tbuckley/cabot-search huggingface dataset:
Altered density, composition and microanatomical distribution of infiltrating immune cells in cutaneous squamous cell carcinoma of organ transplant recipients
Authors: S.B. Strobel, K. Safferling, B. Lahrmann, J.H. Hoffmann, A.H. Enk, E.N. Hadaschik, N. Grabe, A.S. Lonsdorf
Journal: British Journal of Dermatology (2018)

The inflammatory tumour microenvironment is crucial for effective tumour control, and long-term immunosuppression has been identified as a major risk factor for skin carcinogenesis. In solid organ transplant recipients (OTRs) undergoing long-term pharmacological immunosuppression, an increased incidence of cutaneous squamous cell carcinoma (SCC) and more aggressive tumour growth compared with immunocompetent patients has been reported.To determine the density and phenotype of immune cells infiltrating SCC and surrounding skin in OTRs, and to characterize the microanatomical distribution patterns in comparison with immunocompetent patients.We analysed immune cell infiltrates within SCC and at defined regions of interest (ROIs) of tumour-surrounding skin in formalin-fixed paraffin-embedded tissue of 20 renal transplant patients and 18 carefully matched immunocompetent patients by high-resolution semiautomated microscopy on complete tissue sections stained for CD4, CD8, CD20 and CD68.The overall immune cell density of SCC arising in OTRs was significantly reduced compared with immunocompetent patients. Particularly CD4+ infiltrates at the directly invasive margin and tumour vicinity, intratumoral CD8+ T-cell densities and the overall density of CD20+ tumour-infiltrating B cells were significantly reduced in the tissue of OTRs.Immune cell infiltrates within SCC and at defined ROIs of tumour-surrounding skin in OTRs differ markedly in their composition and microanatomical distribution compared with tumours arising in immunocompetent patients. Our findings substantially broaden the understanding of how long-term systemic immunosuppression modulates the local inflammatory microenvironment in the skin and at the site of invasive SCC.
I am a specialist registrar 2 in anaesthetics preparing for the final exam for FRCA. However, I am considering a career change to general practice. Is it possible to be a GP with a special interest in anaesthetics and continue to do sessions in anaesthetics part time? How important is it to have the FRCA if I wish to do this?
Authors: Leyla Sanai
Journal: BMJ (2005)

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 (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.
Constitutive STAT3 phosphorylation and IL-6/IL-10 co-expression are associated with impaired T-cell function in tuberculosis patients
Authors: Kirstin Harling, Ernest Adankwah, Alptekin Güler, Anthony Afum-Adjei Awuah, Louis Adu-Amoah, Ertan Mayatepek, Ellis Owusu-Dabo, Norman Nausch, Marc Jacobsen
Journal: Cellular and Molecular Immunology (2018)
Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma
Authors: Angel C. Y. Mak, Marquitta J. White, Walter L. Eckalbar, Zachary A. Szpiech, Sam S. Oh, Maria Pino-Yanes, Donglei Hu, Pagé Goddard, Scott Huntsman, Joshua Galanter, Ann Chen Wu, Blanca E. Himes, Soren Germer, Julia M. Vogel, Karen L. Bunting, Celeste Eng, Sandra Salazar, Kevin L. Keys, Jennifer Liberto, Thomas J. Nuckton, Thomas A. Nguyen, Dara G. Torgerson, Pui-Yan Kwok, Albert M. Levin, Juan C. Celedón, Erick Forno, Hakon Hakonarson, Patrick M. Sleiman, Amber Dahlin, Kelan G. Tantisira, Scott T. Weiss, Denise Serebrisky, Emerita Brigino-Buenaventura, Harold J. Farber, Kelley Meade, Michael A. Lenoir, Pedro C. Avila, Saunak Sen, Shannon M. Thyne, William Rodriguez-Cintron, Cheryl A. Winkler, Andrés Moreno-Estrada, Karla Sandoval, Jose R. Rodriguez-Santana, Rajesh Kumar, L. Keoki Williams, Nadav Ahituv, Elad Ziv, Max A. Seibold, Robert B. Darnell, Noah Zaitlen, Ryan D. Hernandez, Esteban G. Burchard
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response.Objectives: To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children.Methods: We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR.Measurements and Main Results: We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 × 10−7) and suggestive (P < 7.06 × 10−6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings.Conclusions: The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.
Preclinical analysis of sodium valproate for the treatment of pediatric diffuse intrinsic pontine glioma and adult glioblastoma
Authors: Clare Killick-Cole, Ali Bienemann, Will Singleton, Marcella Wyatt, Daniel Asby, Lisa Boulter, Harry Haynes, Neil Barua, Steven Gill
Journal: Neuro-Oncology (2018)

