tbuckley/cabot-search huggingface dataset:
I'd like to apply for partnerships when I qualify this year, but am worried because I have had depression a couple of times, most recently after a relationship ended. I've only ever had a couple of weeks off. My trainer tells me not to worry, but I'm concerned that I will be looked on less favourably at interviews. Do I need to tell prospective partners about this?
Authors: Brian Keighley
Journal: BMJ (2006)

Have 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 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. <b>www.bmjcareers.com/advicezone</b>
Genomic and immune landscape of metastatic melanoma (MM) treated with pembrolizumab (PEM).
Authors: Yada Kanjanapan, Scott Lien, Cindy Yang, Derek L. Clouthier, Sawako Elston, Haiyan Jiang, Marcus O. Butler, David Hogg, Pamela S Ohashi, Trevor John Pugh, Lillian L. Siu, Anna Spreafico
Journal: Journal of Clinical Oncology (2018)

184 Background: Predictive biomarkers for PEM in MM is an active area of research. Methods: INSPIRE (NCT02644369) is a biomarker-driven Princess Margaret Cancer Centre initiative to evaluate genomic and immunologic changes in tumor and blood of patient (pts) treated with PEM at 200 mg IV Q3W. Baseline (BL) and on treatment (post 2-3 doses of PEM) fresh tumor biopsies were collected for DNA/RNA sequencing, immune-profiling, and tumor PD-L1 expression by immunohistochemistry (QualTek), with longitudinal blood collection for immunophenotyping. Results: As of 9/2017, 11 MM pts (9 cutaneous, 1 choroidal, 1 mucosal) were enrolled. Median treatment duration was 6 months (0.75 – 14.25); 7 pts remain on study. 7/11 (64%) pts had partial response (PR), 3/11 (27%) progressive disease (PD) and 1 was not evaluable (NE) per RECIST 1.1. Based on data for 8 pts (6 PR, 2 PD), higher percentage (%) PD-1 (mean 70 vs 12%), TIGIT (82 vs 43%) and 4-1BB (23 vs 4%) positivity on CD8 T cells in tumor vs blood was seen (all p &lt; 0.05). In BL blood, lower % TIGIT positive CD8 T cells was detected in pts with PR vs PD (38 vs 58%, p &lt; 0.05). T cell profile of 4 pts with paired BL and post PEM samples is shown in Table 1. Mean tumor PD-L1 score was 24% (0 - 90%), with no correlation to PEM response. Genomic analysis on 8 pts (5 PR, 2 PD, 1 NE) found mean tumor mutation burden (TMB) of 538. B2M deletion was seen in 2/2 PD and 0/6 PR pts. Among pts with PRs, 4/6 (67%) had TAP1 and TAP2 amplification post PEM therapy. HLA-A and HLA-B amplifications were each found in 3/6 (50%) PR pts, with only 1 present at BL. TMB was not associated with response to PEM. Conclusions: In this exploratory analysis of MM pts treated with PEM, there was significantly discordant T cell phenotype in tumor vs blood at BL. Our findings suggest B2M deletion to be associated with PEM resistance. The observed development of HLA-A/B and TAP1/2 amplification in 50-67% pts with PR post PEM suggests potential predictive significance, although further validation is warranted. Clinical trial information: NCT02644369. [Table: see text]
Is “hyper-progression” a relevant clinical item for patient with solid tumours candidate to check-point inhibitor treatment?
Authors: F. de Braud, M. Di Nicola, S. Damian, S. Cresta, M. Duca, A. Indini, M. Di Bartolomeo, G. Galli, E. Farè, E. Verzoni
Journal: Annals of Oncology (2018)
Associations of Obstructive Sleep Apnea With Atrial Fibrillation and Continuous Positive Airway Pressure Treatment
Authors: Dominik Linz, R. Doug McEvoy, Martin R. Cowie, Virend K. Somers, Stanley Nattel, Patrick Lévy, Jonathan M. Kalman, Prashanthan Sanders
Journal: JAMA Cardiology (2018)

