tbuckley/cabot-search huggingface dataset:
Hepatic effects assessed by review of safety data in enzalutamide castration-resistant prostate cancer (CRPC) trials.
Authors: Tomasz M. Beer, Simon Chowdhury, Fred Saad, Neal D. Shore, Celestia S. Higano, Peter Iversen, Karim Fizazi, Kurt Miller, Axel Heidenreich, Choung Soo Kim, De Phung, Jeffrey Kent Barrus, Natalia Nikolayeva, Andrew Krivoshik, Javier Waksman, Bertrand F. Tombal
Journal: Journal of Clinical Oncology (2018)

199 Background: Androgen receptor inhibitor enzalutamide (ENZA) improves survival in patients with metastatic CRPC. As the liver is the main route of ENZA elimination, this post hoc analysis evaluated the hepatic effects of ENZA versus comparators in controlled CRPC trials. Methods: Safety data from two large Phase 3, placebo (PBO)- (PREVAIL, NCT0121299; AFFIRM, NCT00974311) and two smaller Phase 2, bicalutamide (BIC)-controlled (STRIVE, NCT01664923; TERRAIN, NCT01288911) ENZA trials in men with CRPC were assessed for hepatic impairment-related adverse events (AEs) using the following standardized narrow MedDRA queries V19.1: hepatic failure, fibrosis and cirrhosis, and other liver damage-related conditions; hepatitis, non-infectious; and liver-related investigation, signs, and symptoms. Liver-related laboratory test results were also evaluated. Data were summarized as follows: patients receiving ENZA in Phase 3 trials (n = 1671); patients receiving ENZA in Phase 2 trials (n = 380); patients receiving PBO (n = 1243); patients receiving BIC (n = 387); and combined ENZA-treated patients (n = 2051). Results: Percentages of hepatic impairment-related AEs ranged between 2.9% and 4.5% with ENZA, and were 2.7% with PBO and 5.4% with BIC (Table). The most common hepatic impairment-related AEs were increased aspartate (AST) and alanine aminotransferase (ALT; Table). Within each trial, the incidences of grade ≥3 AEs were similar, and dose reductions or discontinuations due to hepatic impairment-related AEs were low (Table). When adjusted for treatment exposure, AEs per 100 patient-years were lower with ENZA versus either PBO or BIC (Table). Conclusions: This combined analysis of CRPC trials demonstrates no hepatic safety signal with ENZA and thus routine liver tests are not required. Clinical trial information: NCT0121299; NCT00974311; NCT01664923; NCT01288911. [Table: see text]
Getting even more serious about prevention: “social injustice is killing on a grand scale”
Authors: Sebastian Kraemer
Journal: BMJ (2018)

Oliver’s welcome call for public health interventions “throughout the whole of life” does not go far enough.1 Only a reversal of our continuing drift into social disintegration can begin to restore the nation’s health. Seven decades ago, Britain was terribly poor but the new NHS was embedded in relatively secure provisions of housing, education, employment, and welfare. We are far richer now, but we can’t rely on …
GP contests claim that online provider passed CQC inspection “with flying colours”
Authors: Susan Mayor
Journal: BMJ (2018)

A GP who is spearheading a campaign against the risk to NHS services from the online primary care service GP at Hand has complained to the Care Quality Commission (CQC) after the CEO of Babylon, the service’s digital provider, claimed in an interview that it had passed the CQC inspection “with flying colours.”