Epigenetic dysregulation is evident in high grade glioma, particularly diffuse intrinsic pontine glioma (DIPG), which often present with histone mutations and 46% of adult glioblastomas (GBM) harbour at least one mutation of an epigenetic regulator. Cell viability assays were used to investigate the effects of sodium valproate (VPA) on five ex vivo DIPG cell lines, three commercial glioblastoma cell lines and two ex vivo GBM cell lines and determine the IC50 dose. Cytotoxic IC50s range from 1.8-10mM after a 72 hour drug exposure. To examine the mechanism of cell death caused by VPA, Annexin V and 7-AAD positivity was analysed by flow cytometry. In DIPG cells, sodium valproate induced apoptosis, further confirmed by the presence of cleaved caspase 3 and PARP as determined by western blotting. Clonogenic capacity of glioma cells post VPA treatment was assessed by colony formation assays using one GBM and one DIPG cell line. According to published data, 15% of VPA serum levels can be achieved in the brain by systemic delivery. Therefore, to achieve significant glioma cytotoxicity clinically, other methods of drug delivery may be required. As such, ongoing preclinical in vivo work is underway to assess the effects of VPA when delivered directly to the brain of Wistar rats by convection enhanced delivery (CED). To summarise, the histone deacetylase inhibitor sodium valproate, causes glioma cytotoxicity in both pediatric DIPG cells and adult glioblastoma stem cell lines in vitro. DIPG cell death was a result of apoptosis and VPA reduced the long-term proliferation of both DIPG and GBM cells. Initial, in vivo work has demonstrated that VPA can feasibly be delivered by CED to the brain of Wistar rats at high concentration. Further work is needed to determine the efficacy of sodium valproate when delivered by CED to a relevant orthotopic glioma model.
Health-related quality of life in lower-risk MDS patients compared with age- and sex-matched reference populations: a European LeukemiaNet study
Authors: Reinhard Stauder, Ge Yu, Karin A. Koinig, Tim Bagguley, Pierre Fenaux, Argiris Symeonidis, Guillermo Sanz, Jaroslav Cermak, Moshe Mittelman, Eva Hellström-Lindberg, Saskia Langemeijer, Mette Skov Holm, Krzysztof Mądry, Luca Malcovati, Aurelia Tatic, Ulrich Germing, Aleksandar Savic, Corine van Marrewijk, Agnès Guerci-Bresler, Elisa Luño, Jackie Droste, Fabio Efficace, Alex Smith, David Bowen, Theo de Witte
Journal: Leukemia (2018)

In myelodysplastic syndromes (MDS), health-related quality of life (HRQoL) represents a relevant patient-reported outcome, which is essential in individualized therapy planning. Prospective data on HRQoL in lower-risk MDS remain rare. We assessed HRQOL by EQ-5D questionnaire at initial diagnosis in 1690 consecutive IPSS-Low/Int-1 MDS patients from the European LeukemiaNet Registry. Impairments were compared with age- and sex-matched EuroQol Group norms. A significant proportion of MDS patients reported moderate/severe problems in the dimensions pain/discomfort (49.5%), mobility (41.0%), anxiety/depression (37.9%), and usual activities (36.1%). Limitations in mobility, self-care, usual activities, pain/discomfort, and EQ-VAS were significantly more frequent in the old, in females, and in those with high co-morbidity burden, low haemoglobin levels, or red blood cells transfusion need (p < 0.001). In comparison to age- and sex-matched peers, the proportion of problems in usual activities and anxiety/depression was significantly higher in MDS patients (p < 0.001). MDS-related restrictions in the dimension mobility were most prominent in males, and in older people (p < 0.001); in anxiety/depression in females and in younger people (p < 0.001); and in EQ-VAS in women and in persons older than 75 years (p < 0.05). Patients newly diagnosed with IPSS lower-risk MDS experience a pronounced reduction in HRQoL and a clustering of restrictions in distinct dimensions of HRQoL as compared with reference populations.
Changes in Health Insurance Coverage Under the Affordable Care Act: A National Sample of U.S. Adults With Diabetes, 2009 and 2016
Authors: Sarah S. Casagrande, Laura N. McEwen, William H. Herman
Journal: Diabetes Care (2018)

