tbuckley/cabot-search huggingface dataset:
Secondary resectability in locally advanced pancreatic cancer (LAPC) after nab-paclitaxel/gemcitabine- versus FOLFIRINOX-based induction chemotherapy: Interim results of a randomized phase II AIO trial (NEOLAP).
Authors: Volker Kunzmann, Uwe Marc Martens, Hana Alguel, Jens T. Siveke, Eray Goekkurt, Uwe Pelzer, Gabriele Margareta Siegler, Elke Hennes, Dirk Waldschmidt, Ralf Jakobs, Peter Ferenczy, Ralph Keller, Stefan Hubert Boeck, Frank Kullmann, Markus Kapp, Christoph Thomas Germer
Journal: Journal of Clinical Oncology (2018)

348 Background: Although there is a strong rationale for downstaging non-resectable pancreatic ductal adenocarcinoma (PDAC) for secondary resections by multi-agent chemotherapy, evidence from prospective randomized studies is missing. Methods: This prospective, randomized, open-label, phase II study aims to assess the activity, safety and feasibility of nab-paclitaxel/gemcitabine (nPG)- and FOLFIRINOX-based induction chemotherapy for patients (pts) with non-resectable PDAC. After two cycles of nPG pts are randomly allocated to receive either two additional cycles of nPG (arm A) or four cycles of FOLFIRINOX (arm B). Secondary resectability is assessed by exploratory laparotomy in all pts with at least stable disease (SD) after induction chemotherapy. The primary endpoint is to compare secondary complete macroscopic resection rates (R0/R1) in both arms. Results: We report the results of a planned interim (futility) analysis for efficacy data after at least 50 patients had completed induction chemotherapy and are evaluable for secondary surgical resection. Of pts who underwent randomization 42 pts were allocated to arm A and 44 pts to arm B, respectively. Disease control rate (DCR) after randomization was 93% in arm A and 89% in arm B. Explorative laparotomy was performed in 55% of randomized pts in arm A and 48% in arm B. Complete macroscopic resection (R0/R1) rate of randomized pts was 24% in arm A and 29% in arm B. For pts who received surgical exploration by laparotomy after completion of induction chemotherapy (n = 44) the complete macroscopic resection (R0/R1) rate was 43% in arm A and 62% in arm B. No new safety signals were identified thus far. Conclusions: nPG- and FOLFIRINOX-based induction chemotherapy approach revealed both effective and feasible in pts with LAPC supporting completion of patient recruitment in this trial. Interim results suggest promising secondary resection rates after multi-agent chemotherapy, especially when secondary resectability is assessed by surgical exploration. Clinical trial information: NCT02125136.
Impact of Bystander Automated External Defibrillator Use on Survival and Functional Outcomes in Shockable Observed Public Cardiac Arrests
Authors: Ross A. Pollack, Siobhan P. Brown, Thomas Rea, Tom Aufderheide, David Barbic, Jason E. Buick, Jim Christenson, Ahamed H. Idris, Jamie Jasti, Michael Kampp, Peter Kudenchuk, Susanne May, Marc Muhr, Graham Nichol, Joseph P. Ornato, George Sopko, Christian Vaillancourt, Laurie Morrison, Myron Weisfeldt
Journal: Circulation (2018)