Obstructive sleep apnea (OSA) is the most common clinically significant breathing abnormality during sleep. It is highly prevalent among patients with atrial fibrillation (AF), and it promotes arrhythmogenesis and impairs treatment efficacy.The prevalence of OSA ranges from 3% to 49% in population-based studies and from 21% to 74% in patients with AF. Diagnosis and treatment of OSA in patients with AF requires a close interdisciplinary collaboration between electrophysiologists, cardiologists, and sleep specialists. Because the prevalence of OSA is high in patients with AF and most do not report daytime sleepiness, sleep-study evaluation may be reasonable for patients being considered for rhythm control strategy. Acute, transient apnea-associated atrial electrophysiological changes and increased occurrence of AF triggers associated with short episodes of intermittent deoxygenation and reoxygenation, intrathoracic pressure changes during obstructed breathing efforts, and sympathovagal activation combine to create a stimulus for AF triggers and a complex and dynamic substrate for AF during sleep. Repeated episodes of long-term OSA are eventually associated with structural remodeling and changes in electrical conduction in the atrium. Observational data suggest OSA reduces the efficacy of catheter-based and pharmacological antiarrhythmic therapy. Nonrandomized studies have shown that treatment of OSA by continuous positive airway pressure can help to maintain a sinus rhythm after electrical cardioversion and catheter ablation in patients with AF. However, it remains unclear which sleep apnea metric should be used to determine severity and guide such treatment in patients with AF.Data from nonrandomized studies of patients with AF suggest that treatment of OSA by continuous positive airway pressure may help to maintain sinus rhythm after electrical cardioversion and improve catheter ablation success rates. Randomized clinical trials are needed to confirm the association between OSA and AF the benefits of treatment of OSA and the need for and cost-effectiveness of routine OSA screening and treatment.
Winter pressure funding will not solve recruitment problems in A&E, warns BMA
Authors: Abi Rimmer
Journal: BMJ (2013)

The BMA has called for the government to tackle the recruitment and retention “crisis” in hospital emergency departments, after details were released of how the winter pressure funding had been spent.

The Department of Health said that additional staffing equivalent to 320 full time doctors, 1400 nurses, and 1200 other NHS staff will be deployed across the country during the …
GENDER DIFFERENCE AND OUTCOME AFTER PERCUTANEOUS INTERVENTION IN PATIENTS WITH CHRONIC TOTAL OCCLUSION: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Pattara Rattanawong, Tanawan Riangwiwat, Wasawat Vutthikraivit, Prapaipan Putthapiban, Weera Sukhumthammarat, Chanavuth Kanitsoraphan, Pakawat Chongsathidkiet
Journal: Journal of the American College of Cardiology (2018)
BMA condemns squeeze on schemes to get GPs back into work in Scotland and Wales
Authors: Helen Jaques
Journal: BMJ (2012)

Returner and retainer schemes for GPs are being squeezed in Scotland and Wales, risking the health service losing expensively trained, experienced GPs, the BMA has warned.

The Welsh government has funded only five places on its scheme for GPs seeking to return to practice, although 20 GPs are currently on the waiting list, the association has said.

In Scotland some health boards have capped the number of sessions for GPs on retainer schemes to two a week, when ideally GPs seeking to maintain their clinical skills should complete four sessions a week, it adds.

Reducing the number of places on the returners …
BMA to enter negotiations on junior doctor contract
Authors: Helen Jaques
Journal: BMJ (2013)

The BMA has decided to enter formal talks on updating the junior doctor contract, having received a mandate to do so from its Junior Doctors Committee.

