tbuckley/cabot-search huggingface dataset:
I'm finishing at medical school in Greece and I'm interested in studying psychiatry in the United Kingdom. What's the procedure, and is there a hospital or university that is highly recommended?
Authors: Kallur Suresh
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.
NHS needs more generalists not specialists, says Labour
Authors: Abi Rimmer
Journal: BMJ (2014)

The NHS needs more generalists rather than specialists, Labour’s shadow health secretary, Andy Burnham, has said.

Speaking at the BMA’s staff, associate specialists, and specialty (SAS) doctors conference on Tuesday 3 June, Burnham said that there needed to be a focus on “whole person care” in the NHS of the future. “For all its great strengths, I would argue that the NHS isn’t ready to face up to the challenges of 21st century care,” he said. “I believe it’s trapped in a 20th …
Early results of lower-dose dasatinib, 50 mg daily, in newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase.
Authors: Kiran Naqvi, Jorge E. Cortes, Jeffrey A Skinner, Elias Jabbour, Naveen Pemmaraju, Gautam Borthakur, Zeev Estrov, Prithviraj Bose, Philip A. Thompson, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2017)

e18551 Background: Dasatinib, a potent BCR-ABL tyrosine kinase inhibitor (TKI), is approved for the treatment of chronic phase CML (CML-CP) in the frontline and salvage settings. The approved dose in chronic phase is 100mg orally daily. Notable side effects include pleural effusions and myelosuppression.We evaluated the efficacy and toxicity profile of dasatinib 50mg orally daily in patients with newly diagnosed CML-CP. Methods: Adults with newly diagnosed CML-CP were eligible. Prior TKI therapy for up to 1 month was allowed. Eligibility criteria were standard. Patients received dasatinib 50mg daily. Responses were defined according to the European LeukemiaNet guidelines (Baccarani et al. Blood 2013 122:872-884). Results: From March 2016 until January 2017, 30 patients were enrolled. Median age was 47 years (22 to 84). Sokal risk was low in 17 patients, intermediate in 10, and high in 3. Response data are shown below. Among 7 patients not in CCyR at 3 months by FISH (% FISH + 3, 3.5, 4.5, 5.5, 7, 9 and 83%), the respective BCR-ABL transcripts (IS) were 0.49, 0.08, 0.1, 0.09, 0.60, 0.69 and 9.2%. Thus, 6/7 patients with FISH + disease at 3 months had BCR-ABL transcripts (IS) &lt; 1%, and 17/18 patients evaluable at 3 months had BCR-ABL transcripts (IS) &lt; 1% (equivalent to CCyR). Significant myelosuppression requiring treatment interruption occurred in only 1 patient. No patients so far had pleural effusions requiring intervention. To date, there have been no dose modifications. Conclusions: Dasatinib 50mg daily is active and well-tolerated in newly diagnosed CML-CP. It should be further explored as a new potential dose-schedule standard-of-care in CML. [Table: see text]
Medicology foundation course in leadership and management for foundation year doctors
Authors: Joy Chang
Journal: BMJ (2009)

This course is aimed at foundation year doctors and early specialty trainees who want to gain a further understanding of leadership and management and improve their skills in these areas. A separate course is available for senior doctors.

At the beginning of my foundation year 2 on 26 October 2008.

As a foundation programme trainee with specialty applications looming I wanted to build on my weaker points such as leadership skills. I attended the course to expand my knowledge, understanding, and skills in leadership and management. At medical school I was not exposed to these topics or given any talks on them. I felt that it was important as a practising doctor to know how to apply these …
Pazopanib with low fat meal (PALM) in advanced renal cell carcinoma (RCC).
Authors: Melissa Andrea Reimers, Stephanie Daignault, Maryann Shango, Rachel Dedinsky, Liam Riddle, Bo Wen, Bruce G. Redman, Ajjai Shivaram Alva
Journal: Journal of Clinical Oncology (2018)

