tbuckley/cabot-search huggingface dataset:
Female doctors unlikely to become academics without more exposure to research, study finds
Authors: Matthew Limb
Journal: BMJ (2016)

Women are unlikely to consider careers in academic medicine without more exposure to research during their education and training, a new study has suggested.

The researchers behind the study said that women were still significantly under-represented in the field and many faced “gender discrimination and unconscious bias” while still at medical school. Senior systematic reviewer Laurel Edmunds told BMJ Careers , “The bottom line is that the whole culture is still male dominated. There are ways of encouraging women—it needs to be more people friendly.”

The Oxford University researchers asked why, when entry to medical schools was evenly split between men and women, those working in university medical departments were predominantly men. In the UK, women made up 55% of medical school entrants but just 28% were employed in academic medicine. In the United …
18F-FDG PET/CT for Monitoring Response of Merkel Cell Carcinoma to the Novel Programmed Cell Death Ligand 1 Inhibitor Avelumab
Authors: Naghmehossadat Eshghi, Tamara F. Lundeen, Lea MacKinnon, Ryan Avery, Phillip H. Kuo
Journal: Clinical Nuclear Medicine (2018)

An 85-year-old man with stage IIIA Merkel cell carcinoma of the left arm was initially treated with local excision and axillary node dissection followed by radiation therapy. Eight months after surgery, whole-body FDG PET/CT demonstrated intensely hypermetabolic hepatic metastases and abdominal lymphadenopathy. Given his age and comorbidities, he was considered a poor candidate for chemotherapy, and therefore the novel programmed cell death ligand 1 inhibitor avelumab was initiated. FDG PET/CT after 4 cycles showed complete resolution of hepatic and nodal metastases. Whole-body FDG PET/CT can be used for monitoring response of multisystem metastases from Merkel cell carcinoma to active immunotherapy.
Validation of a genetic risk score for atrial fibrillation: A prospective multicenter cohort study
Authors: Evan D. Muse, Nathan E. Wineinger, Emily G. Spencer, Melissa Peters, Riley Henderson, Yunyue Zhang, Paddy M. Barrett, Steven P. Rivera, Jay G. Wohlgemuth, James J. Devlin, Dov Shiffman, Eric J. Topol
Journal: PLoS Medicine (2018)

Background Atrial fibrillation (AF) is the most commonly encountered arrhythmia and is associated with an elevated risk of stroke. Improving the identification of patients with the highest risk for AF to enable appropriate surveillance and treatment, if necessary, is critical to reducing AF-associated morbidity and mortality. Multiple common single nucleotide polymorphisms (SNPs) are unequivocally associated with the lifetime risk of AF. In the current study we aimed to prospectively validate an AF genetic risk score (GRS) in previously undiagnosed patients at risk for AF. Methods and findings Individuals 40 years of age or older with 1 clinical risk factor for AF, presenting with symptoms of AF, or with a first diagnosis of AF, were enrolled for genetic testing and ambulatory cardiac rhythm monitoring with an adhesive patch monitor or a long-term Holter monitor (mean wear time 10 days 21 hours and 13 days 18 hours, respectively). An AF event was the first diagnosis of AF by ECG, patch monitor, or long-term Holter monitor. The AF GRS was determined for each participant based on the weighted contribution of 12 genetic risk loci. Of 904 participants, 85 manifested AF. Their mean age was 66.2 (SD 11.8) years; 38% of participants were male. Participants in the highest quintile of AF GRS were more likely (odds ratio 3.11; 95% CI 1.27–7.58; p = 0.01) to have had an AF event than participants in the lowest quintile after adjusting for age, sex, smoking status, BMI, hypertension, diabetes mellitus, heart failure, and prior myocardial infarction. Study limitations included an ethnically homogenous population, a restricted rhythm monitoring period, and the evolving discovery of SNPs associated with AF. Conclusions Prospective assessment of a GRS for AF identified participants with elevated risk of AF beyond established clinical criteria. Accordingly, a GRS for AF could be incorporated into overall risk assessment to better identify patients at the highest risk of developing AF, although further testing in larger populations is needed to confirm these findings. Trial registration ClinicalTrials.gov NCT01970969
GPs anticipate workload crisis if GMS contract proposals go ahead
Authors: Helen Jaques
Journal: BMJ (2013)

Over 90% of GPs expect that their workload would increase to unmanageable levels and that they would experience more work related stress if the government went ahead with its plan to change the general medical services (GMS) contract for 2013-14.