Should NHS Employers receive its own mandate from the four UK governments, negotiations are likely to start in the autumn and to conclude by the end of the year. Last year a report by NHS Employers branded the current junior doctor contract as “no longer fit for purpose,” prompting the government to call for the terms and conditions for trainee doctors to be renegotiated.1

Earlier this year the BMA and NHS Employers agreed on the main areas that would be discussed should both groups agree to go ahead with contract negotiations. …
Field investigation with real-time virus genetic characterisation support of a cluster of Ebola virus disease cases in Dubréka, Guinea, April to June 2015
Authors: Alessandro Pini, Delayo Zomahoun, Sophie Duraffour, Tarik Derrough, Myrna Charles, Joshua Quick, Nick Loman, Lauren Cowley, Mamadou Leno, Nobila Ouedraogo, Oumou Thiam, Alfonso Hernández-Romieu, Annie Iko, Halimatou Keita, Djiba Konate, Aboubacar Aboubak Soumah, Etran Bouchouar, Samuel Ileka-Priouzeau, Sakoba Keita, Boubacar Diallo, Fode Cisse, Josep Jansa, Miles Carroll, Stephan Günther, Ettore Severi, Pierre Formenty
Journal: Eurosurveillance (2018)

On 11 May 2015, the Dubréka prefecture, Guinea, reported nine laboratory-confirmed cases of Ebola virus disease (EVD). None could be epidemiologically linked to cases previously reported in the prefecture. We describe the epidemiological and molecular investigations of this event. We used the Dubréka EVD registers and the Ebola treatment centre's (ETC) records to characterise chains of transmission. Real-time field Ebola virus sequencing was employed to support epidemiological results. An epidemiological cluster of 32 cases was found, of which 27 were laboratory confirmed, 24 were isolated and 20 died. Real-time viral sequencing on 12 cases demonstrated SL3 lineage viruses with sequences differing by one to three nt inside a single phylogenetic cluster. For isolated cases, the average time between symptom onset and ETC referral was 2.8 days (interquartile range (IQR): 1-4). The average time between sample collection and molecular results' availability was 3 days (IQR: 2-5). In an area with scarce resources, the genetic characterisation supported the outbreak investigations in real time, linking cases where epidemiological investigation was limited and reassuring that the responsible strain was already circulating in Guinea. We recommend coupling thorough epidemiological and genomic investigations to control EVD clusters.
Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion
Authors: Yubin Huang, Zhen Xu, Shanshan Xiong, Fangfang Sun, Guangrong Qin, Guanglei Hu, Jingjing Wang, Lei Zhao, Yu-Xiang Liang, Tianzhun Wu, Zhonghua Lu, Mark S. Humayun, Kwok-Fai So, Yihang Pan, Ningning Li, Ti-Fei Yuan, Yanxia Rao, Bo Peng
Journal: Nature Neuroscience (2018)
Abstract P5-12-02: B-vitamin intake from diet and supplements and breast cancer risk in middle-aged women: Results from the prospective NutriNet-Santé cohort
Authors: M Egnell, P Fassier, L Lécuyer, L Zelek, M-P Vasson, S Hercberg, P Latino-Martel, P Galan, M Deschasaux, M Touvier
Journal: Cancer Research (2018)