683 Background: Pazopanib, a highly lipophilic standard first-line therapy for metastatic RCC, is conventionally taken in a fasting state but has significant gastrointestinal toxicities and 96% of ingested drug is fecally excreted, with major financial implications. Single dose studies with fat meals suggested bioavailability is increased two-fold. We sought to evaluate toxicity/safety, bioavailability and anti-tumor efficacy of daily pazopanib taken with a low fat meal over 12 weeks. Methods: Enrolled pts had unresectable locally advanced or metastatic RCC with clear cell component, RECIST 1.1 measurable disease, ECOG PS ≤2, adequate organ function, and up to 3 prior therapies including VEGF(R) and checkpoint inhibitors. Subjects took pazopanib, starting dose of 400 mg, once daily with low-fat meal ( &lt; 400 cal with &lt; 20% fat/10 g of fat) in 2 wk cycles with MD discretion to dose-escalate q2wks up to 800 mg or irreversibly dose-reduce as low as 200 mg based on tolerance/toxicity for 12 wks. Baseline and end of study echocardiograms, and triplicate ECGs at each cycle start were monitored. Home pill diaries were collected. PK was analyzed in the first 3 cycles. Results: Sixteen pts were accrued: median age 60 (range: 47 – 75),75% men,11 were ECOG PS 0. Most (12/16) subjects with no prior therapy, 13/16 had intermittent Heng risk criteria, 3 favorable; 5 sarcomatoid component. Diet compliance by pill diary was outstanding, except for 1 pt for 1 cycle. Calculated mean daily dose was 535 mg (153-750 mg). Therapy was well tolerated; 5 Grade 3 AEs (1 HTN, 1 chest pain, 2 AST/ALT elevations, 1 Abd pain) occurred. LVEF declined by &gt; 15% in 3 pts but none to &lt; 50%. QTc prolongation &gt; 450 ms did not occur. All but 3 pts completed protocol (off d/t toxicity-HTN, LFTs, chest pain). ORR was PR 5 (31%); SD 7 (44%). PK data and pharmacogenomics CYP3A4 polymorphism data correlated with toxicity. Conclusions: Pazopanib taken with a low fat meal appears to be better tolerated compared to published data on empty stomach administration, especially with fewer GI toxicities, including diarrhea. It also resulted in comparable efficacy with fewer cumulative pills over the 12-week period, with substantial cost implications. Larger trials of pazopanib with low fat meal are warranted. Clinical trial information: NCT02729194.
Long-term Air Pollution Exposure, Genome-wide DNA Methylation and Lung Function in the LifeLines Cohort Study
Authors: Ana Julia de F.C. Lichtenfels, Diana A. van der Plaat, Kim de Jong, Cleo C. van Diemen, Dirkje S. Postma, Ivana Nedeljkovic, Cornelia M. van Duijn, Najaf Amin, Sacha la Bastide-van Gemert, Maaike de Vries, Cavin K. Ward-Caviness, Kathrin Wolf, Melanie Waldenberger, Annette Peters, Ronald P. Stolk, Bert Brunekreef, H. Marike Boezen, Judith M. Vonk
Journal: Environmental Health Perspectives (2018)