In fact, latest CQC inspections queried whether GP at Hand was providing a safe service1 and found that Babylon in some respects was not.2

During an interview on BBC Radio 4’s Today programme on 23 March about the CQC’s new report on online GP service providers,3 Ali Parsa, CEO of Babylon Healthcare Services, said that the CQC had passed the provider “with …
Comparison of HPV E6,E7 mRNA/PD-L1 assay using flow cytometry and p16 IHC expression in oral cancer samples.
Authors: Yvette Carrasco, Amanda Chargin, Haitham Mirghani, Bruce Kendrick Patterson
Journal: Journal of Clinical Oncology (2018)

114 Background: Research into causality of head and neck squamous cell carcinoma (HNSCC) has found a link to HPV infections affiliated with better survival than tobacco associated HNSCC. Currently, p16 immunohistochemistry is used as a predictive biomarker for HPV infection in HNSCC. We were interested in looking at an additional biomarker, HPV E6,E7 mRNA overexpression by flow cytometry, to see if it correlated with p16 status. Each test looks at a different marker of HPV infection, p16 as a surrogate of E7 activity, and E6,E7 mRNA overexpression as a marker of transcriptionally active and integrated virus. Currently p16 positive samples are confirmed with an ISH assay. Additionally, we looked at the PD-L1 expression in these tumors to see if it correlated with HPV mRNA overexpression. Advances in immuno-oncology have brought immunotherapy to the forefront of cancer treatment including HNSCC. Methods: Swabs were collected from Institut Gustave Roussy patients with lesions of the oral pharynx. Swabs were placed into a vial with a proprietary fixation solution and shipped overnight for processing. Upon receipt, samples were passed through a 35 uM filter to remove aggregates. Cells underwent in situ hybridization with E6, E7 mRNA probes (HPV OncoTect), were labeled with PD-L1 Ab, and then stained with a cell cycle dye identify single nucleated cells prior to analysis on the flow cytometer. FFPE biopsy tissue of the lesion was tested with p16 IHC. Positive samples were confirmed by ISH. Results: We analyzed samples from 27 patients with oral cancer with the combined E6, E7 mRNA/PD-L1 assay by flow cytometry and p16/ISH. Concordance between HPV E6,E7 mRNA positive results and p16 positive confirmed by ISH was 74%. Interestingly, PD-L1 expression was seen only in samples without HPV infection (according to HPV E6,E7 mRNA flow result). Samples are still being accrued and updated data will be presented at the meeting. Conclusions: Here we report a novel assay to quantify both HPV E6, E7 mRNA and PD-L1 simultaneously in single cells from head and neck squamous cell carcinoma. In addition, the ability to characterize both E6,E7 mRNA expression and PD-L1 in one test can provide clinicians with insight into treatment options.
Antithyroid Drugs and Congenital Malformations
Authors: Gi Hyeon Seo, Tae Hyuk Kim, Jae Hoon Chung
Journal: Annals of Internal Medicine (2018)

Untreated or insufficiently treated Graves disease in pregnancy may pose risks to both mother and fetus. Antithyroid drugs (ATDs) are the treatment mainstay, but the potential teratogenic effect of these drugs has prompted clinicians to question the safe management of this vulnerable population.To examine the association between maternal prescriptions for ATDs and congenital malformations in live births.Nationwide cohort study.Korean National Health Insurance database.A cohort of 2 886 970 completed pregnancies linked to live-born infants in 2 210 253 women between 2008 and 2014.Maternal prescriptions for ATDs in the first trimester.The risk for overall and organ-specific congenital malformations in offspring, with logistic regression models used to control for potential confounders.12 891 pregnancies (0.45%) were exposed to ATDs during the first trimester. The prevalence of malformations in exposed offspring was 7.27%, compared with 5.94% in offspring of women who were not prescribed ATDs during pregnancy (P < 0.001) (adjusted odds ratio, 1.19 [95% CI, 1.12 to 1.28]). Absolute increases in the prevalence of congenital malformations per 1000 live births were 8.81 cases (CI, 3.92 to 13.70 cases) for propylthiouracil alone, 17.05 cases (CI, 1.94 to 32.15 cases) for methimazole (MMI) alone, and 16.53 cases (CI, 4.73 to 28.32 cases) for propylthiouracil and MMI, compared with pregnancies without ATD prescriptions. In the MMI group, a high cumulative dose (>495 mg) during the first trimester was associated with an increased risk for malformations compared with a low dose (1 to 126 mg) (adjusted odds ratio, 1.87 [CI, 1.06 to 3.30]).The study used a prescription claims database to assess ATD exposure.Exposure to ATDs during the first trimester was associated with increased risk for congenital malformations, particularly for pregnancies in which women received prescriptions for MMI or both ATDs.None.
The trust where I am working as a senior house officer does not pay me for my overseas experience (which amounts to five years) and pays me only on point 0 scale. How can I challenge this?
Authors: John Adsett
Journal: BMJ (2004)