Background: Survival following out-of-hospital cardiac arrest (OHCA) with shockable rhythms can be improved with early defibrillation. Although shockable OHCA accounts for only ≈25% of overall arrests, ≈60% of public OHCAs are shockable, offering the possibility of restoring thousands of individuals to full recovery with early defibrillation by bystanders. We sought to determine the association of bystander automated external defibrillator use with survival and functional outcomes in shockable observed public OHCA. Methods: From 2011 to 2015, the Resuscitation Outcomes Consortium prospectively collected detailed information on all cardiac arrests at 9 regional centers. The exposures were shock administration by a bystander-applied automated external defibrillator in comparison with initial defibrillation by emergency medical services. The primary outcome measure was discharge with normal or near-normal (favorable) functional status defined as a modified Rankin Score ≤2. Survival to hospital discharge was the secondary outcome measure. Results: Among 49 555 OHCAs, 4115 (8.3%) observed public OHCAs were analyzed, of which 2500 (60.8%) were shockable. A bystander shock was applied in 18.8% of the shockable arrests. Patients shocked by a bystander were significantly more likely to survive to discharge (66.5% versus 43.0%) and be discharged with favorable functional outcome (57.1% versus 32.7%) than patients initially shocked by emergency medical services. After adjusting for known predictors of outcome, the odds ratio associated with a bystander shock was 2.62 (95% confidence interval, 2.07–3.31) for survival to hospital discharge and 2.73 (95% confidence interval, 2.17–3.44) for discharge with favorable functional outcome. The benefit of bystander shock increased progressively as emergency medical services response time became longer. Conclusions: Bystander automated external defibrillator use before emergency medical services arrival in shockable observed public OHCA was associated with better survival and functional outcomes. Continued emphasis on public automated external defibrillator utilization programs may further improve outcomes of OHCA.
Foreign graduates of UK medical schools to gain equal access to specialty training, says BMA
Authors: Abi Rimmer
Journal: BMJ (2014)

Students from countries outside Europe who have graduated from a UK medical school will have equal access to specialty training opportunities in England as their UK and European peers, the BMA has said.

After lobbying by the BMA, Health Education England has agreed to end a system that meant that students from outside the European Economic Area were considered for specialty training placements only in a second round of …
New contract will increase rota gaps, striking doctors warn
Authors: Abi Rimmer
Journal: BMJ (2016)

Junior doctors taking part in industrial action have expressed concerns over the effect that their new contract could have on the NHS in the future.

Junior doctors across England are taking part in industrial action between 8 am on Wednesday 6 April and 8 am on Friday 8 April over government plans to impose a new contract in August.1

Speaking from the picket line at Northwick Park Hosptial in London, Mhairi Murdoch, a core medical trainee, said that she was concerned that the new contract would lead to unsafe working hours.

“We already have gaps in our rota across core medicine in London and it looks likely that the new contract will lead to even more gaps,” …
Yorkshire chest imaging course
Authors: Suman Thullimalli
Journal: BMJ (2012)

The course is organised by radiology registrars and is held twice a year, in May and November. It provides teaching on different chest imaging modalities, such as chest radiography and computed tomography, and has been approved by the Royal College of Radiology for seven category 1 credits in continuing professional development.

To develop an understanding of radiological pattern recognition.

Junior doctors in all specialties, including specialist registrars in radiology. The course attracts doctors working in intensive care and accident and emergency departments and is also suitable for doctors in general and respiratory medicine.

It is a well structured, comprehensive one day course. Candidates are welcomed by the course …
Revising the Structural Diversity of Ribosomal Proteins Across the Three Domains of Life
Authors: Sergey Melnikov, Kasidet Manakongtreecheep, Dieter Söll
Journal: Molecular Biology and Evolution (2018)

Ribosomal proteins are indispensable components of a living cell, and yet their structures are remarkably diverse in different species. Here we use manually curated structural alignments to provide a comprehensive catalog of structural variations in homologous ribosomal proteins from bacteria, archaea, eukaryotes, and eukaryotic organelles. By resolving numerous ambiguities and errors of automated structural and sequence alignments, we uncover a whole new class of structural variations that reside within seemingly conserved segments of ribosomal proteins. We then illustrate that these variations reflect an apparent adaptation of ribosomal proteins to the specific environments and lifestyles of living species. Finally, we show that most of these structural variations reside within nonglobular extensions of ribosomal proteins—protein segments that are thought to promote ribosome biogenesis by stabilizing the proper folding of ribosomal RNA. We show that although the extensions are thought to be the most ancient peptides on our planet, they are in fact the most rapidly evolving and most structurally and functionally diverse segments of ribosomal proteins. Overall, our work illustrates that, despite being long considered as slowly evolving and highly conserved, ribosomal proteins are more complex and more specialized than is generally recognized.
Fatal Powassan Encephalitis (Deer Tick Virus, Lineage II) in a Patient With Fever and Orchitis Receiving Rituximab
Authors: Isaac H. Solomon, Kristyn M. Spera, Sophia L. Ryan, Jeffrey Helgager, Juliana Andrici, Sherif R. Zaki, Henrikas Vaitkevicius, Kristoffer E. Leon, Michael R. Wilson, Joseph L. DeRisi, Sophia Koo, Stelios M. Smirnakis, Umberto De Girolami
Journal: JAMA Neurology (2018)