Background: Long-term air pollution exposure is negatively associated with lung function, yet the mechanisms underlying this association are not fully clear. Differential DNA methylation may explain this association. Objectives: Our main aim was to study the association between long-term air pollution exposure and DNA methylation. Methods: We performed a genome-wide methylation study using robust linear regression models in 1,017 subjects from the LifeLines cohort study to analyze the association between exposure to nitrogen dioxide ( NO2) and particulate matter ( PM2.5, fine particulate matter with aerodynamic diameter ≤2.5μm; PM10, particulate matter with aerodynamic diameter ≤10μm) and PM2.5absorbance, indicator of elemental carbon content (estimated with land-use-regression models) with DNA methylation in whole blood (Illumina® HumanMethylation450K BeadChip). Replication of the top hits was attempted in two independent samples from the population-based Cooperative Health Research in the Region of Augsburg studies (KORA). Results: Depending on the p-value threshold used, we found significant associations between NO2 exposure and DNA methylation for seven CpG sites (Bonferroni corrected threshold p<1.19×10−7) or for 4,980 CpG sites (False Discovery Rate<0.05). The top associated CpG site was annotated to the PSMB9 gene (i.e., cg04908668). None of the seven Bonferroni significant CpG-sites were significantly replicated in the two KORA-cohorts. No associations were found for PM exposure. Conclusions: Long-term NO2 exposure was genome-wide significantly associated with DNA methylation in the identification cohort but not in the replication cohort. Future studies are needed to further elucidate the potential mechanisms underlying NO2-exposure–related respiratory disease. https://doi.org/10.1289/EHP2045
Truncated Glioma-Associated Oncogene Homolog 1 (tGLI1) Mediates Mesenchymal Glioblastoma via Transcriptional Activation of CD44
Authors: Tadas K. Rimkus, Richard L. Carpenter, Sherona Sirkisoon, Dongqin Zhu, Boris C. Pasche, Michael D. Chan, Glenn J. Lesser, Stephen B. Tatter, Kounosuke Watabe, Waldemar Debinski, Hui-Wen Lo
Journal: Cancer Research (2018)

Abstract The molecular pathways driving mesenchymal glioblastoma (GBM) are still not well understood. We report here that truncated glioma-associated oncogene homolog 1 (tGLI1) is a tumor-specific transcription factor that facilitates GBM growth, is enriched in the mesenchymal subtype of GBM and glioma stem cells (GSC), and promotes mesenchymal GSC by upregulating transcription of CD44. In an orthotopic GBM xenograft mouse model, tGLI1-overexpressing tumors grew more aggressively with increased proliferation and angiogenesis compared with control and GLI1-overexpressing xenografts. tGLI1 was highly expressed in GBM clinical specimens but undetectable in normal brains, whereas GLI1 was expressed in both tissues. A tGLI1 activation signature (tGAS) correlated with glioma grade, tumor angiogenesis, and poor overall survival, and GBMs with high tGAS were enriched with mesenchymal GBM/GSC gene signatures. Neurospheres contained increased levels of tGLI1, but not GLI1, compared with the monolayer culture; mesenchymal GSC expressed more tGLI1 than proneural GSC. Ectopic tGLI1 expression enhanced the ability of mesenchymal GSC to yield neurospheres in vitro and to form tumors in mouse brains. Selective tGLI1 knockdown reduced neurosphere formation of GBM cells. tGLI1 bound to and transactivated the promoter of the CD44 gene, a marker and mediator for mesenchymal GSC, leading to its expression. Collectively, these findings advance our understanding of GBM biology by establishing tGLI1 as a novel transcriptional activator of CD44 and a novel mediator of mesenchymal GBM and GSC. Significance: These findings highlight the role of a tumor-specific gain-of-function transcription factor tGLI1 in mesenchymal glioma stem cell maintenance and mesenchymal GBM growth. Cancer Res; 78(10); 2589–600. ©2018 AACR.
PREDICTION OF CARDIAC MECHANICAL RELAXATION ABNORMALITIES FROM SURFACE ECG WAVELETS: REPLICATION IN TWO COHORTS
Authors: Marton Tokodi, Hemant Kulkarni, Lan Hu, Ali Hama Amin, Muhammad Ashraf, Grace Casaclang-Verzosa, Partho P. Sengupta
Journal: Journal of the American College of Cardiology (2018)
When Do α-Synucleinopathies Start? An Epidemiological Timeline
Authors: Rodolfo Savica, Bradley F. Boeve, Michelle M. Mielke
Journal: JAMA Neurology (2018)

