tbuckley/cabot-search huggingface dataset:
Single-Cell RNA-Seq Reveals the Transcriptional Landscape and Heterogeneity of Aortic Macrophages in Murine Atherosclerosis
Authors: Clément Cochain, Ehsan Vafadarnejad, Panagiota Arampatzi, Jaroslav Pelisek, Holger Winkels, Klaus Ley, Dennis Wolf, Antoine-Emmanuel Saliba, Alma Zernecke
Journal: Circulation Research (2018)

Rationale: It is assumed that atherosclerotic arteries contain several macrophage subsets endowed with specific functions. The precise identity of these subsets is poorly characterized as they have been defined by the expression of a restricted number of markers. Objective: We have applied single-cell RNA sequencing as an unbiased profiling strategy to interrogate and classify aortic macrophage heterogeneity at the single-cell level in atherosclerosis. Method and Results: We performed single-cell RNA sequencing of total aortic CD45 + cells extracted from the nondiseased (chow fed) and atherosclerotic (11 weeks of high-fat diet) aorta of low-density lipoprotein receptor–deficient ( Ldlr −/− ) mice. Unsupervised clustering singled out 13 distinct aortic cell clusters. Among the myeloid cell populations, resident-like macrophages with a gene expression profile similar to aortic resident macrophages were found in healthy and diseased aortas, whereas monocytes, monocyte-derived dendritic cells, and 2 populations of macrophages were almost exclusively detectable in atherosclerotic aortas, comprising inflammatory macrophages showing enrichment in Il1b and previously undescribed TREM2 hi (triggered receptor expressed on myeloid cells 2) macrophages showing enrichment in Trem2 . Differential gene expression and gene ontology enrichment analyses revealed specific gene expression patterns distinguishing these 3 macrophage subsets and monocyte-derived dendritic cells and uncovered putative functions of each cell type. Notably, TREM2 hi macrophages seemed to be endowed with specialized functions in lipid metabolism and catabolism and presented a gene expression signature reminiscent of osteoclasts, suggesting a role in lesion calcification. TREM2 expression was moreover detected in human lesional macrophages. Importantly, these macrophage populations were present also in advanced atherosclerosis and in Apoe −/− aortas, indicating relevance of our findings in different stages of atherosclerosis and mouse models. Conclusions: These data unprecedentedly uncovered the transcriptional landscape and phenotypic heterogeneity of aortic macrophages and monocyte-derived dendritic cells in atherosclerotic and identified previously unrecognized macrophage populations and their gene expression signature, suggesting specialized functions. Our findings will open up novel opportunities to explore distinct myeloid cell populations and their functions in atherosclerosis.
<i>I am due to start my general practice registrar year (I am on a vocational scheme), but I am seven months pregnant. What should I do?</i>
Authors: Pauline Brimblecome
Journal: BMJ (2004)

Got a career or related problem that needs answering? Can't 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.
A critical epitope in CD147 facilitates memory CD4+ T-cell hyper-activation in rheumatoid arthritis
Authors: Na Guo, Sheng Ye, Kui Zhang, Xiaoling Yu, Hongyong Cui, Xiangmin Yang, Peng lin, Minghua Lv, Jinlin Miao, Yang Zhang, Qing Han, Rongguang Zhang, Zhinan Chen, Ping Zhu
Journal: Cellular and Molecular Immunology (2018)

The abnormal activation of CD4+CD45RO+ memory T (Tm) cells plays an important role in the pathogenesis of rheumatoid arthritis (RA). Previous studies have shown that CD147 participates in T-cell activation. However, it remains unclear whether CD147 is involved in abnormal Tm-cell activation in RA patients. In this study, we demonstrated that CD147 was predominantly upregulated in Tm cells derived from RA patients. The anti-CD147 mAb 5A12 specifically inhibited Tm-cell activation and proliferation and further restrained osteoclastogenesis. Using a structural-functional approach, we depicted the interface between 5A12 and CD147. This allowed us to identify two critical residues, Lys63 and Asp65, as potential targets for RA treatment, as the double mutation K63A/D65A inhibited Tm-cell activation, mimicking the neutralization by 5A12. This study provides not only a theoretical basis for a "CD147-Tm/Osteoclast-RA chain" for the potential prevention and treatment of RA or other T-cell-mediated autoimmune diseases but also a new target for related drug design and development.
Women’s progress in science is undermined by stereotyping and short term contracts, MPs conclude
Authors: Caroline White
Journal: BMJ (2014)

Gender stereotyping, a lack of senior role models, and short term contracts are undermining the recruitment and retention of women in scientific careers, MPs have warned.