Of 7746 GPs in England who responded to a survey by the BMA (response rate 30.4%), 91% said that they would be less likely to be able to manage their workload if the government imposed the contract changes. 

A total of 92% said that they would be less able to achieve a satisfactory work-life balance if the contract proposals …
INFARCT HEALING DURING LONG-TERM FOLLOW-UP AFTER ST-ELEVATION MYOCARDIAL INFARCTION
Authors: Christina Tiller, Hans-Josef Feistritzer, Gert Klug, Sebastian Reinstadler, Martin Reindl, Lukas Müller, Agnes Mayr, Bernhard Metzler
Journal: Journal of the American College of Cardiology (2018)
Laboratory eligibility criteria as potential barriers to participation by black men in prostate cancer clinical trials.
Authors: Marie Vastola, David Dewei Yang, Brandon Arvin Virgil Mahal, Vinayak Muralidhar, Christopher S. Lathan, Bradley Alexander McGregor, Paul L. Nguyen
Journal: Journal of Clinical Oncology (2018)

73 Background: Eligibility criteria may disproportionately affect black patients and contribute to their underrepresentation in clinical trials. We studied this potential barrier by examining clinical trials in prostate cancer, a disease in which black men face higher incidence and mortality. Specifically, we investigated the use of serum creatinine (sCr) alone instead of race-adjusted measurements for renal function, and the use of an absolute neutrophil count (ANC) threshold that could exclude men with benign ethnic neutropenia, which afflicts 6.7-8% of black patients and could lead to the exclusion of patients despite having healthy immune systems. Methods: We identified 401 interventional prostate cancer clinical trials with an overall survival endpoint. The list of trials was collected on January 16, 2017 from clinicaltrials.gov using the following criteria – study type: interventional studies; conditions: prostate cancer; interventions: drug; outcome measures: overall survival. Characteristics gathered from each trial included sponsor type, phase, accrual goal, start year, and toxicity. Results: Overall, 47.9% (192) of these trials used either sCr alone and/or required participants to have ANC ≥1.5×10 9 cells/L. Specifically, 25.2% (101) of the trials used sCr alone to determine eligibility, and 41.4% (166) of the trials required patients to have an ANC ≥1.5×10 9 cells/L. Conclusions: Of clinical trials in prostate cancer, 47.9% used criteria that disproportionately excluded black patients. The reevaluation of these two eligibility criteria could improve minority trial enrollment. First, lowering the ANC cutoff for patients with benign ethnic neutropenia would increase the number of eligible black participants, as 89% of these patients have an ANC ≥1.0×10 9 cells/L. Second, using race-adjusted equations for renal function would take into account racial differences in creatinine. While adopting race-based differences in trial criteria may add slight logistical challenges when ensuring patients meet trial eligibility, these adjustments would prevent healthy patients from being excluded solely because of benign laboratory differences caused by their race.
Glucose‐6‐phosphate‐dehydrogenase deficient red blood cell units are associated with decreased posttransfusion red blood cell survival in children with sickle cell disease
Authors: Eyal Sagiv, Ross M. Fasano, Naomi L. C. Luban, Cassandra D. Josephson, Sean R. Stowell, John D. Roback, Richard O. Francis, Marianne E. M. Yee
Journal: American Journal of Hematology (2018)

Chronic transfusion therapy (CTT) for sickle cell disease (SCD) reduces disease morbidity by suppressing the amount of circulating hemoglobin S (HbS)-containing red blood cells (RBC). The effectiveness of CTT depends on the rate of RBC clearance. Glucose-6-phosphate dehydrogenase (G6PD) deficient donor RBC may exhibit increased hemolysis, but it is unknown if transfusion of these units results in less effective transfusion outcomes in SCD. Children with SCD on CTT were followed prospectively for multiple transfusions. G6PD activity of transfused units was measured prior to expiration date. HbA clearance (ΔHbA) was calculated as the difference of estimated posttransfusion HbA to the pretransfusion HbA of the subsequent transfusion episode. Sixty-two patients received 388 transfusions. Of 755 RBC units, 687 (91%) had normal G6PD (>60% activity), 38 (5%) had moderately low G6PD (10-60% activity), and 30 (4%) had severely low G6PD (<10% activity). Of 358 evaluable transfusions, 54 (15%) included ≥1 G6PD deficient units, and 22 (6%) had ≥1 severely deficient units. The proportion of the transfusion episode consisting of G6PD deficient units was associated with increased ΔHbA for all G6PD deficient units (P = .05) and for severely G6PD deficient units (P = .0070). In multivariate mixed effects modeling, ΔHbA was positively associated with severely G6PD deficient units (P = .0074) and RBC alloimmunization (P = .03) and negatively associated with recipient splenectomy (P = .015). Higher ΔHbA was associated with higher HbS and reticulocyte counts at the subsequent transfusion episode. In conclusion, G6PD deficient RBC transfusions may have shorter in vivo survival and adversely affect the suppression of sickle erythropoiesis.
Hope at Havens
Authors: Jan Welch
Journal: BMJ (2004)