This article reviews the epidemiological evidence of features of α-synucleinopathies that precede clinical onset of disease, proposes a clinical timeline, and attempts to define the different premotor and clinical phenotypes associated with α-synucleinopathies.The pathological hallmarks of the α-synucleinopathies (Parkinson disease, Parkinson disease dementia, dementia with Lewy bodies, and multisystem atrophy) begin years before a clinical diagnosis. Epidemiologic studies support the long gap between pathology and symptoms and suggest that certain nonmotor conditions (constipation, anxiety, and rapid eye movement sleep behavior disorder) precede the traditional motor Parkinson disease phenotype by long intervals.Characterizing the temporal onset of these conditions will help to better recognize the premotor phase of the α-synucleinopathies and specific clinical phenotypes and will guide the search for predictive biomarkers and risk or protective factors for Parkinson disease and other synucleinopathies.
LEFT ATRIAL ABNORMAL MECHANICS BY CARDIAC MAGNTIC RESONANCE FEATURE TRACKING AS AN EARLY SUBCLINICAL MANIFESTATION IN PATIENTS WITH SYSTEMIC SCLEROSIS
Authors: Ana G. Almeida, Gustavo Lima Silva, Rui Plácido, Ana Rita Francisco, Tatiana Guimaraes, Claudio David, Fausto Pinto
Journal: Journal of the American College of Cardiology (2018)
CLCN2 chloride channel mutations in familial hyperaldosteronism type II
Authors: Ute I. Scholl, Gabriel Stölting, Julia Schewe, Anne Thiel, Hua Tan, Carol Nelson-Williams, Alfred A. Vichot, Sheng Chih Jin, Erin Loring, Verena Untiet, Taekyeong Yoo, Jungmin Choi, Shengxin Xu, Aihua Wu, Marieluise Kirchner, Philipp Mertins, Lars C. Rump, Ali Mirza Onder, Cory Gamble, Daniel McKenney, Robert W. Lash, Deborah P. Jones, Gary Chune, Priscila Gagliardi, Murim Choi, Richard Gordon, Michael Stowasser, Christoph Fahlke, Richard P. Lifton
Journal: Nature Genetics (2018)
CYP2C19 GENOTYPE ETHNIC AND GENDER DISTRIBUTION FOR A TREATMENT-BASED COHORT RECEIVING CLOPIDOGREL AFTER PCI IN THE UPPER MIDWEST
Authors: Maheedhar Gedela, Filip Oleszak, Shenjing Li, Udit Bhatnagar, Jeffrey Wilson, Chirag Desai, Paul Thompson, Russell Wilke, Adam Stys, Tomasz Stys
Journal: Journal of the American College of Cardiology (2018)
Clinical experience with 100 consecutive patients treated with Lu-177-labeled PSMA-I&amp;T radioligand therapy for metastatic castration-resistant prostate cancer.
Authors: Matthias Michael Heck, Sebastian Schwaiger, Karina Knorr, Margitta Retz, Tobias Maurer, Friederike Janssen, Calogero D´Alessandria, Hans-Juergen Wester, Juergen E. Gschwend, Markus Schwaiger, Robert Tauber, Matthias Eiber
Journal: Journal of Clinical Oncology (2018)