OBJECTIVE To assess national changes in health insurance coverage and related costs before and after implementation of the Affordable Care Act (ACA) among U.S. adults with diabetes. RESEARCH DESIGN AND METHODS Data were cross-sectional from the 2009 and 2016 National Health Interview Surveys (NHIS). Participants were adults age ≥18 years with a previous diagnosis of diabetes who self-reported on their health insurance coverage, demographic information, diabetes-related factors, and amount spent on medical expenses and insurance premiums (N = 6,220). RESULTS Among adults with diabetes age 18–64 years, health insurance coverage increased from 84.7% in 2009 to 90.1% in 2016 (P &amp;lt; 0.001). Coverage remained near universal for those age ≥65 years (99.5%). For adults age 18–64 years, coverage increased for almost all subgroups and significantly for men; non-Hispanic whites, non-Hispanic blacks, and Hispanics; those who were married; those with less than or more than a high school education, family income &amp;lt;$35,000, or diabetes duration &amp;lt;5 or &amp;gt;15 years; and those taking oral agents (P &amp;lt; 0.05 for all). Among adults age 18–64 years, Medicaid coverage significantly increased between 2009 and 2016 (19.4% vs. 24.3%, P = 0.006), and for those with private insurance, 7.8% acquired their plan through HealthCare.gov. For adults age ≥65 years, private insurance decreased and Medicare Part D increased (P &amp;lt; 0.007 for both). Among those age 18–64 years with an income &amp;lt;$35,000, the proportion of income spent on family medical costs decreased (6.3% vs. 4.8% for 2009 vs. 2016, respectively; P = 0.004). CONCLUSIONS Health insurance coverage among adults with diabetes age 18–64 years increased significantly after implementation of the ACA, and medical costs to families decreased among those with lower incomes.
The potential role of γδ T cells after allogeneic HCT for leukemia
Authors: Rupert Handgretinger, Karin Schilbach
Journal: Blood (2018)

Allogeneic hematopoetic stem cell transplantation (HCT) offers an option for patients with hematologic malignancies, in whom conventional standard therapies failed or are not effective enough to cure the disease. Successful HCT can restore functional hematopoiesis and immune function, and the new donor-derived immune system can exert a graft-versus-leukemia (GVL) effect. However, allogenic HCT can also be associated with serious risks for transplantation-related morbidities or mortalities such as graft-versus-host disease (GVHD) or life-threatening infectious complications. GVHD is caused by alloreactive T lymphocytes, which express the αβ T-cell receptor, whereas lymphocytes expressing the γδ T-cell receptor are not alloreactive and do not induce GVHD but can exhibit potent antileukemia and anti-infectious activities. Therefore, γδ T cells are becoming increasingly interesting in allogeneic HCT, and clinical strategies to exploit the full function of these lymphocytes have been and are being developed. Such strategies comprise the in vivo activation of γδ T cells or subsets after HCT by certain drugs or antibodies or the ex vivo expansion and manipulation of either patient-derived or donor-derived γδ T cells and their subsets and the adoptive transfer of the ex vivo-activated lymphocytes. On the basis of the absence of dysregulated alloreactivity, such approaches could induce potent GVL effects in the absence of GVHD. The introduction of large-scale clinical methods to enrich, isolate, expand, and manipulate γδ T cells will facilitate future clinical studies that aim to exploit the full function of these beneficial nonalloreactive lymphocytes.
DOES HIGH DOSE DOXORUBICIN BASED CHEMOTHERAPY INDUCE CARDIOTOXICITY IN PATIENTS WITH SARCOMA? RESULTS FROM A PILOT RETROSPECTIVE STUDY
Authors: Juan Simon Rico Mesa, Maria Arciniegas, Laura B. Garcia Bello, Harika Dasari, Steven I. Robinson, Joerg Herrmann, Randolph S. Marks, Scott H. Okuno, Hector R. Villarraga
Journal: Journal of the American College of Cardiology (2018)
ELECTROANATOMIC GUIDED BIVENTRICULAR IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR IMPLANTATION UTILIZING CARTO 3 AND ENSITE NAVX MAPPING SYSTEMS FOR REDUCTION OF FLOUROSCOPY AND INTRAVENOUS CONTRAST USAGE
Authors: Nicholas Serafini, Parikshit Sharma, Richard Trohman, Henry Huang
Journal: Journal of the American College of Cardiology (2018)
NHS response to vaginal mesh scandal will be reviewed
Authors: Jacqui Wise
Journal: BMJ (2018)

