tbuckley/cabot-search huggingface dataset:
Survival Analysis After Neoadjuvant Chemotherapy With Trastuzumab or Lapatinib in Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer in the GeparQuinto (G5) Study (GBG 44)
Authors: Michael Untch, Gunter von Minckwitz, Bernd Gerber, Christian Schem, Mahdi Rezai, Peter A. Fasching, Hans Tesch, Holm Eggemann, Claus Hanusch, Jens Huober, Christine Solbach, Christian Jackisch, Georg Kunz, Jens-Uwe Blohmer, Maik Hauschild, Tanja Fehm, Valentina Nekljudova, Sibylle Loibl
Journal: Journal of Clinical Oncology (2018)

Purpose The GeparQuinto phase III trial demonstrated a lower pathologic complete response (pCR; pT0 ypN0) rate when lapatinib was added to standard anthracycline-taxane chemotherapy compared with trastuzumab in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer. Here, we report the long-term outcomes. Methods Patients with HER2-positive tumors (n = 615) received neoadjuvant treatment with epirubicin (E) plus cyclophosphamide (C), followed by docetaxel (T) in combination with either lapatinib (L) or trastuzumab (H; ECH-TH arm: n = 307; ECL-TL arm: n = 308). All patients received adjuvant trastuzumab for a total of 12 months and 18 months in the ECH-TH and ECL-TL arms, respectively. Median follow-up was 55 months. Results Three-year disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS) were not significantly different between the two treatment arms. Long-term outcomes correlated with pCR (DFS: hazard ratio [HR], 0.63; P = .042; DDFS: HR, 0.55; P = .021; and OS: HR, 0.31; P = .004). A benefit only for OS was observed in patients who were treated with trastuzumab and achieved pCR versus no pCR (HR, 0.15; P = .010), whereas no difference was found in patients with pCR versus without pCR in the lapatinib arm. DFS and DDFS remained unchanged in both treatment arms according to hormone receptor status, whereas OS was significantly better in hormone receptor-positive patients who were treated with neoadjuvant lapatinib (HR, 0.32; P = .019), followed by adjuvant trastuzumab. No difference was observed in hormone receptor-negative patients; however, the small number of events limits this interpretation. Within the hormone receptor-negative cohort, pCR was significantly associated with DFS, DDFS, and OS ( P = .002, .005, and .002, respectively). Conclusion pCR correlated with long-term outcome. In patients with hormone receptor-positive tumors, prolonged anti-HER2 treatment-neoadjuvant lapatinib for 6 months, followed by adjuvant trastuzumab for 12 months-significantly improved survival compared with anti-HER2 treatment with trastuzumab alone.
Managing dyslipidaemia for the primary prevention of cardiovascular disease
Authors: Aidan Ryan, Simon Heath, Paul Cook
Journal: BMJ (2018)

Ryan et al have recently written a useful article on managing dyslipidaemia for the primary prevention of cardiovascular disease1.They consider the evidence regarding the benefits and harms of statin medication and conclude that, "At present we have no way of knowing who will experience the benefits or harms of statin therapy before starting medication".We would like to highlight to readers a couple of our papers which have addressed this question2.In 2010, we published a large population-based cohort study using the QResearch database (www.qresearch.org) to individualise the risks of statins in men and women in England.We also produced a web calculator www.qintervention.orgwhich allows an individual calculate these risks.In 2018, we published an update to the QDiabetes-2018 algorithm which, for the first time, quantifies the risk of developing diabetes among patients prescribing statins, taking account of their other risk factors3.The web calculator can be found here www.qdiabetes.org/2018.Lastly, we would also like to highlight the publication of QRISK3 https://qrisk.org/three/index.phplast year in the BMJ4 which will replace QRISK2 later this year.
Convergent Therapeutic Strategies to Overcome the Heterogeneity of Acquired Resistance in <i>BRAF</i>V600E Colorectal Cancer
Authors: Mehlika Hazar-Rethinam, Marianna Kleyman, G. Celine Han, David Liu, Leanne G. Ahronian, Heather A. Shahzade, Lifeng Chen, Aparna R. Parikh, Jill N. Allen, Jeffrey W. Clark, Eunice L. Kwak, Jason E. Faris, Janet E. Murphy, Theodore S. Hong, Emily E. Van Seventer, Brandon Nadres, Catriona B. Hong, Joseph M. Gurski, Nicholas A. Jessop, Dora Dias-Santagata, A. John Iafrate, Eliezer M. Van Allen, Ryan B. Corcoran
Journal: Cancer Discovery (2018)