I n 1991 our sexual health service was approached by the Metropolitan Police to ask if we could provide forensic examinations during the daytime for people who had been sexually assaulted. Traditionally such examinations were carried out by forensic medical examiners, who were often busy during the day with other careers, typically as general practitioners. Several of us went on a weekend course run by forensic scientists and the police to learn more about sexual offences, and subsequently provided daytime forensic examinations at the clinic. At night some doctors joined the medical rota for examinations in police victim examination suites. During the day we felt able to provide an excellent service to distressed and needy people who had been sexually assaulted within the last few hours or days. The examination would go smoothly, supported by a nurse with sexual health skills, who would look after the client as well as assisting in collecting samples and then sealing and labelling them for evidence. Management after sexual assault
A phase II study of degarelix prior to radiation on prostatic tissue androgens.
Authors: Robert B. Montgomery, Kenneth J. Russell, Jay Justin Liao, William J Ellis, Heather H. Cheng, Evan Y. Yu, Elahe A. Mostaghel
Journal: Journal of Clinical Oncology (2018)

103 Background: Optimizing androgen suppression may provide better treatment outcomes for localized prostate cancer (PCa). Numerous trials have supported the benefit of combining androgen deprivation (ADT) with definitive radiotherapy in men with locally advanced or high-grade disease. LHRH agonist (LHRHa) is most commonly used. The LHRH antagonist degarelix may provide more robust androgen suppression. The impact on tissue androgens following use of degarelix prior to radiation has not been reported. We examined the impact on androgens in serum and tissue after 12 weeks of degarelix in this phase II study. Methods: A prospective, phase II study was conducted in men with localized PCa treated with 6 months of neoadjuvant and concurrent degarelix with radiation. Prostate biopsies were obtained at the time of fiducial placement before radiotherapy. Serum and tissue androgen levels were measured by liquid chromatography-tandem mass spectrometry. Needle biopsies from a separate analysis of untreated men or those receiving LHRHa prior to prostatectomy were used as tissue androgen level controls. Results: 16 men with intermediate (4) and high-risk (12) PCa received study therapy. 14 men completed degarelix and planned radiation to 77.4-81 Gy. Serum and tissue androgens after 12 weeks of therapy are compared to untreated control and LHRHa treated patients (12 weeks). Serum levels of dihydrotestosterone (DHT) and testosterone were similarly suppressed by LHRHa or degarelix compared to untreated controls, without statistically significant differences. Degarelix provided statistically greater reduction in androsterone than LHRHa. Conclusions: In this phase II study degarelix and LHRHa achieved similar serum and tissue androgen levels at 12 weeks; however, there was a greater suppression of tissue androsterone with degarelix. The clinical significance of this difference remains uncertain. Clinical trial information: NCT01731912. [Table: see text]
Efficient delivery of nucleic acid molecules into skin by combined use of microneedle roller and flexible interdigitated electroporation array
Authors: Dong Huang, Deyao Zhao, Xiaoxia Wang, Chunhui Li, Tongren Yang, Lili Du, Zewen Wei, Qiang Cheng, Huiqing Cao, Zicai Liang, Yuanyu Huang, Zhihong Li
Journal: Theranostics (2018)

Rationale: Delivery of nucleic acid molecules into skin remains a main obstacle for various types of gene therapy or vaccine applications.Here we propose a novel electroporation approach via combined use of a microneedle roller and a flexible interdigitated electroporation array (FIEA) for efficient delivery of DNA and siRNA into mouse skin.Methods: Using micromachining technology, closely spaced gold electrodes were made on a pliable parylene substrate to form a patch-like electroporation array, which enabled close surface contact between the skin and electrodes.Pre-penetration of the skin with a microneedle roller resulted in the formation of microchannels in the skin, which played a role as liquid electrodes in the skin and provided a uniform and deep electric field in the tissue when pulse stimulation was applied by FIEA.Results: Using this proposed method, gene (RFP) expression and siRNA transfection were successfully achieved in normal mice skin.Anti-SCD1 siRNA electroporated via this method mediated significant gene silencing in the skin.Moreover, electroporation assisted by the microneedle roller showed significant advantages over treatment with FIEA alone.This allowed nucleic acid transportation at low voltage, with ideal safety outcomes.Principal conclusions: Hence, the proposed electroporation approach in this study constitutes a novel way for delivering siRNA and DNA, and even other nucleic acid molecules, to mouse skin in vivo, potentially supporting clinical application in the treatment of skin diseases or intradermal/subcutaneous vaccination.
Single‐Cell Sequencing in Normal and Malignant Hematopoiesis
Authors: Nicola K. Wilson, Berthold Göttgens
Journal: HemaSphere (2018)