Powassan virus is a rare but increasingly recognized cause of severe neurological disease.To highlight the diagnostic challenges and neuropathological findings in a fatal case of Powassan encephalitis caused by deer tick virus (lineage II) in a patient with follicular lymphoma receiving rituximab, with nonspecific anti-GAD65 antibodies, who was initially seen with fever and orchiepididymitis.Comparison of clinical, radiological, histological, and laboratory findings, including immunohistochemistry, real-time polymerase chain reaction, antibody detection, and unbiased sequencing assays, in a single case report (first seen in December 2016) at an academic medical center.Infection with Powassan virus.Results of individual assays compared retrospectively.In a 63-year-old man with fatal Powassan encephalitis, serum and cerebrospinal fluid IgM antibodies were not detected via standard methods, likely because of rituximab exposure. Neuropathological findings were extensive, including diffuse leptomeningeal and parenchymal lymphohistiocytic infiltration, microglial proliferation, marked neuronal loss, and white matter microinfarctions most severely involving the cerebellum, thalamus, and basal ganglia. Diagnosis was made after death by 3 independent methods, including demonstration of Powassan virus antigen in brain biopsy and autopsy tissue, detection of viral RNA in serum and cerebrospinal fluid by targeted real-time polymerase chain reaction, and detection of viral RNA in cerebrospinal fluid by unbiased sequencing. Extensive testing for other etiologies yielded negative results, including mumps virus owing to prodromal orchiepididymitis. Low-titer anti-GAD65 antibodies identified in serum, suggestive of limbic encephalitis, were not detected in cerebrospinal fluid.Owing to the rarity of Powassan encephalitis, a high degree of suspicion is required to make the diagnosis, particularly in an immunocompromised patient, in whom antibody-based assays may be falsely negative. Unbiased sequencing assays have the potential to detect uncommon infectious agents and may prove useful in similar scenarios.
LEFT VENTRICULAR UNLOADING WITH VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION USING INTRA-AORTIC BALLOON PUMP OR PERCUTANEOUS LEFT VENTRICULAR ASSIST DEVICE IS ASSOCIATED WITH IMPROVED SURVIVAL TO DISCHARGE
Authors: Andy Lee, Omar Hernandez, Sabrie Howell, Huanying Qin, Fayez Raza, Aayla Jamil, Joost Felius, Gonzalo Gonzalez-Stawinski, Shelley Hall, Amarinder Bindra
Journal: Journal of the American College of Cardiology (2018)
Medical resource utilization (MRU) of abiraterone acetate plus prednisone (AAP) added to androgen deprivation therapy (ADT) in metastatic castration-naive prostate cancer: Results from LATITUDE.
Authors: Tracy Li, Conrado Franco-Villalobos, Irina Proskorovsky, Sonja V Sorensen, Namphuong Tran, Giri Sulur, Kim N. Chi
Journal: Journal of Clinical Oncology (2018)

201 Background: AAP + ADT demonstrated significant improvements in overall survival and disease progression in the LATITUDE trial. The objective of this analysis was to assess event-driven MRU from AAP + ADT vs ADT alone. Methods: MRU data from the LATITUDE trial were obtained and consisted of medical utilization other than that mandated by protocol while patients were on treatment. MRU types included overnight hospitalizations and length of stay (LOS), emergency room (ER) visits, radiotherapy, surgery, imaging, and specialist and general practitioner (GP) visits. Rates by treatment (per 100 person-years) and rate ratios were estimated using zero-inflated Poisson regression. Difference in average LOS between treatment arms was assessed using repeated measures regression. Results: A total of 1199 patients were evaluated. Statistically significantly lower rates (24% reduction) of hospitalizations were observed with AAP + ADT compared with ADT alone (Table). The most common hospitalization reasons were bladder/urethral symptoms and infections, lung infections, and musculoskeletal/connective tissue pain. Average LOS per hospitalization episode was similar. Statistically significantly lower rates of imaging (40% reduction) and radiotherapy were also observed for AAP + ADT vs ADT alone. Rates for specialist visits, surgery ER visits, and GP visits were not statistically different. Conclusions: Adding AAP to ADT does not increase MRU and leads to lower rates of hospitalization, imaging, and radiotherapy. This likely reflects the more favorable clinical outcomes with AAP + ADT therapy. Clinical trial information: NCT01715285. [Table: see text]
<scp>ILC</scp>2 frequency and activity are inhibited by glucocorticoid treatment via <scp>STAT</scp> pathway in patients with asthma
Authors: Q. N. Yu, Y. B. Guo, X. Li, C. L. Li, W. P. Tan, X. L. Fan, Z. L. Qin, D. Chen, W. P. Wen, S. G. Zheng, Q. L. Fu
Journal: Allergy (2018)