Abstract Clonal heterogeneity associated with acquired resistance presents a critical therapeutic challenge. Whole-exome sequencing of paired tumor biopsies and targeted sequencing of cell-free DNA (cfDNA) from patients with BRAFV600E colorectal cancer receiving BRAF inhibitor combinations identified 14 distinct alterations in MAPK pathway components driving acquired resistance, with as many as eight alterations in a single patient. We developed a pooled clone system to study clonal outgrowth during acquired resistance, in vitro and in vivo. In vitro, the dynamics of individual resistant clones could be monitored in real time in cfDNA isolated from culture media during therapy. Outgrowth of multiple resistant clones was observed during therapy with BRAF, EGFR, and MEK inhibitor combinations. However, ERK inhibition, particularly in combination with BRAF and EGFR inhibition, markedly abrogated clonal outgrowth in vitro and in vivo. Thus, convergent, up-front therapy may suppress outgrowth of heterogeneous clones harboring clinically observed resistance alterations, which may improve clinical outcome. Significance: We observed heterogeneous, recurrent alterations in the MAPK pathway as key drivers of acquired resistance in BRAFV600E colorectal cancer, with multiple concurrent resistance alterations detectable in individual patients. Using a novel pooled clone system, we identify convergent up-front therapeutic strategies capable of intercepting multiple resistance mechanisms as potential approaches to suppress emergence of acquired resistance. Cancer Discov; 8(4); 417–27. ©2018 AACR. See related commentary by Janku, p. 389. See related article by Corcoran et al., p. 428. This article is highlighted in the In This Issue feature, p. 371
Controlled release of collagen-binding SDF-1α from the collagen scaffold promoted tendon regeneration in a rat Achilles tendon defect model
Authors: Jie Sun, Chenchen Mou, Qin Shi, Bing Chen, Xianglin Hou, Wen Zhang, Xiaoran Li, Yan Zhuang, Jiajia Shi, Yanyan Chen, Jianwu Dai
Journal: Biomaterials (2018)
Mast cell–derived plasminogen activator inhibitor type 1 promotes airway inflammation and remodeling in a murine model of asthma
Authors: Ara Jo, Sun H. Lee, Dong-Young Kim, Seung-Jae Hong, Michael N. Teng, Narasaiah Kolliputi, Richard F. Lockey, Robert P. Schleimer, Seong H. Cho
Journal: Journal of Allergy and Clinical Immunology (2018)
Improve routes back to work for doctors who take time out, says Future Forum
Authors: Helen Jaques
Journal: BMJ (2012)

The processes for doctors who take time out of work and want to return at a later date need to be improved, in particular for female doctors taking time out to have children, the Future Forum has recommended.

In its second phase report on education and training, the Future Forum called for clear and recognised pathways back into the workforce for doctors who have taken a break from work; for example for childcare reasons, to work overseas or follow a partner overseas, or owing to ill health. 

This is of particular importance to general practice, they say, where there are …
SAS grade to specialist registrar grade possession, should I actively apply or wait for PMETB to consider experience for training?
Authors: Romeh Gupta
Journal: BMJ (2005)

<b>www.bmjcareers.com/advicezone</b> 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.
Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms
Authors: Yong Li, Peggy Sekula, Matthias Wuttke, Judith Wahrheit, Birgit Hausknecht, Ulla T. Schultheiss, Wolfram Gronwald, Pascal Schlosser, Sara Tucci, Arif B. Ekici, Ute Spiekerkoetter, Florian Kronenberg, Kai-Uwe Eckardt, Peter J. Oefner, Anna Köttgen
Journal: Journal of the American Society of Nephrology (2018)

