, Gerty Schreibelt, Katrin Rabold, Stefanie K. Wculek, Julia Katharina Schwarze, Andrzej Dzionek, Alvaro Teijeira, Lana E. Kandalaft, Pedro Romero, George Coukos, Bart Neyns, David Sancho, Ignacio Melero, I. Jolanda M. de Vries
Journal: Journal for ImmunoTherapy of Cancer (2019)

Dendritic cells (DCs) can initiate and direct adaptive immune responses. This ability is exploitable in DC vaccination strategies, in which DCs are educated ex vivo to present tumor antigens and are administered into the patient with the aim to induce a tumor-specific immune response. DC vaccination remains a promising approach with the potential to further improve cancer immunotherapy with little or no evidence of treatment-limiting toxicity. However, evidence for objective clinical antitumor activity of DC vaccination is currently limited, hampering the clinical implementation. One possible explanation for this is that the most commonly used monocyte-derived DCs may not be the best source for DC-based immunotherapy. The novel approach to use naturally circulating DCs may be an attractive alternative. In contrast to monocyte-derived DCs, naturally circulating DCs are relatively scarce but do not require extensive culture periods. Thereby, their functional capabilities are preserved, the reproducibility of clinical applications is increased, and the cells are not dysfunctional before injection. In human blood, at least three DC subsets can be distinguished, plasmacytoid DCs, CD141+ and CD1c+ myeloid/conventional DCs, each with distinct functional characteristics. In completed clinical trials, either CD1c+ myeloid DCs or plasmacytoid DCs were administered and showed encouraging immunological and clinical outcomes. Currently, also the combination of CD1c+ myeloid and plasmacytoid DCs as well as the intratumoral use of CD1c+ myeloid DCs is under investigation in the clinic. Isolation and culture strategies for CD141+ myeloid DCs are being developed. Here, we summarize and discuss recent clinical developments and future prospects of natural DC-based immunotherapy.
Abstract P4-16-06: Radiotherapy to the Primary Tumor Is Associated with Improved Survival in Stage IV Breast Cancer
Authors: SC Morgan, J-M Caudrelier, MJ Clemons
Journal: Cancer Research (2012)

Abstract Background: In patients found to have metastatic disease at the time of breast cancer diagnosis, the role of local therapy is undefined. Numerous retrospective analyses have suggested that surgery and/or external beam radiotherapy (EBRT) directed at the primary tumor may improve overall survival (OS). All these analyses, however, are subject to significant selection bias. The current retrospective analysis of a large registry dataset attempts to limit the effect of this bias. Methods: The study population consisted of women in the Surveillance, Epidemiology, and End Results (SEER) program database diagnosed with stage IV breast cancer between 1988 and 2009. Only those patients for whom surgery to the primary tumor was recommended but was not undertaken (due to patient refusal or other uncategorized reasons) were included. In this population of patients deemed candidates for surgery, the association between receipt of primary tumor-directed EBRT and overall survival was studied. Descriptive statistics were used to characterize the study population. OS was estimated using the Kaplan-Meier (KM) method. Univariate and multivariate Cox regression were used to identify factors associated with OS. Results: A total of 3,529 cases were analyzed. EBRT was received in 768 cases. Median age at diagnosis was 68 years (IQR, 56–79 years). Median follow-up by reverse KM estimate was 98 months (range, 0–252 months). On univariate analysis, EBRT was associated with improved OS (hazard ratio 0.80, 95% CI 0.74–0.87, p &amp;lt; 0.001). 1-year, 3-year, and 5-year OS was 56.9%, 24.2%, and 10.7% respectively in those receiving EBRT and 44.3%, 16.6%, and 7.2% respectively in those not receiving EBRT. Median OS in those receiving EBRT was 15 months compared to 7 months in those not receiving EBRT. In a multivariate Cox model taking into account receipt of EBRT, age at diagnosis, year of diagnosis, ethnicity, number of primary cancers, estrogen and progesterone receptor status, histologic grade, and size of primary tumor, EBRT remained significantly associated with improved survival (hazard ratio 0.86, 95% CI 0.76–0.97, p = 0.011). Conclusions: In a population of women presenting with metastatic breast cancer, all of whom were deemed candidates for surgery to the primary tumor but who did not undergo surgery, receipt of EBRT was associated with improved OS. The observed 8-month absolute difference in median OS is clinically significant. This analysis could not account for performance status, extent of metastatic disease, co-morbidities, use of systemic therapies, and other potentially confounding factors. Only randomized studies, such as the Eastern Cooperative Oncology Group E2108 trial currently underway, will be able to definitively assess the value of local therapy directed at the primary tumor in this setting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-16-06.
Abstract P3-06-03: Copy number analysis identifies <i>ESR1</i> and <i>MDM4</i> as drivers of progression in invasive lobular breast carcinoma
Authors: JM Atkinson, L Cao, A Basudan, MJ Sikora, A Bahreini, N Tasdemir, RC Jankowitz, PF McAuliffe, D Dabbs, S Haupt, Y Haupt, PC Peter Lucas, AV Lee, S Oesterreich
Journal: Cancer Research (2019)