A report by the House of Commons Science and Technology Committee concluded that it was much harder for women than men to progress in academic careers in science.1 The committee described it as “astonishing” that, despite attempts to increase the representation of women in science, technology, engineering, and maths (STEM) careers, just 17% of UK professors in these disciplines were female.

The committee said that greater standardisation …
European Council formally adopts regulations to ease movement of doctors
Authors: Caroline White
Journal: BMJ (2013)

The European Council has formally adopted new regulations to make it easier for doctors and other health professionals to work in other European countries.

The sign-off on the revised Directive on Mutual Recognition of Professional Qualifications on 15 November marks the conclusion of an approval process that began in 2011. European Union countries will now have two years to pass the directive into national law.

The General Medical Council has welcomed the move, saying that the new regulations will enhance the safety of patients.

The updated directive will permit national regulatory bodies to check the language skills of health professionals when a concern is raised during the registration process and to test their linguistic ability where necessary before allowing them to practise.

A GMC spokesperson told …
Patterns of prostate cancer management across Canadian prostate cancer treatment specialists.
Authors: Bobby Shayegan, Alan I. So, Shawn Malone, Sebastien J. Hotte, Antonio Finelli, Christina M. Canil, Huong Hew, Laura Park-Wyllie, Kim N. Chi, Fred Saad
Journal: Journal of Clinical Oncology (2018)

321 Background: The Canadian GU Research Consortium (GURC) was recently established to bring comprehensive prostate cancer centres together to collaborate on research, education, and adoption of best practices. As an initial step to inform the work of the GURC, an electronic questionnaire was designed to assess management of advanced prostate cancer care in Canada and better understand patterns of care. Methods: A 59-item online questionnaire was developed by a multidisciplinary scientific committee to measure physician practices, patterns of care, treatment sequencing, and management of mCRPC. After pre-testing, the online questionnaire was sent to 93 urologists, uro-oncologists, medical oncologists, radiation oncologists, and general practitioner oncologists who are actively involved in the treatment of prostate cancer. Results: A total of 49 (53%) respondents completed the questionnaire between April 17, 2017 to May 17, 2017. Although all respondents indicated a role in initiating life-prolonging oral therapy for mCRPC and monitoring treatment and side effects, chemotherapy initiation was mainly a medical oncologist role compared to other specialties (p &lt; 0.05, chi-square). Symptom management such as palliative care and end-of-life care were provided mainly by radiation oncologists (100%) and medical oncologists (81%) compared to urologists (33%) and uro-oncologists (50%), p &lt; 0.05, chi-square). Patient mix varied across the disciplines. Urologist practices were composed primarily of non-metastatic prostate cancer patients (73%), as were radiation oncologist practices (77%), while uro-oncologist practices included both non-metastatic (58%) and metastatic (40%) patients. Medical oncologists practices were mainly (91%) metastatic patients. Referral patterns also varied by discipline. Conclusions: In Canada, prostate cancer treatment involves multiple disciplines providing a range of care at different points across the treatment continuum. We plan to do further research to better understand variation in practice and improve multidisciplinary coordination for patients with advanced prostate cancer.
GPs could answer to three levels of responsible officer
Authors: Helen Jaques
Journal: BMJ (2012)

The NHS Commissioning Board is likely to have three tiers of responsible officer so as to avoid conflicts of interest where individuals responsible for revalidating GPs are also in charge of overseeing clinical commissioning.

All GPs who are on a primary care performers list, responsible officers in certain designated bodies, and some secondary care locums would be revalidated by responsible officers …
Abstract P188: Differences in Statin Utilization for Persons Living With HIV (PLWH) and Uninfected Controls in the HIV Electronic Comprehensive Cohort of CVD Complications (HIVE-4CVD)
Authors: Robert Riestenberg, Andrew Furman, Anna Pawlowski, Daniel Schneider, Chad J Achenbach, Donald M Lloyd-Jones, Matthew J Feinstein
Journal: Circulation (2018)