Background The kidneys have a central role in the generation, turnover, transport, and excretion of metabolites, and these functions can be altered in CKD. Genetic studies of metabolite concentrations can identify proteins performing these functions. Methods We conducted genome-wide association studies and aggregate rare variant tests of the concentrations of 139 serum metabolites and 41 urine metabolites, as well as their pairwise ratios and fractional excretions in up to 1168 patients with CKD. Results After correction for multiple testing, genome-wide significant associations were detected for 25 serum metabolites, two urine metabolites, and 259 serum and 14 urinary metabolite ratios. These included associations already known from population-based studies. Additional findings included an association for the uremic toxin putrescine and variants upstream of an enzyme catalyzing the oxidative deamination of polyamines ( AOC1 , P -min=2.4×10 −12 ), a relatively high carrier frequency (2%) for rare deleterious missense variants in ACADM that are collectively associated with serum ratios of medium-chain acylcarnitines ( P -burden=6.6×10 −16 ), and associations of a common variant in SLC7A9 with several ratios of lysine to neutral amino acids in urine, including the lysine/glutamine ratio ( P =2.2×10 −23 ). The associations of this SLC7A9 variant with ratios of lysine to specific neutral amino acids were much stronger than the association with lysine concentration alone. This finding is consistent with SLC7A9 functioning as an exchanger of urinary cationic amino acids against specific intracellular neutral amino acids at the apical membrane of proximal tubular cells. Conclusions Metabolomic indices of specific kidney functions in genetic studies may provide insight into human renal physiology.
Nearly one in 10 doctors in training has been bullied, says GMC
Authors: Abi Rimmer
Journal: BMJ (2014)

Nearly one in 10 doctors in training has been bullied, the General Medical Council (GMC) has found.

A GMC report on the findings of the 2014 national training survey said that, of 49 994 doctors in training who responded, 8% (4000) had been bullied and 14% (6784) had witnessed bullying in their workplace.1

Despite the relatively high proportion of respondents who had experienced bullying just 518 made a free text comment about bullying and undermining as part of the survey. Of those, 54% (277) said that the source of the bullying behaviour they had experienced was a consultant or GP who they had worked with. Just over 20% (114) said that the source of the bullying was …
Improving survivorship in brain metastases patents: assessing and addressing educational needs in non-neuro-oncology health professionals
Authors: Sara Robson, Liz Molloy, Charlotte Smith, Julie Emerson, Gillian Whitfield, Rovel Colaco, James Leggate, Catherine McBain
Journal: Neuro-Oncology (2018)

Outcomes of patients treated for brain metastases are improving, with growing numbers of long-term survivors following surgery and stereotactic radiosurgery (SRS). Many patients continue predominantly under the care of their site-specific team (breast, lung etc). It was proposed that survivorship in brain metastases patients might be enhanced by assessing and addressing neuro-oncology-specific educational needs in less specialised health professionals. Educational need in an unselected, diverse group of health professionals involved in brain metastases patient-care in hospital and community settings was evaluated via an electronically-disseminated survey. Results were collated to inform the contentof a training day. Attendees rated their confidence in managing a range of aspects of care from on a scale of 1–5 (low to high confidence) at registration, end of day and 5 weeks later. A two-sample Wilcoxon rank-sum (Mann-Whitney) test was applied to compare the data. 266 responses were received; 90 respondents attended the training day. Educational needs were identified in all domains. Delivered teaching reflected areas of lowest baseline confidence, prioritising acute and late toxicity of brain metastases treatments, steroids, management of epilepsy and the role of rehabilitation in preserving function and enhancing quality of life. Results showed statistically significant improvement in confidence across all aspects at both comparative time-points. Mean confidence scores for epilepsy, practical aspects and side effects increased from 1.8, 2.2 and 2.4 to 3.9, 3.9 and 4.3 respectively. The percentage of participants who scored their baseline confidence in managing steroid side-effects as 1/5 or 2/5 was 50% compared to 0% post-event. Significant unmet educational need was demonstrated in a range of non-neuro-oncology professionals caring for brain metastases patients. Targeted educational intervention achieved measurable improvement, still retained 5 weeks after the event. Further work to evaluate whether this translates into an improved survivorship experience for brain metastases patients is warranted.
The health and economic benefits of climate mitigation and pollution control
Authors: Philip J Landrigan
Journal: The Lancet Planetary Health (2018)

The heat waves, floods, rising sea levels, violent storms, and expanded ranges of vector-borne diseases associated with global climate change and the diseases and premature deaths caused by pollution are responsible for enormous economic losses. Yet despite the great magnitude of these costs, they are frequently overlooked and generally undercounted. The problem is that the links between floods, storms, rising rates of disease, and disruption of the earth's support systems1 are not widely recognised, and the costs of these events are spread across large populations, extend over many years, and are not neatly collected in one place.
LONG-TERM RENAL FUNCTION WORSENS IN HIGH CARDIOVASCULAR RISK PATIENTS WITH HIGH TRIGLYCERIDES AND WELL-CONTROLLED LOW-DENSITY LIPOPROTEIN CHOLESTEROL IN A REAL-WORLD ANALYSIS
Authors: Peter Toth, Craig Granowitz, Michael Hull, Djibril Liassou, Amy Anderson, Sephy Philip
Journal: Journal of the American College of Cardiology (2018)
Association of changes in functional status with radiation for prostate cancer in older veterans.
Authors: Carling Jade Ursem, L. Griselle Diaz-Ramirez, Sean Lang-Brown, Xiao X. Wei, Ronald C. Chen, Sei Lee
Journal: Journal of Clinical Oncology (2018)