Group 2 innate lymphoid cells (ILC2s) were closely associated with asthma. However, there were no perspective studies about the effects of glucocorticoid on ILC2s in asthma patients. Our objective was to perform a perspective study and evaluate the ILC2 activity after glucocorticoid therapy in asthma patients.The asthma and asthma with allergic rhinitis patients were treated with glucocorticoid for 3 months. The circulating ILC2 levels were evaluated. The effects of glucocorticoid on ILC2s and possible signalling pathways were investigated in vitro.The patients were well-controlled, and the high ILC2 levels were significantly decreased at 1 and 3 months after treatment. Peripheral blood monocytes from allergic patients produced dramatic IL-5, IL-13 and IL-9 in response to IL-25, IL-33 plus IL-2, and glucocorticoid significantly decreased their levels. Moreover, ILC2s were identified to be the predominant source of IL-5, IL-13 and IL-9, and glucocorticoid treatment was able to reverse their high levels. STAT3, STAT5, STAT6, JAK3 and MEK signalling pathways were proved to be involved in regulating ILC2 activity under the glucocorticoid treatment.The data suggested that glucocorticoid administration could be effective in treating asthma by regulating ILC2s via MEK/JAK-STAT signalling pathways. This provides a new understanding of glucocorticoid application in regard to allergic diseases.
BMA denies that 90% of junior doctor contract is agreed
Authors: Abi Rimmer
Journal: BMJ (2016)

The chair of the BMA’s Junior Doctors Committee has refuted a government claim that 90% of the junior doctor contract in England had been agreed.

In February England’s health secretary, Jeremy Hunt, announced that he would impose a new contract on junior doctors in England.1

On Wednesday 19 April Johann Malawana, chair of the Junior Doctors Committee, wrote to the health secretary and offered to call off an all-out strike planned for next week if the government abandoned its plan to impose the contract in August.2 In a letter in reply, sent on the same day, Hunt said that 90% of the contract had …
I was training in obstetrics and gynaecology and then joined a GP training scheme. Now, after six months, I want to return to obstetrics and gynaecology. What implications will this change have on my future career?
Authors: Dharani Hapangama
Journal: BMJ (2004)

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.
Debriefing may help manage burnout among junior doctors, researchers say
Authors: Matthew Limb
Journal: BMJ (2015)

Junior doctors who experience high levels of burnout gain comfort and reassurance from debriefing sessions, say Australian researchers. Further investigation is now needed to see whether such interventions should be implemented more widely, the researchers argue.

Few studies so far have investigated strategies to prevent or reduce burnout among juniors. Now a small pilot study has been carried out in an inner city teaching hospital in Sydney involving 31 postgraduate year one doctors.1

Burnout …
Hospital deaths fall more quickly in England than in Scotland over past 17 years
Authors: Nigel Hawkes
Journal: BMJ (2018)

The number of hospital deaths has fallen more quickly in England than in Scotland since 1997, an analysis of administrative data has shown.1

The differences are substantial, said Maria Jose Aragon and Martin Chalkley of the Centre for Health Economics at the University of York, and apply to both emergency and elective care. Explaining the divergence is not possible from the data sources they used, they said, but finding an explanation “has great potential importance for policy makers.”