The government has announced a nine month review of how the NHS responded to public concerns over the safety of vaginal mesh implants, the pregnancy test Primodos, and the epilepsy drug sodium valproate.

Jeremy Hunt, England’s health and social care secretary, also announced £1.1m (€1.24m; $1.53m) to develop a prospective registry of all mesh procedures used for treating incontinence and prolapse in women—something the Royal College of Obstetricians and Gynaecologists has been calling for.1

NHS England estimates that more than 100 000 women have had surgery involving mesh and that 3-5% have had complications, but some recent studies have suggested that the true complication rate is much higher.

Speaking in the House of Commons, Hunt admitted that the official response to public health scandals caused by the side effects …
Exercise Therapy and Cardiovascular Toxicity in Cancer
Authors: Jessica M. Scott, Tormod S. Nilsen, Dipti Gupta, Lee W. Jones
Journal: Circulation (2018)

Cardio-oncology is an emerging discipline focused predominantly on the detection and management of cancer treatment–induced cardiac dysfunction (cardiotoxicity), which predisposes to development of overt heart failure or coronary artery disease. The direct adverse consequences, as well as those secondary to anticancer therapeutics, extend beyond the heart, however, to affect the entire cardiovascular-skeletal muscle axis (ie, whole-organism cardiovascular toxicity). The global nature of impairment creates a strong rationale for treatment strategies that augment or preserve global cardiovascular reserve capacity. In noncancer clinical populations, exercise training is an established therapy to improve cardiovascular reserve capacity, leading to concomitant reductions in cardiovascular morbidity and its attendant symptoms. Here, we overview the tolerability and efficacy of exercise on cardiovascular toxicity in adult patients with cancer. We also propose a conceptual research framework to facilitate personalized risk assessment and the development of targeted exercise prescriptions to optimally prevent or manage cardiovascular toxicity after a cancer diagnosis.
NHS must ensure recruitment of foreign doctors is fair, research paper urges
Authors: Abi Rimmer
Journal: BMJ (2014)

The NHS should ensure that enough is being done to “ensure equity and fairness” when recruiting international medical graduates (IMGs), a research paper has argued.1

Luisa Pettigrew, a general practitioner in London, said that IMGs were more likely than their UK counterparts to face difficulties but that there was “little doubt” that the NHS would be unsustainable without their contribution to the health service. 

Writing in Education for Primary Care she said, “With this in mind the NHS and the institutions that surround it should ask if really enough has been done to ensure equity and fairness …
Over 80% of doctors know a colleague with mental health issues, survey finds
Authors: Abi Rimmer
Journal: BMJ (2016)

More than four in five doctors say that they know another doctor experiencing mental health problems, a survey has found, but over 80% said that they would be reluctant to seek help for themselves.