<i>Got a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone (www.bmjcareers.com/advicezone) for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site.</i>
The subconsultant may actually see you now
Authors: Edward Davies
Journal: BMJ (2012)

Four years ago, the first article I edited for BMJ Careers looked at the issue of subconsultants. And it was a long way from being the first that we had carried on the issue. In the intervening years it has been a subject that has constantly loitered around our pages as a threat, but real action and change have never materialised.

Most recently, we published research from the Centre for Workforce Intelligence highlighting a 60% oversupply of consultants by 2020.1 Among its recommendations was for a “consolidation period” to be introduced between attaining a certificate of completion of training and taking up a consultant post and for “a multilevel career structure that recognises different levels of expertise, competence, and intensity of work”—we can argue the semantics, but basically these are types of subconsultant.

These were just ideas, however, …
CARVEDILOL EXERTS POSITIVE INOTROPY IN CARDIOMYOCYTES BY UNIQUELY STIMULATING BETA-ARRESTIN2-DEPENDENT SERCA2A ACTIVITY VIA THE BETA1-ADRENERGIC RECEPTOR
Authors: Anastasios Lymperopoulos, Katie A. McCrink, Jennifer Maning, Ava Brill, Victoria L. Desimine, Shelby L. Wertz, Walter Koch
Journal: Journal of the American College of Cardiology (2018)
Facet Joints of the Spine: Structure–Function Relationships, Problems and Treatments, and the Potential for Regeneration
Authors: Siobhan A. O'Leary, Nikolaos K. Paschos, Jarrett M. Link, Eric O. Klineberg, Jerry C. Hu, Kyriacos A. Athanasiou
Journal: Annual Review of Biomedical Engineering (2018)

The zygapophysial joint, a diarthrodial joint commonly referred to as the facet joint, plays a pivotal role in back pain, a condition that has been a leading cause of global disability since 1990. Along with the intervertebral disc, the facet joint supports spinal motion and aids in spinal stability. Highly susceptible to early development of osteoarthritis, the facet is responsible for a significant amount of pain in the low-back, mid-back, and neck regions. Current noninvasive treatments cannot offer long-term pain relief, while invasive treatments can relieve pain but fail to preserve joint functionality. This review presents an overview of the facet in terms of its anatomy, functional properties, problems, and current management strategies. Furthermore, this review introduces the potential for regeneration of the facet and particular engineering strategies that could be employed as a long-term treatment.
Three-year outcomes of two phase II studies of adjuvant chemotherapy with S-1 plus oxaliplatin or capecitabine plus oxaliplatin in patients with stage III gastric cancer after D2 gastrectomy.
Authors: Yoshiaki Nakamura, Takeharu Yamanaka, Keisho Chin, Haruhiko Cho, Hitoshi Katai, Masanori Terashima, Seiji Ito, Motohiro Hirao, Kazuhiro Yoshida, Eiji Oki, Mitsuru Sasako, Yasunori Emi, Hideaki Bando, Yoshiyuki Kawashima, Tetsu Fukunaga, Masahiro Gotoh, Takako Ishibashi, Kohei Shitara
Journal: Journal of Clinical Oncology (2018)

