tbuckley/cabot-search huggingface dataset:
P117 Effect of different janus kinase inhibitors on fibroblast-like synoviocytes in rheumatoid arthritis
Authors: M Diller, M-L Hülser, S Rehart, M Fleck, E Neumann, U Müller-Ladner
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> In 2017, the Janus kinase inhibitors (JAKi) Tofacitinib and Baricitinib were approved for the treatment of Rheumatoid arthritis (RA) in the European Union (EU) by the European Medicines Agency (EMA). Other JAKi like Peficitinib, Filgotinib and Upadacitinib are currently examined in clinical trials. The effect of these substances is mainly based on blocking the IL-6 pathway in immune cells.<sup>1</sup> However the effect of the different JAKi on activated fibroblast-like synoviocytes from patients with RA (RA-FLS) is not well characterised. <h3>Objectives</h3> This study compared the effect of different JAKi on the pro-inflammatory response of activated RA-FLS. <h3>Methods</h3> RA-FLS were isolated from synovial tissue of patients with known RA undergoing joint replacement surgery. The cells were pretreated with different concentrations of JAKi or vehicle control and then stimulated with IL1-β (10 or 20 ng/ml) or Oncostatin M (OSM, 100 ng/ml). After the indicated time (17–24 hour), the supernatants were collected and the concentrations of IL-6 were measured by ELISA. An assay combining the measurement of cell viability, cytotoxicity and apoptosis was performed to exclude effects of JAKi caused by cell toxicity. <h3>Results</h3> In a pretest-setting, RA-FLS were pretreated with JAKi for 2 hour with concentrations of 1 µM and 10 µM and then stimulated with IL1-β (20 ng/ml) for 18 hour. At the concentration of 10 µM, Peficitinib, Filgotinib and Upadacitinib reduced the IL-6 release by RA-FLS, whereas Tofacitinib and Baricitinib did not change the IL-6-levels. Tofacitinib and Baricitinib at 1 and 5 µM only reduced the cytokine release if the IL-6 pathway was activated selectively with OSM (n=3). In further analyses, RA-FLS were again pretreated with Filgotinib and Peficitinib for 2 hour with clinically relevant concentrations (range between 0.01 µM and 5 µM) and then stimulated with IL1-β (10 ng/ml) for 17 hour. At the concentration of 5 µM, Peficitinib caused a reduction of IL-6 levels of 66% compared to control with IL1-β (p&lt;0.01, n=5). However, a reduction of only 24% (p=0.12, n=5) could be observed at 1 µM. Filgotinib did not decrease IL-6 levels. Peficitinib did not change the viability, cytotoxicity or apoptosis (n=2), confirming that the observed effects were JAKi dependent. <h3>Conclusions</h3> Peficitinib reduced the inflammatory response of RA-FLS after activation with IL1-β and appeared to be superior to Tofacitinib and Baricitinib in targeting RA-FLS. The lack of effect of Tofacitinib and Baricitinib on RA-FLS activated by IL1-β could explain the treatment failure in some patients. <h3>Reference</h3> . Schwartz, et al. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol2016January;12(1):25–36. <h3>Disclosure of interest</h3> None declared
American College of Physicians Ethics Manual (Fifth Edition)
Authors: Iona Heath
Journal: BMJ (2007)

When I was invited to write this review, the ponderous title suggested an intimidating tome with a minimum of 450 pages and my heart sank. Imagine my delight to discover that it is, in fact, a pamphlet with only 66 pages, reprinted from the Annals of Internal Medicine (2005;142:561-83). It is a genuine, pocket sized manual, firmly grounded in the daily reality of clinical work.