Abstract Experimental studies suggest a protective effect of B-vitamins on breast cancer risk, potentially modulated by alcohol intake. However, epidemiological studies are limited, especially regarding non-folate B-vitamins. Furthermore, few of them included quantitative assessment of supplemental intake. This prospective study aimed at investigating the associations between intakes of B-vitamins (dietary, supplemental, total) and breast cancer risk. 27,853 women aged ≥45y from the NutriNet-Santé cohort (2009-2016) were included, with a median follow-up time of 4.2 years. Dietary data were collected using repeated 24h records. A specific questionnaire assessed dietary supplement use over a 12-month period. A composition database of 8000 supplements was developed. Associations were characterized by multivariable Cox models. 462 incident breast cancers were diagnosed. Dietary (HRQ4vs.Q1=0.74(0.55,0.99), P-trend=0.05), supplemental (HRQ4vs.Q1=0.61(0.38,0.98), P-trend=0.05) and total (HRQ4vs.Q1=0.67(0.50,0.91), P-trend=0.01) pyridoxine intakes were inversely associated with breast cancer risk. Total thiamin intake was borderline inversely associated with breast cancer risk (HRper 1-unit increment=0.78(0.61,1.00), P=0.05). Statistically significant interactions between alcohol consumption and B-vitamin (thiamin, riboflavin, niacin, pantothenic acid, pyridoxine, folate, and cobalamin) supplemental intake were observed, the latter being inversely associated with breast cancer risk in non-to-low alcohol drinkers but not in higher drinkers. This large prospective study, including quantitative assessment of supplemental intake, suggests a potential protective effect of pyridoxine and thiamin on breast cancer risk in middle-aged women. Citation Format: Egnell M, Fassier P, Lécuyer L, Zelek L, Vasson M-P, Hercberg S, Latino-Martel P, Galan P, Deschasaux M, Touvier M. B-vitamin intake from diet and supplements and breast cancer risk in middle-aged women: Results from the prospective NutriNet-Santé cohort [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 P5-12-02.
Phase II trial of carfilzomib for metastatic castration-resistant prostate cancer (mCRPC) following androgen pathway inhibitors.
Authors: Gurudatta Naik, Sejong Bae, Mollie R. De Shazo, Pam Dixon, Lynn Merritt, A. Oliver Sartor, Frederick M. Schnell, Guru Sonpavde
Journal: Journal of Clinical Oncology (2018)

224 Background: mCRPC is an incurable disease with suboptimal outcomes following prior therapy. Bortezomib, a proteasome inhibitor, has exhibited activity in a subset of patients. Carfilzomib is a second-generation selective and irreversible proteasome inhibitor and is approved for refractory myeloma. Methods: A non-randomized phase II trial (NCT02047253) was designed to evaluate carfilzomib for mCRPC following abiraterone acetate (AA) and/or enzalutamide (enza); prior docetaxel (D) was allowed. A 6-month progression-free survival (PFS) rate ≥30% defined by Prostate Cancer Working Group (PCWG) guidelines was considered important, while PFS &lt; 10% was not. History and physical exam, and prostate specific antigen (PSA) was performed every 4 weeks. Circulating tumor cells (CTCs) were measured at baseline and 12 weeks later. Radiographic evaluation was performed every 12 weeks. Carfilzomib was administered on days 1,2,8,9,15,16 every 28 days. The starting dose was 20 mg/m 2 during the first week followed by dose escalation to 56 mg/m 2 if no serious toxicities occurred. Daily oral acyclovir was administered for herpes zoster prophylaxis. Therapy continue until PCWG or symptomatic progression or severe toxicities. Results: Twenty-eight patients were recruited and prior AA, enza or D had been received by 21 pts each and 20 pts received &gt; 1 of these agents. The median age was 70 (range 55-88). One patient attained 6-month PFS; 2 other patients progressed at 6 months. Minor PSA declines and CTC declines were observed in 3 patients each, and one patient exhibited both PSA and CTC declines. The major toxicities of any grade were: anemia (n = 13, 46%), Fatigue (n = 7, 25%), and Constipation (n = 5, 18%), with anorexia, cough, fever, headache and thrombocytopenia in 4 patients each (14%). The major toxicities of grade ≥3 in &gt; 1 patient were: anemia (n = 3, 11%) and hypertension (n = 2, 7%). Conclusions: Carfilzomib is not active as salvage therapy following AA and/or enza in unselected patients with mCRPC. Minor and transient activity may be present in a small subset of patients. Clinical trial information: NCT02047253.
Private company criticised over exaggerated screening claims
Authors: Anne Gulland
Journal: BMJ (2018)

A company offering health screening has been ordered to withdraw marketing material that claimed their tests for peripheral arterial disease (PAD) could reduce the risk of stroke or heart attacks.

GP and BMJ columnist Margaret McCartney made a complaint to the Advertising Standards Authority (ASA) after receiving a letter from Bluecrest Health Screening offering screening for a range of conditions including PAD.