94 Background: Two phase II trials of oxaliplatin-based adjuvant chemotherapy for patients (pts) with gastric cancer (GC) after D2 gastrectomy have been conducted in Japan; the J-CLASSIC study of capecitabine plus oxaliplatin (CAPOX) and the SOXaGC study of S-1 plus oxaliplatin (SOX). In the current study, we evaluated survival outcomes of the two trials. Methods: The J-CLASSIC, enrolling stage II and III pts from 12 centers between July 2012 and July 2013, evaluated eight cycles of CAPOX. The SOXaGC, enrolling stage III pts from 11 centers between July 2013 and February 2014, evaluated seven cycles of SOX after one cycle of S-1 monotherapy. The two studies were conducted sequentially and most centers (9 centers) participated in both trials. In this pooled analysis, we updated relapse-free survival (RFS) and overall survival (OS) information. The median follow-up time was 49 months in the J-CLASSIC and 39 months in the SOXaGC. Results: Fifty-nine stage III pts treated with CAPOX and 62 stage III pts treated with SOX were analyzed. The 3-year RFS and OS rates of SOX were 70.9% (57.8-80.5%) and 75.7% (63.0-84.6%), respectively, whereas the 3-year RFS and OS rates of CAPOX were 67.8% (54.3-78.1%) and 79.3% (66.5-87.7%), respectively. The hazard ratio (HR) of SOX in comparison to CAPOX was 0.925 (0.498-1.720) for RFS, suggesting the efficacy of the two treatments was similar. Trend of a different efficacy was observed in some particular subgroups; the HR for RFS was 1.732 (0.506-5.927) in the intestinal type and 0.735 (0.353-1.528) in the diffuse type, while that was 2.008 (0.447-9.016) in stage IIIA, 0.872 (0.266-2.857) in stage IIIB, and 0.597 (0.258-1.383) in stage IIIC. Conclusions: This is the first report of survival follow-up in Japanese GC pts with oxaliplatin-based adjuvant chemotherapy, which suggests comparable outcomes in both treatments for stage III GC. Different trend in the treatment effect by histologic type or stage warrants further evaluation in a larger cohort. Clinical trial information: UMIN000026883.
THE IMPACT OF PLATELET-FIBRIN CLOT STRENGTH AND INFLAMMATION ON INCIDENCE OF PERIPHERAL ARTERY DISEASE AND CLINICAL OUTCOMES IN PATIENTS WITH SIGNIFICANT CORONARY ARTERY DISEASE
Authors: Jae Seok Bae, Jong-Hwa Ahn, Jeong Yoon Jang, Min Gyu Kang, Kyehwan Kim, Hyun Woong Park, Jin-Sin Koh, Yongwhi Park, Choong Hwan Kwak, Jin-Yong Hwang, Young-Hoon Jeong
Journal: Journal of the American College of Cardiology (2018)
Prioritisation of food-borne parasites in Europe, 2016
Authors: Martijn Bouwknegt, Brecht Devleesschauwer, Heather Graham, Lucy J Robertson, Joke WB van der Giessen
Journal: Eurosurveillance (2018)

Background and aimsPriority setting is a challenging task for public health professionals. To support health professionals with this and in following a recommendation from the Food and Agriculture Organization of the United Nations (FAO) and World Health Organization (WHO), 35 European parasitologists attended a workshop from 8-12 February 2016 to rank food-borne parasites (FBP) in terms of their importance for Europe and regions within Europe. Methods: Countries were divided into European regions according to those used by the European Society of Clinical Microbiology and Infectious Diseases. We used the same multicriteria decision analysis approach as the FAO/WHO, for comparison of results, and a modified version, for better regional representation. Twenty-five FBP were scored in subgroups, using predefined decision rules. Results: At the European level, Echinococcus multilocularis ranked first, followed by Toxoplasma gondii and Trichinella spiralis. At the regional level, E. multilocularis ranked highest in Northern and Eastern Europe, E. granulosus in South-Western and South-Eastern Europe, and T. gondii in Western Europe. Anisakidae, ranking 17th globally, appeared in each European region's top 10. In contrast, Taenia solium, ranked highest globally but 10th for Europe. Conclusions: FBP of importance in Europe differ from those of importance globally, requiring targeted surveillance systems, intervention measures, and preparedness planning that differ across the world and across Europe.
Five facts about the paediatrician workforce
Authors: Abi Rimmer
Journal: BMJ (2017)