Abstract Background: Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer after invasive ductal carcinoma (IDC). While specific clinical and pathological features differ between ILC and IDC, both histologies are treated the same, due to a lack of knowledge of targetable pathways underlying the observed differences. To identify potential genetic drivers of ILC progression, we set out to identify genes with copy number (CN) alterations, comparing tumors with good outcome to those with poor outcome. Method: We designed probes for a total of 67 genes known to be frequently altered in breast cancer and used sensitive nanoString technology to comprehensively investigate CN alterations of these genes in 70 well-curated primary ILCs. ILC cell lines MDA-MB-134-VI, SUM44PE, and BCK4 were used for functional studies including proliferation, apoptosis, colony formation, and analysis of gene expression. Results: Our studies reveal that ESR1 is frequently amplified in primary ILC (14% gains and 10% amplification), and that tumors with amplified ESR1 are more likely to recur compared to those with normal CN. Our analysis also identified a subset of ILCs with HER2 amplification (19%) despite a negative clinical IHC score, and these tumors expressed high HER2 mRNA, protein, and demonstrated enrichment of a molecular HER2 signature. The other most frequently amplified genes included CCND1 (33%), MDM4 (17%), and MYC (17%), and most frequently lost genes were NCOR2 (7%), FGFR4 (6%) and TP53 (6%). MDM4, a negative regulator of p53, has previously been reported to play a role in breast cancer, though little is known about its role in ILC. We demonstrate that decreasing MDM4 levels in p53 wild type ILC cell lines results in increased apoptosis, decreased proliferation associated with cell cycle arrest, and activation of p53 target genes. Intriguingly, a similar induction of G0/G1 cell cycle arrest and increase in apoptosis was observed in p53 mutant ILC cells after MDM4 downregulation, suggesting a p53-independent function of MDM4. Conclusion: Sensitive detection of CN changes identified amplifications of ESR1 and MDM4 as potential drivers of ILC. Functional studies demonstrate that MDM4 has both p53 dependent and independent functions that warrant further study. Citation Format: Atkinson JM, Cao L, Basudan A, Sikora MJ, Bahreini A, Tasdemir N, Jankowitz RC, McAuliffe PF, Dabbs D, Haupt S, Haupt Y, Peter Lucas PC, Lee AV, Oesterreich S. Copy number analysis identifies ESR1 and MDM4 as drivers of progression in invasive lobular breast carcinoma [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-03.
How to pursue a career in sports and exercise medicine?
Authors: Caroline Elton
Journal: BMJ (2015)

Dear Caroline

I’m interested in looking at a career in sport and exercise medicine. What is the best way to find out more?