The letter said that despite the fact “you are probably very well looked after by your NHS GP when you are ill . . . you may also appreciate that many serious health conditions don’t …
EVALUATION OF FLOW DYNAMICS IN BIFURCATIONS BY FUSION OF 3-DIMENSIONAL ANGIOGRAPHY AND TWO-VESSEL OPTICAL COHERENCE TOMOGRAPHY
Authors: Antonios Karanasos, Konstantinos Toutouzas, Ioannis Andrikos, Antonis Sakellarios, Panagiotis Siogkas, George Rigas, Themis Exarchos, Andreas Synetos, George Latsios, Eleftherios Tsiamis, Lampros Michalis, Dimitris Fotiadis, Dimitris Tousoulis
Journal: Journal of the American College of Cardiology (2018)
The hard road to data interpretation: 3 or 6 months of adjuvant chemotherapy for patients with stage III colon cancer?
Authors: A. Sobrero, A. Grothey, T. Iveson, R. Labianca, T. Yoshino, J. Taieb, T. Maughan, M. Buyse, T. André, J. Meyerhardt, A.F. Shields, I. Souglakos, J.-Y. Douillard, A. Cervantes
Journal: Annals of Oncology (2018)
The reality of achieving a work-life balance
Authors: Sarah J Llewellyn-Davies
Journal: BMJ (2007)

We welcome your rapid responses, whether in direct response to an article in Career Focus or as a way of sharing your own ideas. As long as it isn9t libellous or offensive, we9ll post it on our website. We print a selection of rapid reponses here and the writer of the best each month wins an <i>Oxford Handbook</i> of their choice. Letter of the month prize is donated by OUP.
SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma
Authors: Pierce K.H. Chow, Mihir Gandhi, Say-Beng Tan, Maung Win Khin, Ariunaa Khasbazar, Janus Ong, Su Pin Choo, Peng Chung Cheow, Chanisa Chotipanich, Kieron Lim, Laurentius A. Lesmana, Tjakra W. Manuaba, Boon Koon Yoong, Aloysius Raj, Chiong Soon Law, Ian H.Y. Cua, Rolley R. Lobo, Catherine S.C. Teh, Yun Hwan Kim, Yun Won Jong, Ho-Seong Han, Si-Hyun Bae, Hyun-Ki Yoon, Rheun-Chuan Lee, Chien-Fu Hung, Cheng-Yuan Peng, Po-Chin Liang, Adam Bartlett, Kenneth Y.Y. Kok, Choon-Hua Thng, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, David C.E. Ng, Ganesh Lekurwale, Wei Ming Liew, Val Gebski, Kenneth S.W. Mak, Khee Chee Soo
Journal: Journal of Clinical Oncology (2018)