The survey of 1351 doctors by the Royal Medical Benevolent Fund found that 82% were aware of other doctors with mental health conditions, such as …
Metabolic Determinants of Sensitivity to Phosphatidylinositol 3-Kinase Pathway Inhibitor in Small-Cell Lung Carcinoma
Authors: Hideki Makinoshima, Shigeki Umemura, Ayako Suzuki, Hiroki Nakanishi, Ami Maruyama, Hibiki Udagawa, Sachiyo Mimaki, Shingo Matsumoto, Seiji Niho, Genichiro Ishii, Masahiro Tsuboi, Atsushi Ochiai, Hiroyasu Esumi, Takehiko Sasaki, Koichi Goto, Katsuya Tsuchihara
Journal: Cancer Research (2018)

Abstract Comprehensive genomic analysis has revealed that the PI3K/AKT/mTOR pathway is a feasible therapeutic target in small-cell lung carcinoma (SCLC). However, biomarkers to identify patients likely to benefit from inhibitors of this pathway have not been identified. Here, we show that metabolic features determine sensitivity to the PI3K/mTOR dual inhibitor gedatolisib in SCLC cells. Substantial phosphatidyl lipid analysis revealed that a specific phosphatidylinositol (3,4,5)-trisphosphate (PIP3) subspecies lipid product PIP3 (38:4) is predictive in assessing sensitivity to PI3K/mTOR dual inhibitor. Notably, we found that higher amounts of purine-related aqueous metabolites such as hypoxanthine, which are characteristic of SCLC biology, lead to resistance to PI3K pathway inhibition. In addition, the levels of the mRNA encoding hypoxanthine phosphoribosyl transferase 1, a key component of the purine salvage pathway, differed significantly between SCLC cells sensitive or resistant to gedatolisib. Moreover, complementation with purine metabolites could reverse the vulnerability to targeting of the PI3K pathway in SCLC cells normally sensitive to gedatolisib. These results indicate that the resistance mechanism of PI3K pathway inhibitors is mediated by the activation of the purine salvage pathway, supplying purine resource to nucleotide biosynthesis. Metabolomics is a powerful approach for finding novel therapeutic biomarkers in SCLC treatment. Significance: These findings identify features that determine sensitivity of SCLC to PI3K pathway inhibition and support metabolomics as a tool for finding novel therapeutic biomarkers. Cancer Res; 78(9); 2179–90. ©2018 AACR.
More trainees are raising patient safety concerns
Authors: Abi Rimmer
Journal: BMJ (2013)

The number of trainees raising concerns about patient safety has risen by 12% since last year, the General Medical Council’s national training survey has found.

The GMC’s survey, carried out between March and May 2013, received responses from 52 797 trainee doctors (response rate 97.7%), 2746 of whom (5.2%) raised patient safety concerns. This was an increase of 12% on the 2012 figure of 2444 (4.7%).

Trainees with a primary medical qualification gained in the UK were more likely to raise concerns (5.8% of 42 282) than those with a primary medical qualification from other countries in the European Economic Area (4% of 1940). …
GP who squeezed and stroked girl’s breasts unnecessarily is struck off
Authors: Clare Dyer
Journal: BMJ (2018)

A GP has been ordered to be struck off the UK medical register after a medical practitioners tribunal found that he had stroked and squeezed the breasts of a 16 year old girl during a consultation over her recent missed periods.

Jonathan Raphael, 65, a former England rugby player who captained Northampton Saints, examined first the patient’s abdomen and then her breasts at the consultation in May 2014. Later that day she went to the police, who did …
Competition for foundation places will rise if GMC registration moves to point of graduation, BMA warns
Authors: Abi Rimmer
Journal: BMJ (2014)

Plans to bring full General Medical Council registration forward to the point of graduation will increase the competition for places on the oversubscribed foundation programme, the BMA has warned.

Last year Health Education England (HEE) published proposals to bring full GMC registration forward to the point of graduation. The proposals also included plans to introduce an “enhanced selection process” for the foundation programme, open to applicants from the UK, the European Economic Area, and the rest of the world. 1 In a response to HEE’s proposals, the BMA argued that the plans failed to “resolve the workforce question it was ostensibly intended to address, i.e. oversubscription to the foundation programme.” 2

The association warned that the proposals would increase competition in the foundation programme by increasing the number of graduates who were …
Appropriately Framing Child Health Care Spending
Authors: Kao-Ping Chua, Rena M. Conti, Gary L. Freed
Journal: JAMA (2018)

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