In a 2001 paper in the Journal of the Royal College of Physicians of London , Douglas Black, referring to “the cloven hoof …
Abstract 17512: Differences in Hospital Risk-standardized Mortality Rates for Percutaneous Coronary Intervention by Patient Age Group: Implications for Hospital Outcome Profiling
Authors: Kumar Dharmarajan, Wang Yongfei, Robert McNamara, Frederick Masoudi, Joseph Ross, Nihar Desai, Erica Spatz, Paul Heidenreich, Gregg Fonarow, James de Lemos, Deepak Bhatt, Susannah Bernheim, Lara Slattery, Yosef Khan, Jeptha Curtis
Journal: Circulation (2016)

Introduction:  Hospital 30-day risk-standardized mortality rates (RSMRs) for percutaneous coronary intervention (PCI), a marker of PCI quality, are only calculated for Medicare beneficiaries ≥65 years-old. Whether these data also reflect hospital PCI quality for younger patients is unknown.   Hypothesis:  Hospital 30-day RSMRs for older patients ≥65 years-old undergoing PCI strongly correlate with 30-day RSMRs for younger patients    Methods:  We examined all PCI hospitalizations from 12/1/2011 to 11/30/2012 in the NCDR CathPCI registry linked to the National Death Index with direct identifiers. Hospital 30-day RSMRs for older and younger patients were calculated using two measures of 30-day mortality after PCI endorsed by the National Quality Forum. One was designed for patients with STEMI and/or cardiogenic shock (STEMI/shock) and the other was designed for patients without STEMI and without cardiogenic shock (no STEMI/no shock). We calculated the correlation of hospital 30-day RSMRs for older PCI patients with 30-day RSMRs for younger PCI patients among hospitals with ≥25 PCI patients in each age group for both STEMI/shock and no STEMI/no shock cohorts.   Results:  We identified 112,429 and 524,702 PCI hospitalizations with and without STEMI/shock, respectively (1357 hospitals). Median hospital 30-day RSMRs were 12.3% and 4.4% for older and younger PCI patients with STEMI/shock and 1.3% and 0.4% for older and younger PCI patients with no STEMI/no shock. Hospital 30-day RSMRs for older PCI patients were weakly correlated with 30-day RSMRs for younger PCI patients in both STEMI/shock and no STEMI/no shock cohorts (Pearson R=0.25 and 0.20, respectively) (Figure).   Conclusions:  Hospital 30-day RSMRs for older patients undergoing PCI poorly correlate with 30-day RSMRs for younger patients. Hospital outcomes for Medicare beneficiaries should therefore not be assumed to reflect hospital quality for all patient groups.
Abstract P4-12-02: Cost-effectiveness of genetic testing with a hereditary cancer panel in women at risk of hereditary breast cancer
Authors: Y Li, AR Arellano, LA Bare, JJ Devlin
Journal: Cancer Research (2018)

Abstract Background: The role of the BRCA1/2 genes in breast cancer risk has been well characterized. However, pathogenic variants in additional genes also confer hereditary breast cancer risk and if detected can lead to interventions that can facilitate increased life expectancy. For example, the National Comprehensive Cancer Network (NCCN) guidelines (Version 2.2017) recommend MRI screening for women who carry a pathogenic variant in CHEK2 and MRI screening or risk-reducing mastectomy for women who carry a pathogenic variant in PALB2. Testing women at risk of hereditary breast cancer with a 7-gene panel was recently reported to be more cost-effective than testing only BRCA1/2 genes (Li et al. Value Health, 2017). Objectives: To evaluate the cost-effectiveness of a multigene panel testing strategy including 11 genes with risk reduction recommendations by the NCCN guidelines compared with testing only BRCA1/2 genes. Methods: Using a Markov model modified from the recent Li et al. publication, the 11-gene model was used to estimate life expectancies and total healthcare costs from a payers' perspective. The model included costs for genetic testing, genetic consultation, and cancer treatment as well as risk reduction strategies recommended by the guidelines: prophylactic surgery, MRI surveillance, and mammography. Probabilistic sensitivity analyses were carried out to determine the robustness of the modeling. Results: In the base case, the incremental cost-effectiveness ratio (ICER) for the 11-gene multigene testing strategy compared with BRCA1/2 testing was $22,377 per life-year gained ($47,240 per quality-adjusted life-year gained) for a 40-year-old cohort and $36,690 per life-year gained ($63,384 per quality-adjusted life-year gained) for a 50-year-old cohort. The sensitivity analysis indicated that the multigene testing strategy had a 97% chance of costing less than $100,000 per quality-adjusted life-year gained for the 40-year-old cohort. Conclusion: In patients at risk of hereditary breast cancer, testing using a multigene panel followed by risk reducing interventions is cost-effective compared with testing only BRCA1/2 genes. Citation Format: Li Y, Arellano AR, Bare LA, Devlin JJ. Cost-effectiveness of genetic testing with a hereditary cancer panel in women at risk of hereditary breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-12-02.
Seven day plans do not rely on spreading workforce more thinly, Hunt says
Authors: Abi Rimmer
Journal: BMJ (2016)