Purpose Selective internal radiation therapy or radioembolization (RE) shows efficacy in unresectable hepatocellular carcinoma (HCC) limited to the liver. This study compared the safety and efficacy of RE and sorafenib in patients with locally advanced HCC. Patients and Methods SIRveNIB (selective internal radiation therapy v sorafenib), an open-label, investigator-initiated, phase III trial, compared yttrium-90 ( 90 Y) resin microspheres RE with sorafenib 800 mg/d in patients with locally advanced HCC in a two-tailed study designed for superiority/detriment. Patients were randomly assigned 1:1 and stratified by center and presence of portal vein thrombosis. Primary end point was overall survival (OS). Efficacy analyses were performed in the intention-to-treat population and safety analyses in the treated population. Results A total of 360 patients were randomly assigned (RE, 182; sorafenib, 178) from 11 countries in the Asia-Pacific region. In the RE and sorafenib groups, 28.6% and 9.0%, respectively, failed to receive assigned therapy without significant cross-over to either group. Median OS was 8.8 and 10.0 months with RE and sorafenib, respectively (hazard ratio, 1.1; 95% CI, 0.9 to 1.4; P = .36). A total of 1,468 treatment-emergent adverse events (AEs) were reported (RE, 437; sorafenib, 1,031). Significantly fewer patients in the RE than sorafenib group had grade ≥ 3 AEs (36 of 130 [27.7%]) v 82 of 162 [50.6%]; P &lt; .001). The most common grade ≥ 3 AEs were ascites (five of 130 [3.8%] v four of 162 [2.5%] patients), abdominal pain (three [2.3%] v two [1.2%] patients), anemia (zero v four [2.5%] patients), and radiation hepatitis (two [1.5%] v zero [0%] patients). Fewer patients in the RE group (27 of 130 [20.8%]) than in the sorafenib group (57 of 162 [35.2%]) had serious AEs. Conclusion In patients with locally advanced HCC, OS did not differ significantly between RE and sorafenib. The improved toxicity profile of RE may inform treatment choice in selected patients.
Prognostic and therapeutic significance of ribonucleotide reductase small subunit M2 in prostate cancer.
Authors: Ying Zhang Mazzu, Travis A. Gerke, Goutam Chakraborty, Joshua Armenia, Mohammad Omar Atiq, Kazumasa Komura, Yuki Yoshikawa, Gwo-Shu Mary Lee, Lorelei A. Mucci, Philip W. Kantoff
Journal: Journal of Clinical Oncology (2018)

240 Background: DNA-repair defects are common in advanced prostate cancer (PC) and high-risk localized tumors. Besides deficiency of DNA repair, overexpression of DNA repair genes could also contribute to poorer outcomes for PC patients. The nucleotide metabolism enzyme ribonucleotide reductase (RNR) plays the key role in DNA synthesis and repair. RRM2, the rate-limiting RNR subunit, is frequently up-regulated in cancer, and its overexpression leads to chemoresistance. Although targeting RRM2 by siRNA and small molecules has been applied in clinical trials in multiple cancers, limited knowledge of RRM2 function in PC delays potential clinical application of RRM2 inhibition. Methods: We leveraged publically available PC clinical cohorts to examine RRM2 levels and clinical outcomes. siRNAs was applied to knockdown of RRM2 in multiple PC cell lines. Cell growth, cell cycle and apoptosis were analyzed to determine siRRM2 or RRM2 inhibitor (COH29)-induced phenotypes. RNA-seq and protein array were performed to identify downstream targets of RRM2. Immunohistochemistry staining was applied to determine prevalence of RRM2 protein expression in PC tissues microarrays (TMAs). Results: In PC cohorts, increased RRM2 expression was associated with a higher likelihood of metastasis, poorer disease-free survival, and increased risk of development of lethal disease (N = 1200, PHS/HPFS cohorts). In PC cells, Inhibition of RRM2 induced remarkable cell growth inhibition, cell cycle arrest (at S phase) and apoptosis. DNA damage was observed in siRRM2/COH29-treated PC cells with increased activation of DNA damage markers. GSEA analysis of the RNA-seq dataset revealed multiple biological processes were affected by inhibition of RRM2, such as cell cycle, apoptosis, and DNA damage response. Intriguingly, MYC oncogenic signaling is the major downstream targets of RRM2. Furthermore, inhibition of RRM2 can block multiple oncogenic signaling including mTOR/AKT, SFK, and STAT signaling by repressing the key phospho-kinases in PC cells. Among 121 cases on the PC TMAs, 20% showed strong RRM2 protein expression. Conclusions: RRM2 may serve as a prognostic biomarker and novel therapeutic target in PC.
Editor’s Choice: Best job in the world?
Authors: Tom Moberly
Journal: BMJ (2015)

Historically, few workers have gained more satisfaction from their jobs than UK doctors in the 21st century. Figures released by the Cabinet Office last year showed that workers in only six of 274 occupations studied were happier than medical practitioners. Members of the clergy, chief executives, and company secretaries were more likely than doctors to be satisfied with their lives, but …