The Royal College of Paediatrics and Child Health (RCPCH) has published a report on the paediatric workforce. The report is based on figures from the college’s 2015 workforce census, Office for National Statistics data, and information from the college’s trainee recruitment processes.

Hospital admissions for children in England rose by 25% between 2013/14 and 2015/16, from …
What makes your heart sink?
Authors: Rhona MacDonald
Journal: BMJ (2004)

I detest labels, especially the “heartsink” one that some doctors use to describe their patients. One labelling approach goes even further—classifying “hateful patients” as either “dependent clingers,” “entitled demanders,” “manipulative health rejecters,” or “self-destructive deniers.” I doubt there are many doctors who haven't, from time to time, felt angry, frustrated, or inadequate after a consultation with a patient who …
Evaluation of the outcome of adjuvant treatment for gastric cancer in Brazil and Peru: A retrospective study in two cancer centers in Latin America.
Authors: Jose Eduardo Nunez, Tiago Felismino, Daniel Enriquez, Paola Catherine Montenegro, Felipe Coimbra, Wilson L. Costa, Maria D. Begnami, Luis Taxa, Sandro Casavilca, Ricardo Fogaroli, Ana Caroline Alves, Celso Lopes Mello
Journal: Journal of Clinical Oncology (2018)

160 Background: Gastric cancer (GC) is one of the most frequent malignancies in developing countries. In Peru, it is the fourth most incident cancer, and the sixth one in Brazil. Mortality is still high. The chance of relapse of patients with non-metastatic disease undergoing surgery is more than 50%. It is suspected that Latin American patients present worse evolution compared to those treated in Asia or in developed countries, therefore it is fundamental to study factors related to the prognosis and evolution of patients with GC in our continent. We aimed to evaluate the outcome of adjuvant treatment for GC in patients from two countries with different racial miscegenation and eating habits, and correlate this with clinicopathological features. Methods: We retrospectively analyzed 187 patients with GC who underwent curative surgery and received CRT at AC Camargo Cancer Center (ACCCC) in Brazil and Instituto Nacional de Enfermedades Neoplasicas (INEN) in Peru. CRT was defined as MacDonald protocol. Primary endpoint was overall survival (OS). Cox regression model was performed in order to calculate hazard ratio (HR) and 95% confidence intervals (95%CI). Results: Median follow up time was 51 and 20 months in Brazil and Peru, respectively. Median age of our cohort was 54 years-old. Male sex was predominant in both countries (Brazil: 54.7%; Peru: 56.9%). Diffuse subtype also was predominant (Brazil: 58.3%; Peru: 55.1%). Median OS was 103.9 and 45.2 months in Brazil and Peru respectively (p &lt; 0.001). In the multiple analysis, we found that pathological stage (I/II vs. III; HR = 4.1, 95%CI 1.4-11.7; p = 0.009) was independent prognostic factor adjusted by country of treatment, histological subtype, localization, age and gender. Conclusions: Survival differences exist between Brazil and Peru. We observed that patients from Peru had more advanced pathological stage after surgery. This difference suggests a possible prognostic factor in OS. Ethnic/genetic factors, eating habits and other clinicopathological or molecular factors may also explain different prognosis. Future studies are warranted to determine these prognostic factors in Latin American gastric cancer patients.
Progress in the management of IPF-related acute exacerbations: a goal for patients, respirologists and intensivists
Authors: François Vincent, Hilario Nunes, Stéphane Gaudry
Journal: European Respiratory Journal (2018)