148 Background: Although radiation therapy (RT) for prostate cancer is generally well tolerated, frail older adults with less functional reserve may experience more toxicity and loss of independence. Our objective was to determine trajectories of activities of daily living (ADL) for prostate cancer patients admitted to a nursing home for RT. Methods: We used the Veterans Affairs (VA) Minimum Data Set (MDS) to identify men age ≥65 with an ICD9 diagnosis of prostate cancer living in a VA nursing facility (CLC) 1/2005-12/2015, an MDS evaluation reporting RT and no ICD9 code for bone metastasis. Functional status was assessed using MDS-ADL score (range 0-28, higher scores = greater disability). A piecewise linear mixed effects model (nodes at months 1 and 3) modeled the relationship between baseline characteristics and MDS-ADL score. Results: 645 patients were identified, of whom 585 (90.7%) had not resided in a CLC prior to RT. Median age 74 (range 65-94), median baseline PSA 5.33 ng/mL (IQR 1-14.57), and median Charlson Comorbidity Index (CCI) 5 (30.5% CCl ≥8). Baseline median MDS-ADL score was 1 (range 0-28). Patients with CCI 2-3 did not have appreciable change in functional status in 6 months following start of RT, while patients with CCI 4-7 had an increase months 1-3, followed by improvement (Table). Compared to patients with CCI 2-3, those with CCl ≥8 had an increase in MDS-ADL score of 1.8 points/month months 1-3 after starting RT (p = 0.008), and increase in MDS-ADL score of 3 points/month from 3 months onward (p &lt; 0.001). Older age and higher CCI were associated with increase in MDS-ADL score (p &lt; 0.05). Conclusions: In a cohort of elderly prostate cancer patients with significant comorbidity, RT led to different functional trajectories depending on comorbidity burden. While patients with moderate comorbidity had an initial decline in functional status followed by improvement, patients with high comorbidity had continued functional decline. [Table: see text]
Radiation Exposure of Operators Performing Transesophageal Echocardiography During Percutaneous Structural Cardiac Interventions
Authors: James A. Crowhurst, Gregory M. Scalia, Mark Whitby, Dale Murdoch, Brendan J. Robinson, Arianwen Turner, Liesie Johnston, Swaroop Margale, Sarvesh Natani, Andrew Clarke, Darryl J. Burstow, Owen C. Raffel, Darren L. Walters
Journal: Journal of the American College of Cardiology (2018)
GMC spells out revalidation deferral rules
Authors: Caroline White
Journal: BMJ (2012)

Doctors who don’t have enough information to support their revalidation could be granted up to 12 further months to supply it, the General Medical Council (GMC) has confirmed, but only one such deferral within each revalidation cycle is likely to be permitted.

New guidance, published last week by the GMC, sets out how responsible officers need to go about making revalidation recommendations and what the regulator expects of them.

Responsible officers will have only three options available when a doctor’s revalidation falls due, which, once submitted to the GMC, can’t be withdrawn.

Recommendations will be based on whether a doctor has participated fully in all the processes required …
Regulation of proliferation and functioning of transplanted cells by using herpes simplex virus thymidine kinase gene in mice
Authors: Mari Tsujimura, Kosuke Kusamori, Chihiro Oda, Airi Miyazaki, Hidemasa Katsumi, Toshiyasu Sakane, Makiya Nishikawa, Akira Yamamoto
Journal: Journal of Controlled Release (2018)
Targeting Amyloid-β Precursor Protein, APP, Splicing with Antisense Oligonucleotides Reduces Toxic Amyloid-β Production
Authors: Jennifer L. Chang, Anthony J. Hinrich, Brandon Roman, Michaela Norrbom, Frank Rigo, Robert A. Marr, Eric M. Norstrom, Michelle L. Hastings
Journal: Molecular Therapy (2018)