Since powers over the NHS in Scotland were devolved to the Scottish parliament in 1999, the two systems have diverged, providing a natural experiment that should enable comparisons to be made. Attempts to do so have, however, been bedevilled by a failure to ensure that healthcare data are gathered in the same way each side of the border. Even comparing waiting times is not simple.

The …
Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases
Authors: Masahiro Kanai, Masato Akiyama, Atsushi Takahashi, Nana Matoba, Yukihide Momozawa, Masashi Ikeda, Nakao Iwata, Shiro Ikegawa, Makoto Hirata, Koichi Matsuda, Michiaki Kubo, Yukinori Okada, Yoichiro Kamatani
Journal: Nature Genetics (2018)

Clinical measurements can be viewed as useful intermediate phenotypes to promote understanding of complex human diseases. To acquire comprehensive insights into the underlying genetics, here we conducted a genome-wide association study (GWAS) of 58 quantitative traits in 162,255 Japanese individuals. Overall, we identified 1,407 trait-associated loci (P < 5.0 × 10-8), 679 of which were novel. By incorporating 32 additional GWAS results for complex diseases and traits in Japanese individuals, we further highlighted pleiotropy, genetic correlations, and cell-type specificity across quantitative traits and diseases, which substantially expands the current understanding of the associated genetics and biology. This study identified both shared polygenic effects and cell-type specificity, represented by the genetic links among clinical measurements, complex diseases, and relevant cell types. Our findings demonstrate that even without prior biological knowledge of cross-phenotype relationships, genetics corresponding to clinical measurements successfully recapture those measurements' relevance to diseases, and thus can contribute to the elucidation of unknown etiology and pathogenesis.
Associations of PD-1 and PD-L1 expression with mismatch repair status and prognosis in chemoradiotherapy-naïve esophageal and gastric adenocarcinoma.
Authors: Maria Svensson, David Borg, Cheng Zhang, Charlotta Hedner, Bjorn Nodin, Mathias Uhlen, Adil Mardinoglu, Karin Leandersson, Karin Jirstrom
Journal: Journal of Clinical Oncology (2018)

9 Background: Although neoadjuvant and/or adjuvant treatment enhances survival in patients with resectable esophageal and gastric (EG) cancer, the prognosis remains poor and there is a great need to identify novel treatment strategies and suitable biomarkers. Expression of programmed death ligand 1 (PD-L1) is, together with mismatch repair (MMR) status, a putative biomarker of response to immune-modulating therapies, but their prognostic value in EG cancer remains unclear. Therefore, the aim of this study was to examine the expression of PD-L1 in tumour cells (TC) and tumour-infiltrating immune cells (TIC), and the receptor PD-1 in TIC, in EG adenocarcinoma. Particular attention was given to their relationship with MMR status, and prognosis. Methods: PD-L1 and PD-1 expression in TC and/or TIC was assessed by immunohistochemistry (IHC) on tissue microarrays with primary tumours from a retrospective consecutive cohort of 174 patients with chemoradiotherapy-naïve resected EG adenocarcinoma. MMR status was determined by IHC. The prognostic value of PD-L1 and PD-1 was also examined at the mRNA level in 354 cases of gastric adenocarcinoma in The Cancer Genome Atlas. Results: PD-1 expression was not associated with MMR status, but PD-L1 expression in TC and TIC was significantly associated with MMR deficiency (p &lt; 0.001 for both). Neither TC PD-L1 nor MMR status was prognostic. However, high PD-1 (10%) and PD-L1 ( &gt; 50%) expression in TIC was significantly associated with a prolonged OS, the latter independently of other prognostic factors and MMR status (hazard ratio = 0.39, 95% confidence interval 0.15-0.99). Moreover, the prognostic value was only evident in MMR proficient tumours, and similar in esophageal and gastric tumours. At the transcript level, PD-L1 expression was not prognostic, but high PD-1 expression was significantly associated with a prolonged OS in gastric adenocarcinoma (p = 0.012). Conclusions: High expression of PD-L1 but not PD-1 is significantly associated with MMR deficiency in EG cancer. High PD-L1 expression in TIC but not in TC, or high PD-1 expression in TIC, signifies a prolonged survival, in particular in MMR proficient tumours.