206 Background: To report our clinical experience with 177 Lutetium-labeled prostate-specific membrane antigen-ligand ( 177 Lu-PSMA-I&amp;T) for systemic radioligand therapy in 100 consecutive patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: All patients were treated under a review board-approved compassionate use protocol. Eligibility criteria for 177 Lu-PSMA-I&amp;T therapy included previous treatment with abiraterone or enzalutamide, previous taxane-based chemotherapy or unsuitability for taxanes as well as positive 68 Ga-PSMA tracer uptake of metastases in a prior PET-scan. Intravenous treatment with 177 Lu-PSMA-I&amp;T was given 6- to 8-weekly with an activity of 7.4GBq up to 6 cycles in patients without clinical or radiographic progression. We report prostate-specific antigen (PSA) decline, PSA progression-free survival (PSA-PFS), clinical progression-free survival (cPFS) and overall survival (OS) as well as toxicity. Results: Median age was 72 years (range 46-85) and median PSA level was 164 ng/ml (range 0-6178). Bone, lymph node and visceral metastases were present in 94%, 85% and 33% of patients, respectively. The median number of previous treatment regimens for mCRPC was 3 (range 1-6) and 84% of patients were pretreated with chemotherapy. At the time of evaluation, 286 cycles with 177 Lu-PSMA-I&amp;T were applied (median 2 cycles per patient, range 1-6), while treatment was still ongoing in 27% of patients. Overall, 4 and 6 cycles were applied in 33 and 15 patients, respectively. PSA decline ≥30%, ≥50% and ≥90% was achieved in 40%, 32% and 9% of patients, respectively. Median PSA-PFS was 3.4 months (95%CI 2.7-4.0), median cPFS was 4.1 months (95%CI 2.5-5.7) and median OS was 12.2 months (95%CI 8.8-15.7). Treatment-emergent hematologic grade 3/4 toxicities were anemia in 7%, thrombocytopenia in 5% and neutropenia in 4% of patients. Grade 3/4-non-hematologic toxicities were not observed. The main non-hematologic grade 1/2 toxicities were dry mouth in 18%, fatigue in 16% and loss of appetite in 9/% of patients. Conclusions: Radioligand therapy with 177 Lu-PSMA I&amp;T appears to be safe and active in late-stage mCRPC.
Metabolic Changes in Central Poststroke Pain Following Thalamic Intracerebral Hemorrhage
Authors: Na Young Kim, Sang Chul Lee, Young-sil An, Ji-Cheol Shin, Yong Wook Kim
Journal: Clinical Nuclear Medicine (2018)

Central poststroke pain (CPSP) is one of the most refractory neuropathic pains following stroke. Injury in the spinothalamic pathway appears crucial for the development of CPSP, but changes in activity in multiple brain regions may also be related. We investigated brain metabolic changes in patients with CPSP following thalamic intracerebral hemorrhage (ICH).Forty-three patients with thalamic ICH were examined. Overall brain metabolism was measured with F-FDG PET. Images were analyzed with statistical parametric mapping (SPM12). Patients with CPSP (n = 20) were compared with patients without CPSP (n = 23). In addition, the association between regional brain metabolism and the severity of CPSP was investigated.In comparison to patients in the non-CPSP group, the CPSP group exhibited significant hypometabolism in the ipsilesional precentral, postcentral gyri, and the contralesional cuneus (Puncorrected < 0.001), whereas significant hypermetabolism was found in the medial dorsal nucleus of the contralesional thalamus (Puncorrected < 0.001). In addition, brain metabolism in the ipsilesional Crus I and Crus II of the cerebellum was positively correlated to pain intensity ratings (Puncorrected < 0.001).Our findings suggested that an altered state of resting brain metabolism in various brain regions related to sensory processing and cognitive functioning may be involved in the underlying mechanism of CPSP following thalamic ICH.
Comment on Lent et al. All-Cause and Specific-Cause Mortality Risk After Roux-en-Y Gastric Bypass in Patients With and Without Diabetes. Diabetes Care 2017;40:1379–1385
Authors: Antonio E. Pontiroli, Ahmed S. Zakaria
Journal: Diabetes Care (2018)

Lent et al. (1) report on mortality in patients with and without diabetes undergoing gastric bypass or medical treatment. After a mean follow-up period of 5.8 years, they show that the benefit of gastric bypass versus medical treatment is confined to patients with diabetes.

A few articles, analyzed in a meta-analysis by our group (2), have shown that long-term mortality is reduced with bariatric surgery in comparison with nonsurgical treatment; these studies …
A novel T-cell bispecific antibody platform for efficient T-cell mediated killing of tumor cells with minimal cytokine release.
Authors: Udaya Rangaswamy, Andrew Boudreau, Ben Buelow, Starlynn Clarke, Kevin Dang, Laura Davison, Shelley Force Aldred, Katherine Harris, Suhasini Iyer, Brett Jorgensen, Heather Ogana, Duy Pham, Payal Pratap, Nathan Trinklein, Ute Schellenberger, Harshad Ugamraj, Omid Vafa, Wim Van Schooten
Journal: Journal of Clinical Oncology (2018)