Background: Real-world clinical data on statin use and intensity among PLWH are sparse. We hypothesized that significant differences exist regarding statin utilization and dosing as well as on-statin total cholesterol (TC) lowering for PLWH compared with uninfected controls. Methods: HIVE-4CVD is an electronic data repository of 5,041 PLWH and 10,082 uninfected controls frequency matched on age, sex, race, zip code, and clinic location receiving care at Northwestern Medicine from 1/1/2000 to 5/17/2017. Medication administration records, prescription data, and validated natural language extraction algorithms were used to extract statin utilization information. Statins were categorized by generic name and intensity (high, moderate, and low). Lipid values were analyzed and categorized as before or after statin initiation. We compared statin utilization for PLWH vs. controls and used multivariable-adjusted regression models to compare changes in TC levels after statin initiation for PLWH vs. controls. Results: Among people on statins, PLWH were more likely than controls to have ever taken pravastatin (34.8% vs. 12.3%, p &lt; 0.001) and atorvastatin (72.2% vs. 65.6%, p = 0.002), and less likely to have ever taken simvastatin (14.2% vs. 39.5%, p &lt; 0.001). PLWH on statins were more likely to have their intensity reduced (14.6% vs. 11.2%, p = 0.034); this pattern was more apparent when analyses were restricted to patients on high-intensity statins (63.6% vs. 36.4%, p = 0.030). Although PLWH had borderline significantly less TC reduction after statin initiation than controls (-22.9 mg/dL vs. -28.5 mg/dL, p = 0.058; Figure 1), this association was attenuated after adjustment for age, sex, race, and pre-statin TC level (4.2 mg/dL greater TC lowering for controls than PLWH; p = 0.16). Conclusions: Significant differences exist in type and intensity of statin utilized for PLWH compared with uninfected controls. Studies of patient and provider knowledge and preferences are needed to understand reasons underlying these differences.
The benefits of competition
Authors: Clare E Rogers
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.
NHS England to invest £10m in GP workforce expansion
Authors: Abi Rimmer
Journal: BMJ (2015)

NHS England has announced that it will invest £10m in expanding the general practice workforce, through a range of initiatives in collaboration with Health Education England, the Royal College of General Practitioners, and the BMA.

The funding will be used to recruit new GPs, to retain GPs who are thinking of leaving the profession, and to encourage GPs who have taken a break to return to the profession.

One initiative aims to encourage junior doctors to undertake …
Addition of Supervised Exercise Training to a Post-Hospital Disease Management Program for Patients Recently Hospitalized With Acute Heart Failure
Authors: Alison M. Mudge, Charles P. Denaro, Adam C. Scott, Deborah Meyers, Julie A. Adsett, Robert W. Mullins, Jessica M. Suna, John J. Atherton, Thomas H. Marwick, Paul Scuffham, Peter O’Rourke
Journal: JACC Heart Failure (2018)
Abstract P054: Endogenous Sex Hormone Levels and Endothelial Function Among Men and Post-Menopausal Women in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Lena Mathews, Vinita Subramanya, Di Zhao, Pamela Ouyang, Dhanajay Vaidya, Eliseo Guallar, Joseph Yeboah, David Herrington, Matthew J Budoff, Allison G Hays, Erin D Michos
Journal: Circulation (2018)

Background: Sex is a major determinant of cardiovascular disease (CVD). Endogenous sex hormones exert a variety of effects on the vascular endothelium, and changes in sex hormone levels after menopause may play a role in CVD risk in women. We hypothesized that a more androgenic sex hormone profile among post-menopausal women, but not among men, would be associated with reduced blood flow-mediated vasodilation (FMD) of the brachial artery, a marker of worse endothelial function. Methods: We examined 1396 post-menopausal women and 1707 men participating in MESA, who were free of clinical CVD at baseline. Sex hormone levels [total testosterone (T), sex hormone binding globulin (SHBG), estradiol (E2)] were measured at Exam 1 (2000-02); free T and T/E2 ratio were calculated. FMD was measured by high-resolution ultrasound. Using multivariable adjusted Poisson and linear regression methods, we tested the cross-sectional associations of sex hormones (log transformed) with FMD. Results: The mean age of men and women was 61 and 64 years, respectively. Of women, 34% were using hormone therapy (HT). Among women, after adjusting for demographics, CVD risk factors, and HT use, higher SHBG was associated with higher FMD, whereas higher free T was associated with lower FMD (Table, Model 2). In women, when examining the “best FMD response” (top decile vs. bottom 9 deciles), higher E2 was positively associated with a prevalent best response, whereas higher free T was inversely associated. Among men, a higher T/E2 ratio was marginally associated with lower FMD. Conclusion: The association between sex hormones and FMD differs in men and women. Higher E2 and SHBG and lower free T levels were associated with better FMD in post-menopausal women but not in men. Higher T/E2 ratio was associated with lower FMD in men. Further studies are needed to assess longitudinal changes in sex hormone levels and their association with vascular aging. Sex hormone levels may help identify individuals at increased CVD risk who may benefit from other risk reduction strategies.
Prospective evaluation of slow-pull with fanning technique in EUS-guided fine needle aspiration on pancreatic masses.
Authors: Jae Min Lee, Hong Sik Lee, Seong ji Choi, Geeho Min, Woojung Kim, Jung Min Lee, Seung Han Kim, Hyuk Soon Choi, Eun Sun Kim, Bora Keum, Yoon Tae Jeen, Hoon Jai Chun, Chang Duck Kim
Journal: Journal of Clinical Oncology (2018)