Alterations in amyloid beta precursor protein (APP) have been implicated in cognitive decline in Alzheimer's disease (AD), which is accelerated in Down syndrome/Trisomy 21 (DS/TS21), likely due to the extra copy of the APP gene, located on chromosome 21. Proteolytic cleavage of APP generates amyloid-β (Aβ) peptide, the primary component of senile plaques associated with AD. Reducing Aβ production is predicted to lower plaque burden and mitigate AD symptoms. Here, we designed a splice-switching antisense oligonucleotide (SSO) that causes skipping of the APP exon that encodes proteolytic cleavage sites required for Aβ peptide production. The SSO induced exon skipping in Down syndrome cell lines, resulting in a reduction of Aβ. Treatment of mice with the SSO resulted in widespread distribution in the brain accompanied by APP exon skipping and a reduction of Aβ. Overall, we show that an alternatively spliced isoform of APP encodes a cleavage-incompetent protein that does not produce Aβ peptide and that promoting the production of this isoform with an SSO can reduce Aβ in vivo. These findings demonstrate the utility of using SSOs to induce a spliced isoform of APP to reduce Aβ as a potential approach for treating AD. Alterations in amyloid beta precursor protein (APP) have been implicated in cognitive decline in Alzheimer's disease (AD), which is accelerated in Down syndrome/Trisomy 21 (DS/TS21), likely due to the extra copy of the APP gene, located on chromosome 21. Proteolytic cleavage of APP generates amyloid-β (Aβ) peptide, the primary component of senile plaques associated with AD. Reducing Aβ production is predicted to lower plaque burden and mitigate AD symptoms. Here, we designed a splice-switching antisense oligonucleotide (SSO) that causes skipping of the APP exon that encodes proteolytic cleavage sites required for Aβ peptide production. The SSO induced exon skipping in Down syndrome cell lines, resulting in a reduction of Aβ. Treatment of mice with the SSO resulted in widespread distribution in the brain accompanied by APP exon skipping and a reduction of Aβ. Overall, we show that an alternatively spliced isoform of APP encodes a cleavage-incompetent protein that does not produce Aβ peptide and that promoting the production of this isoform with an SSO can reduce Aβ in vivo. These findings demonstrate the utility of using SSOs to induce a spliced isoform of APP to reduce Aβ as a potential approach for treating AD.
Pay protection to end for consultants who no longer hold clinical excellence awards
Authors: Helen Jaques
Journal: BMJ (2013)

Consultants who no longer hold clinical excellence awards but receive pay protection to prevent their salaries falling will lose this protection from autumn next year.

Currently doctors who are unsuccessful in reapplying for a clinical excellence or distinction award, or who allow their award to expire, are able to retain the salary they were receiving while they held the award until their basic pay …
OUTCOMES OF POST-OPERATIVE ATRIAL FIBRILLATION AFTER CORONARY ARTERY BYPASS GRAFT SURGERY: A META-ANALYSIS
Authors: Toufik Mahfood Haddad, Jai Parekh, Aravdeep Jhand, Amjad Kabach, Muhammad Soubhi Azzouz, Michael White, Venkata Alla, Michael Del Core
Journal: Journal of the American College of Cardiology (2018)
Cardiovascular Disease and Breast Cancer: Where These Entities Intersect: A Scientific Statement From the American Heart Association
Authors: Laxmi S. Mehta, Karol E. Watson, Ana Barac, Theresa M. Beckie, Vera Bittner, Salvador Cruz-Flores, Susan Dent, Lavanya Kondapalli, Bonnie Ky, Tochukwu Okwuosa, Ileana L. Piña, Annabelle Santos Volgman
Journal: Circulation (2018)

Cardiovascular disease (CVD) remains the leading cause of mortality in women, yet many people perceive breast cancer to be the number one threat to women's health. CVD and breast cancer have several overlapping risk factors, such as obesity and smoking. Additionally, current breast cancer treatments can have a negative impact on cardiovascular health (eg, left ventricular dysfunction, accelerated CVD), and for women with pre-existing CVD, this might influence cancer treatment decisions by both the patient and the provider. Improvements in early detection and treatment of breast cancer have led to an increasing number of breast cancer survivors who are at risk of long-term cardiac complications from cancer treatments. For older women, CVD poses a greater mortality threat than breast cancer itself. This is the first scientific statement from the American Heart Association on CVD and breast cancer. This document will provide a comprehensive overview of the prevalence of these diseases, shared risk factors, the cardiotoxic effects of therapy, and the prevention and treatment of CVD in breast cancer patients.