Abstract Hematopoiesis is one of the best studied adult stem‐cell systems, with a differentiation hierarchy progressing from immature hematopoietic stem cells to over 10 distinct mature cell types. Recent technological breakthroughs now make it possible to define transcriptional profiles in thousands of individual cells. Facilitated by the wealth of prior data on cell purification and analysis strategies, hematopoiesis has been one of the earliest experimental systems to which many of these new single‐cell sequencing technologies have been applied. In this review, the authors focus on recent studies, which have shed light on heterogeneity within individual populations as well as the relationships between populations, and also attempt to characterize the differences between normal and disease/perturbed states.
Sox7 promotes high-grade glioma by increasing VEGFR2-mediated vascular abnormality
Authors: Il-Kug Kim, Kangsan Kim, Eunhyeong Lee, Dong Sun Oh, Chan Soon Park, Seongyeol Park, Jee Myung Yang, Ju-Hee Kim, Hyung-Seok Kim, David T. Shima, Jeong Hoon Kim, Seok Ho Hong, Young Hyun Cho, Young Hoon Kim, Jong Bae Park, Gou Young Koh, Young Seok Ju, Heung Kyu Lee, Seungjoo Lee, Injune Kim
Journal: The Journal of Experimental Medicine (2018)

High-grade glioma (HGG) is highly angiogenic, but antiangiogenic therapy has transient clinical benefit in only a fraction of patients. Vascular regulators of these heterogeneous responses remain undetermined. We found up-regulation of Sox7 and down-regulation of Sox17 in tumor endothelial cells (tECs) in mouse HGG. Sox7 deletion suppressed VEGFR2 expression, vascular abnormality, hypoxia-driven invasion, regulatory T cell infiltration, and tumor growth. Conversely, Sox17 deletion exacerbated these phenotypes by up-regulating Sox7 in tECs. Anti-VEGFR2 antibody treatment delayed tumor growth by normalizing Sox17-deficient abnormal vessels with high Sox7 levels but promoted it by regressing Sox7-deficient vessels, recapitulating variable therapeutic responses to antiangiogenic therapy in HGG patients. Our findings establish that Sox7 promotes tumor growth via vessel abnormalization, and its level determines the therapeutic outcome of VEGFR2 inhibition in HGG. In 189 HGG patients, Sox7 expression was heterogeneous in tumor vessels, and high Sox7 levels correlated with poor survival, early recurrence, and impaired vascular function, emphasizing the clinical relevance of Sox7 in HGG.
NHS launches national Leadership Academy
Authors: Helen Jaques
Journal: BMJ (2012)

The NHS has launched a national centre designed to produce and inspire current and future generations of NHS leaders. 

The NHS Leadership Academy, first announced by the health secretary for England, Andrew Lansley, in July last year ( BMJ Careers , 12 Jul 2011, http://careers.bmj.com/careers/advice/view-article.html?id=20003742), will help develop outstanding leaders (whether doctors, managers, or others) to improve patients’ experiences, health outcomes, and wellbeing.

The new academy in Leeds will …
Barriers to and Facilitators of Implementing Enhanced Recovery Pathways Using an Implementation Framework
Authors: Alexander B. Stone, Christina T. Yuan, Michael A. Rosen, Michael C. Grant, Lauren E. Benishek, Elizabeth Hanahan, Lisa H. Lubomski, Clifford Ko, Elizabeth C. Wick
Journal: JAMA Surgery (2018)