209 Background: Bispecific antibodies that recruit cytotoxic T cells to kill tumor cells are popular due to their targeted mechanism of action. Despite their attractiveness, there are limitations in the clinic due to undesirable toxicities associated with cytokine release. We describe here a platform for generation of a large collection of human anti-CD3 antibodies obtained from custom transgenic rats. Combining these unique anti-CD3 arms with different tumor targeting arms enables creation of bispecific antibodies of varying tumor cell killing capability. These anti-CD3 arms were combined with tumor antigen binding arms, namely, an anti-BCMA arm for multiple myeloma therapy, or an anti-CD22 arm for B-cell acute lymphoblastic leukemia therapy. Methods: Our platform utilizes a discovery approach involving antibody repertoire deep sequencing, high-throughput gene assembly, and recombinant expression, generating a highly diverse panel of antibodies with varying affinities. The CD3 antibodies were tested in in vitro T cell assays using human PBMCs to measure activation and cytokine release. Bispecific antibodies were evaluated for their ability to kill target cell lines upon co-culture with primary human PBMCs. The in vivo efficacy of bispecific antibodies was evaluated in a xenograft mouse model. Results: The in vitro T cell activity of these antibodies as measured by interleukin-2, interferon gamma levels and upregulation of the activation marker CD69 covered a broad spectrum of EC50 values. In co-culture systems with human PBMCs, anti-BCMA or anti-CD22 bispecific antibodies potently killed their respective target expressing cells with varying strengths. Additionally, the cytokine release from T cell activation correlated with the affinity of the anti-CD3 arms. The in vivo efficacy of the bispecific antibodies in a xenograft model with human PBMCs transferred into NSG mice showed striking tumor clearance at a wide range of doses. Conclusions: Our platform is highly suitable for creation of an extensive collection of bispecific antibodies for a variety of disease models by selecting the ideal anti-CD3 arm for each unique tumor antigen binding arm.
M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in Asian patients with pretreated recurrent or refractory gastric cancer: Preliminary results from a phase I trial.
Authors: Yoon-Koo Kang, Toshihiko Doi, Shunsuke Kondo, Hyun-Choel Chung, Kei Muro, Christoph Helwig, Morihiro Watanabe, Yung-Jue Bang
Journal: Journal of Clinical Oncology (2018)

100 Background: Inhibiting the transforming growth factor β (TGF-β) pathway, which plays a key role in tumor immunosuppression, may enhance the response to programmed death 1/programmed death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs). M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, which serves as a TGF-β “trap.” We report preliminary results in Asian patients with heavily pretreated gastric cancer. Methods: In this expansion cohort of the ongoing, phase 1, open-label trial NCT02699515, patients with recurrent or refractory unresectable stage IV gastric or gastroesophageal junction adenocarcinoma for which no standard therapy exists or standard therapy has failed receive M7824 1200 mg q2w until confirmed progressive disease, unacceptable toxicity or trial withdrawal. The primary objective is safety; secondary objectives include best overall response (BOR) per RECIST v1.1. Results: As of 6 September 2017, 31 heavily pretreated patients with advanced gastric cancer (67.7% received ≥3 prior anticancer therapies) received M7824 for a median duration of 6.1 (range: 2-30) weeks (median number of M7824 infusions: 3 [range: 1-13]); 8 patients remained on treatment. Four patients (12.9%) experienced grade 3 treatment-related adverse events (anemia and diarrhea 1 each and 2 rash). No treatment-related grade 4 AEs occurred. One grade 5 event (total 5 doses received) was considered possibly treatment related, but suspected rupture of preexisting thoracic aortic aneurysm was cited as other probable cause by the investigator. There were 5 confirmed partial responses (4 ongoing after 4-6 months of follow-up) based on investigator assessment of BOR (overall response rate: 16.1%). This is an ongoing study; updated data will be presented. Conclusions: These preliminary data show that M7824 resulted in a manageable safety profile in heavily pretreated Asian patients with gastric cancer. Early signs of clinical efficacy are encouraging. Clinical trial information: NCT02699515.