Aaron Cassidy, second year medical student at University of Leicester, UK

Caroline replies . . .

Sports and exercise medicine (SEM) is a relatively new kid on the block because it only became a specialty in 2005. SEM offers a variety of career options, such as working in NHS funded musculoskeletal services and exercise medicine clinics across primary and secondary care, and also private sports medicine practices …
E-cigarettes helped more smokers quit than nicotine replacement therapy
Authors: Rob Cook, Peter Davidson, Rosie Martin
Journal: BMJ (2019)

The study Hajek P, Phillips-Waller A, Przulj D, et al. A randomised trial of e-cigarettes versus nicotine-replacement therapy. N Engl J Med 2019;380:629-37. This trial was funded by the NIHR Health Technology Assessment Programme (12/167/135) and by Cancer Research UK. To read the full NIHR Signal, go to https://discover.dc.nihr.ac.uk/content/signal-000757/e-cigarettes-helped-more-smokers-quit-than-nicotine-replacement-therapy
Abstract P5-10-01: Using whole genome sequencing and somatic mutation signatures to unravel insight into familial breast cancer aetiology
Authors: P Simpson, K Nones, J Johnson, F Newell, A-M Patch, H Thorne, S Kazakoff, X De Luca, M Parsons, K Ferguson, L Reid, A McCart Reed, S Srihari, V Lakis, A Davidson, P Mukhopadhyay, O Holmes, Q Xu, S Wood, C Leonard, J Beasley, A Degasperi, S Nik-Zainal, M Ragan, A Spurdle, KK Khanna, S Lakhani, J Pearson, G Chenevix-Trench, N Waddell
Journal: Cancer Research (2019)

Abstract Approximately 10-15% of breast cancers are associated with a strong family history of disease. Pathogenic variants in BRCA1, BRCA2 or other moderate to highly penetrant susceptibility genes (e.g. TP53, ATM, CHEK2, PALB2 and PTEN) account for a number of breast cancer families. However, for over 50% of families the underlying genetic contribution to their risk remains unknown (termed here as non-BRCA1/2). This has a profound impact for how individuals and their families are managed in the clinic. We applied whole genome sequencing (WGS) to determine whether somatic mutation analysis can reveal insight into the aetiology of familial breast cancer. The full repertoire of somatic mutations was evaluated in 26 BRCA1, 22 BRCA2 and 32 non-BRCA1/2 tumours; including SNPs, indels, copy number changes and structural rearrangements, and mutational signatures. Genomes were also analysed using the HRD Index and HRDetect, as predictors of homologous recombination deficiency. BRCA1, BRCA2 and non-BRCA1/2 tumours exhibited a different burden of mutations, a different spectrum of mutational signatures and different telomere length. Based on collective patterns of mutation signatures, tumours were classified as 'BRCA1-like', 'BRCA2-like' or 'non-BRCA1/2-like' with a 15% rate of tumour re-classification from their original clinical BRCA status. The results demonstrate the power of WGS to differentiate between BRCA1 and BRCA2 driven tumours; in the identification of double-pathogenic germline mutation carriers based on the resulting somatic mutation signature; and in the interpretation of BRCA unclassified variants. WGS of tumour genomes reveals fascinating insights into tumour aetiology and could compliment current genetic testing of breast cancer families. Citation Format: Simpson P, Nones K, Johnson J, Newell F, Patch A-M, Thorne H, Kazakoff S, De Luca X, Parsons M, Ferguson K, Reid L, McCart Reed A, Srihari S, Lakis V, Davidson A, Mukhopadhyay P, Holmes O, Xu Q, Wood S, Leonard C, Beasley J, Degasperi A, Nik-Zainal S, Ragan M, Spurdle A, Khanna KK, Lakhani S, Pearson J, Chenevix-Trench G, Waddell N. Using whole genome sequencing and somatic mutation signatures to unravel insight into familial breast cancer aetiology [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-10-01.