<h3>Importance</h3> Enhanced recovery pathways (ERPs) have the potential to reduce length of hospital stay, costs, and complications following surgery but can be challenging to implement. <h3>Objective</h3> To examine the body of literature on ERPs to assess how authors describe barriers and facilitators of ERP implementation and identify, in aggregate, the best practices that should be considered utilizing the Consolidated Framework for Implementation Research (CFIR) to extract these elements and summarize common barriers and facilitators according to its 5 major domains: (1) intervention characteristics, (2) inner setting, (3) outer setting, (4) characteristics of the individuals, and (5) the process of implementation. <h3>Evidence Review</h3> A systematic review was conducted in accordance with the PRISMA statement. An ERP was defined as a bundle of multiple perioperative interventions that involve a multidisciplinary team, had a label different than traditional care, and had a formal way of measuring outcomes. Six databases (PubMed, MEDLINE, Cumulative Index to Nursing and Allied Health Literature Complete, Web of Science, PsychINFO, and Cochrane Central Register of Controlled Trials) of articles published from 1990 to November 30, 2016, were searched. Articles that were included had to address barriers and facilitators of ERP implementation and provide sufficient detail that the CFIR domain could be identified. Data were abstracted by 2 independent researchers using a standardized extraction form. <h3>Findings</h3> The initial search strategy returned 4563 results; 3883 studies were eliminated by screening titles and abstracts, leaving 680 articles for full-text screening. Of these, 53 studies were included in the review. The key facilitating factors were (1) adapting the program to fit local contexts, (2) achieving and demonstrating early “wins,” (3) gaining buy-in from both frontline clinicians and hospital leadership, (4) having a strong ERP team that met regularly, and (5) leveraging supporters and full-time ERP staff. The major barriers identified were (1) meeting with resistance to change from frontline clinicians, (2) not having enough resources for implementation, and (3) external factors, such as patient complexity or rural hospital location. <h3>Conclusions and Relevance</h3> Most ERP literature focuses on the efficacy, safety, or cost-effectiveness of these protocols. To promote the spread of ERP programs, more high-quality studies on the implementation process are needed.
Over a fifth of doctors report bullying or harassment by managers, NHS staff survey finds
Authors: Abi Rimmer
Journal: BMJ (2015)

Over a fifth (23%) of doctors and dentists have experienced harassment, bullying, or abuse at work from a manager or colleague, the results of the NHS staff survey show.1

A similar proportion (20%) said that they had been harassed or bullied by a patient, a patient’s relative, or a member of the public. Over half (58%) of doctors …
Disruption of Wnt/β-Catenin Exerts Antileukemia Activity and Synergizes with FLT3 Inhibition in <i>FLT3</i>-Mutant Acute Myeloid Leukemia
Authors: Xuejie Jiang, Po Yee Mak, Hong Mu, Wenjing Tao, Duncan H. Mak, Steven Kornblau, Qi Zhang, Peter Ruvolo, Jared K. Burks, Weiguo Zhang, Teresa McQueen, Rongqing Pan, Hongsheng Zhou, Marina Konopleva, Jorge Cortes, Qifa Liu, Michael Andreeff, Bing Z. Carter
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKI) are used clinically to treat FLT3-mutated AML patients, but with limited efficacy. We investigated the antileukemia activity of combined Wnt/β-catenin and FLT3 inhibition in FLT3-mutant AML. Experimental Design: Wnt/β-catenin signaling was inhibited by the β-catenin/CBP antagonist C-82/PRI-724 or siRNAs, and FLT3 signaling by sorafenib or quizartinib. Treatments on apoptosis, cell growth, and cell signaling were assessed in cell lines, patient samples, and in vivo in immunodeficient mice by flow cytometry, Western blot, RT-PCR, and CyTOF. Results: We found significantly higher β-catenin expression in cytogenetically unfavorable and relapsed AML patient samples and in the bone marrow–resident leukemic cells compared with circulating blasts. Disrupting Wnt/β-catenin signaling suppressed AML cell growth, induced apoptosis, abrogated stromal protection, and synergized with TKIs in FLT3-mutated AML cells and stem/progenitor cells in vitro. The aforementioned combinatorial treatment improved survival of AML-xenografted mice in two in vivo models and impaired leukemia cell engraftment. Mechanistically, the combined inhibition of Wnt/β-catenin and FLT3 cooperatively decreased nuclear β-catenin and the levels of c-Myc and other Wnt/β-catenin and FLT3 signaling proteins. Importantly, β-catenin inhibition abrogated the microenvironmental protection afforded the leukemic stem/progenitor cells. Conclusions: Disrupting Wnt/β-catenin signaling exerts potent activities against AML stem/progenitor cells and synergizes with FLT3 inhibition in FLT3-mutant AML. These findings provide a rationale for clinical development of this strategy for treating FLT3-mutated AML patients. Clin Cancer Res; 24(10); 2417–29. ©2018 AACR.