232 Background: Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) is useful in obtaining pancreatic mass samples. Combination of modified techniques (slow-pull technique and fanning technique) may improve the sample quality obtained by EUS-FNA. We investigated the effectiveness of a slow-pull with fanning technique in EUS-FNA for pancreatic mass. Methods: This prospective comparative study investigated EUS-FNA for pancreatic solid masses from August 2015-July 2016. The pairwise specimens were alternately obtained using two techniques: standard suction or slow-pull with fanning for target pancreatic lesions. We compared the specimen quality, blood contamination, and diagnostic yield of these techniques. Results: Forty-eight consecutive patients were enrolled (29 men; mean age, 68.1±11.9 years), and 96 pancreatic mass specimens were obtained. The slow-pull with fanning technique had significantly superior diagnostic accuracy than the suction technique (88% vs. 71%, p = 0.044). Further, blood contamination significantly reduced when the slow-pull with fanning technique was used (ratio of no or few contamination, 77% vs. 56%, p = 0.041). In the subgroup analysis, tumor size and sampling technique were related to EUS-FNA diagnostic accuracy. Conclusions: The slow-pull with needle fanning technique showed a good diagnostic yield for EUS-FNA for pancreatic mass. It can be useful in performing EUS-guided sampling for diagnosing pancreatic disease.
A professor in Old Age Psychiatry
Authors: Zehanah Izmeth, Gautam Gulati
Journal: BMJ (2008)

Robin Jacoby is professor emeritus of old age psychiatry at the University of Oxford. He is coeditor of the Oxford Textbook of Old Age Psychiatry and chairman of the Global Initiative on Psychiatry.

Initially I did a language degree in Russian and French at Oxford, and then I did one term towards a PhD before deciding to study medicine. My preclinicals were at Oxford and my clinicals at Guy’s. After my house jobs I went to Southampton, where I worked as a medical senior house officer and medical registrar. For various reasons I decided to go into psychiatry, so I went to talk to the vice dean at the Maudsley. I then applied and stayed there about 20 years.

It’s been renamed the Global Initiative on Psychiatry (www.gip-global.org), and it grew out of a group of people who were opposed to the political abuse of psychiatry in the former Soviet Union. I got involved because Jim Birley, who had …
Clinical and molecular characterization of urothelial cancer developing after pelvic radiation.
Authors: Tracy Lynn Rose, Jordan Kardos, Sara Wobker, Matthew I. Milowsky, William Y. Kim
Journal: Journal of Clinical Oncology (2018)