The government’s plans for a seven day NHS do not rely on stretching the existing medical workforce more thinly, the secretary of state for health, Jeremy Hunt, has said.

Speaking in the House of Commons on Monday 5 September Hunt commented on a number of matters that were concerning junior doctors in England.1 His comments came after the BMA announced that it had decided to suspend planned industrial action by junior doctors in England next week, after discussions with NHS England.2

Hunt welcomed the association’s decision to suspend the strike but highlighted concerns over future five day strikes planned for October, November, and December. He said that the planned action was …
The man behind GP contracts and the new tsar for sport and health
Authors: Kieran Walsh
Journal: BMJ (2010)

Yes, especially when you’re losing at home to Darlington on a wet Tuesday night in front of 1000 disgruntled fans! Only joking—there are similarities though, and the ones I carry around with me are, “You’re only as good as your last game” and “better to be a lucky manager than a good one!”

Both my mum (council rent collector) and my dad (NHS Community Services administrator) were in the public services sector and I guess I just …
Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia
Authors: Pankaj Baral, Benjamin D Umans, Lu Li, Antonia Wallrapp, Meghna Bist, Talia Kirschbaum, Yibing Wei, Yan Zhou, Vijay K Kuchroo, Patrick R Burkett, Bryan G Yipp, Stephen D Liberles, Isaac M Chiu
Journal: Nature Medicine (2018)
Cutaneous Manifestation of Sarcoidosis in Lower-Back Tattoo With Increased Uptake of 18F-FDG
Authors: Jirka Grosse, Karin Menhart, Benedikt Schmidbauer, Dirk Hellwig
Journal: Clinical Nuclear Medicine (2018)

Sarcoidosis, a granulomatous T-cell-mediated multisystem disease with a yearly incidence of 10.9 to 35.5 cases per 100,000 in the United States, affects a variety of organ systems. Although the characteristic radiological finding of a bihilar lymphadenopathy still plays a diagnostic key role, FDG PET/CT is more sensitive in detecting and monitoring various manifestations. We present a rare case of a 37-year-old woman with bihilar, mediastinal, and abdominal lymphadenopathy in conjunction with a histologically proven cutaneous manifestation of sarcoidosis in a tattoo of the lower back exhibiting an increased uptake of FDG.
INCREASED LEFT ATRIAL VOLUME INDEX IS ASSOCIATED WITH WORSE OUTCOMES IN HEART FAILURE WITH PRESERVED EJECTION FRACTION
Authors: Alex Michael Parker, Kenneth Bilchick, Hunter Mwansa, Anthony Peters, Khadijah Breathlet, Mwenya Mubanga, Jamie Kennedy, Mohammed Abuannadi, James Bergin, Sula Mazimba
Journal: Journal of the American College of Cardiology (2018)
Natural pattern-recognition-receptor agonists as adjuvants for in situ vaccination lymphoma immunotherapy.
Authors: Mark Aleynick, Paul Peng, Linda Hammerich, Ranjan Upadhyay, Netonia Marshall, Judith Agudo, Michael Jay Yellin, Tibor Keler, Thomas A. Davis, Brian Brown, Joshua Brody
Journal: Journal of Clinical Oncology (2018)