We read with interest the illuminating review on the pharmacological management of idiopathic pulmonary fibrosis (IPF) recently published in the European Respiratory Journal [1]. Raghu [1] did not detail the pharmacological management of acute exacerbations (AEs). AEs often lead to the question of whether to transfer the patient to the intensive care unit (ICU) for respiratory support, whether this is invasive mechanical ventilation (IMV) or not, and to the choice of adequate pharmacological agent(s) [2]. This is a critical issue for respirologists and intensivists as it is estimated that ∼3 million patients suffer from this disease worldwide [3]. When making the decision of whether to transfer to the ICU, it should be kept in mind that ≤46% of IPF-related deaths are preceded by an AE, with the majority of patients dying within the first month and most of the remaining within a year [2, 4]. IPF-related acute exacerbations: further research needed <http://ow.ly/CB3W30hzYNq>
A Novel Mechanism for Activation of GLI1 by Nuclear SMO That Escapes Anti-SMO Inhibitors
Authors: Muhammad M. Rahman, Allon Hazan, Joanne L. Selway, Dimalee S. Herath, Catherine A. Harwood, Muhammad S. Pirzado, Ravinder Atkar, David P. Kelsell, Kenneth J. Linton, Mike P. Philpott, Graham W. Neill
Journal: Cancer Research (2018)

Small-molecule inhibitors of the Hedgehog (HH) pathway receptor Smoothened (SMO) have been effective in treating some patients with basal cell carcinoma (BCC), where the HH pathway is often activated, but many patients respond poorly. In this study, we report the results of investigations on PTCH1 signaling in the HH pathway that suggest why most patients with BCC respond poorly to SMO inhibitors. In immortalized human keratinocytes, PTCH1 silencing led to the generation of a compact, holoclone-like morphology with increased expression of SMO and the downstream HH pathway transcription factor GLI1. Notably, although siRNA silencing of SMO in PTCH1-silenced cells was sufficient to suppress GLI1 activity, this effect was not phenocopied by pharmacologic inhibition of SMO, suggesting the presence of a second undefined pathway through which SMO can induce GLI1. Consistent with this possibility, we observed increased nuclear localization of SMO in PTCH1-silenced cells as mediated by a putative SMO nuclear/nucleolar localization signal [N(o)LS]. Mutational inactivation of the N(o)LS ablated this increase and suppressed GLI1 induction. Immunohistologic analysis of human and mouse BCC confirmed evidence of nuclear SMO, although the pattern was heterogeneous between tumors. In PTCH1-silenced cells, >80% of the genes found to be differentially expressed were unaffected by SMO inhibitors, including the putative BCC driver gene CXCL11. Our results demonstrate how PTCH1 loss results in aberrant regulation of SMO-independent mechanisms important for BCC biology and highlights a novel nuclear mechanism of SMO-GLI1 signaling that is unresponsive to SMO inhibitors.Significance: This study describes novel noncanonical Hedgehog signaling, where SMO enters the nucleus to activate GLI1, a mode that is unaffected by SMO inhibitors, thus prompting re-evaluation of current BCC treatment as well as new potential therapies targeting nuclear SMO. Cancer Res; 78(10); 2577-88. ©2018 AACR.
NHS should be proud of how it responded to Mid Staffordshire, health secretary says
Authors: Abi Rimmer
Journal: BMJ (2013)

Health service staff should be proud of the way they responded to failings at Mid Staffordshire NHS Foundation Trust, the health secretary, Jeremy Hunt, has said.

Speaking at the General Medical Council’s conference on professionalism in Manchester on 12 December, he praised the way the NHS had dealt with “the horrific challenge of Mid Staffs.” He said that, because of the professionalism of NHS staff, problems had been dealt with rather than ignored. “That is something we can really be proud of,” he said.

“Within the last year I have not …