518 Background: The development of urothelial cancer (UC) after pelvic radiotherapy (RT) is an increasingly recognized phenomenon. Numerous studies show a relationship between ionizing radiation and urothelial dysplasia and DNA damage. It is not known if UC that develops after pelvic RT is associated with a distinct molecular signature, which could have treatment implications for this subset of UC. Methods: The University of North Carolina (UNC) Genitourinary Oncology Database was queried for cases of UC between 01/2012 and 06/2016 in patients with prior pelvic RT. Demographics, clinical stage, and details of prior RT were collected. Patients with available archival FFPE tumor tissue underwent next generation targeted exome sequencing per the UNCSeq pipeline. Somatic mutations and copy number alterations were analyzed. Total mutation burden (TMB) (mutations per total Megabase region of 30X coverage, mut/Mb) and insertion-to-deletion (indel) ratio was calculated. Wilcoxon rank sum was used to compare TMB and indel ratio of RT-associated cases with all cases of UC sequenced at UNC. Results: 38 patients with UC developing after prior pelvic RT were identified. 68% had muscle-invasive UC. Median age was 76. Prior RT was for the purpose of prostate cancer treatment in all patients. 26% had received external beam radiotherapy, 29% brachytherapy, and 16% both (29% unknown). Median time from RT to diagnosis of UC was 8 years. Ten patients with muscle-invasive UC had tumors available for sequencing. The most commonly identified somatic alterations were TP53 in 60%, RB1 40%, CREBBP 30%, ELF3 30%, HLA-DRB1 30%, KDM6A 30%, and MLL2 30%, including co-occurrence of TP53 and RB1 mutations in 30% of patients. The median TMB was 12.1 mut/Mb, significantly lower than the median TMB of 25.6 mut/Mb in all cases of UC sequenced at UNC (p = 0.006). The indel ratio was not different between the two groups (p = 0.11). Conclusions: UC that develops after pelvic RT is a frequent entity that occurs years after RT. Tumors of patients who received prior RT had a lower overall TMB than other UC tumors, suggesting that RT-induced UC may be a different entity than carcinogen-induced UC. Further studies should expand our analysis to confirm these findings.
Minimising length of stay following brain tumour surgery: benefits to patients, providers and the NHS
Authors: Paul Grundy
Journal: Neuro-Oncology (2018)

Length of stay (LOS) following surgery is highly variable between providers. Techniques can be employed to minimise LOS to the benefit of patients, providers and the NHS. Data is now available to benchmark and to provide an opportunity for aspiring to best practice. We introduced measures to reduce LOS. We explored data from Hospital Episode Statistics published for providers by the National Neurosurgical Audit Program (NNAP) and Get It Right First Time (GIRFT) in 2016/7. In our unit the most frequent pathway for surgery for brain tumours was as elective admissions: 75% of patients with high-grade gliomas; 81% with metastases and 85% with benign tumours were admitted for surgery in an elective manner. Median LOS for intrinsic tumours was 1 day (versus national 6 days, NNAP). Mean LOS (vs national) was 2.5 (6.4) days for HGG; 2.9 (6.5) days for metastases; 4.7 (9.2) days for benign tumours; all the lowest in UK. Despite this, readmission rates were within the normal range at 20% (18%) for HGG; 21% (20%) for metastases;15% (14%) for benign tumours. Re-operation rates over 1 year were also in normal range: 11% (12%) HGG; 9% (11%) for metastases; 12% (11%) for benign tumours. Elective cranial mortality was 0.87 (0.94). Adopting several strategies to minimise LOS has proven very successful and resulted in excellent benchmarked data. This has proven popular with patients, has improved efficiency at our trust, reduced cost, cancellations and waiting times and has more widespread implications across the NHS. Short stay neurosurgery for brain tumours is safe and does not significantly increase readmission, re-operation or mortality rates.Techniques employed to deliver this will be discussed. All providers of neurosurgery should use national data to improve practice in the future, including engaging with peers and utilising strategies proven to be successful elsewhere.
2017 Update on Pediatric Medical Overuse
Authors: Eric R. Coon, Paul C. Young, Ricardo A. Quinonez, Daniel J. Morgan, Sanket S. Dhruva, Alan R. Schroeder
Journal: JAMA Pediatrics (2018)

Medical overuse has historically focused on adult health care, but interest in how children are affected by medical overuse is increasing. This review examines important research articles published in 2016 that address pediatric overuse.A structured search of PubMed and a manual review of the tables of contents of 10 journals identified 169 articles related to pediatric overuse published in 2016, from which 8 were selected based on the quality of methods and potential harm to patients in terms of prevalence and magnitude. Articles were categorized by overtreatment, overmedicalization, and overdiagnosis. Findings included evidence of overtreatment with commercial rehydration solution, antidepressants, and parenteral nutrition; overmedicalization with planned early deliveries, immobilization of ankle injuries, and use of hydrolyzed infant formula; and evidence of overdiagnosis of hypoxemia among children recovering from bronchiolitis.The articles were of high quality, with most based on randomized clinical trials. The potential harms associated with pediatric overuse were significant, including increased risk of infection, developmental disability, and suicidality.