123 Background: In patients with low-grade lymphoma, in situ vaccination has yielded both partial and complete remissions in clinical trials. Though clinical responses have been observed with multiple pattern recognition receptor agonists (PRRa), the optimal immune stimulant is unknown. We hypothesize that natural PRRa, such as the attenuated pathogens or subunits found in common prophylactic vaccines, could target multiple PRR in a physiologically relevant context and lead to a more robust activation of dendritic cells (DCs) versus synthetic PRRa. Methods: 20 vaccines, including BCG, Typhim Vi, MMR-II, etc. were screened in vitro, where DC phenotype and function were evaluated by flow cytometry. Flt3L-mobilized DC ability to phagocytose, process, present, and cross-present soluble protein or tumor derived antigen, were assessed using CRISPR gene-edited, β2m(-/-) GFP-lymphoma cells and a novel GFP-specific (‘JEDI’) CD8 T cell system. Vaccine mechanism of immune activation was elucidated using a library of PRR-null macrophage cell lines. Potent vaccines were also evaluated in vivo in a Flt3L-primed in situ vaccination using the A20 murine lymphoma model. Results: Several vaccines induced robust DC activation and several showed significant increases in subsequent T cell activation, proliferation, and tumor killing, suggesting increased antigen processing and cross-presentation by DCs. Some vaccines, either as single agents or in combination, were significantly more effective than synthetic PRRa in activating DCs and inducing a T cell response. In vivo, vaccine combination therapies induced tumor regression in a majority of animals, suggesting synergistic immune activation. Conclusions: This data suggests prophylactic vaccines are effective clinical-grade DC activators and can be repurposed for use in the in situ vaccination maneuver, with immediate translation into the clinic. Additionally, by extensive in vitro evaluation in parallel with in vivo studies, this work aims to identify a predictive in vitro molecular immune signature that correlates closely with adjuvant efficacy in vivo.
P038 Recent thymic emigrant t cells increase in rheumatoid patients treated with abatacept
Authors: S Piantoni, F Regola, A Tincani, P Airò
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> CD4 +T cells in rheumatoid arthritis (RA) display a peculiar restriction of the <i>T-cell receptor</i> (TCR) repertoire which compromises their ability to react to novel antigens.<sup>1</sup> We demonstrated that this process could be partially reverted by abatacept (ABA), which is a blocker of T lymphocyte co-stimulation, used in the treatment of RA.<sup>2</sup> To better understand the mechanisms underlying this phenomenon, we speculated that ABA could influence the frequency of peripheral T cell subpopulations, even at early stages of maturation. The homeostasis of the <i>naïve</i> T cell pool is maintained not only by thymus production, but also by mechanisms of peripheral replication involving TCR activation revealed by CD31 down-modulation. Indeed, CD4+CD45RA+CD31+T cells have been described as <i>recent thymic emigrants</i> (<i>RTE</i>) newly produced by the thymus and CD4+CD45RA+CD31 T cells as <i>central naïve</i>, involved in a self-renewal peripheral process. <h3>Objectives</h3> We aimed at profiling circulating <i>naïve</i> CD4+CD45RA+T cells, by assessing their expression of CD31 (PECAM-1).<sup>3</sup> <h3>Methods</h3> Thirty-one RA patients (median age [10°−90° percentile] 42 [25–64] years) were evaluated before and after 6 month of ABA therapy. Phenotypic analysis of peripheral blood T lymphocytes was made by flow-cytometry. Wilcoxon-signed rank test and Spearman rank correlation were used for the comparisons. <h3>Results</h3> After ABA therapy, the absolute number of total T CD4 +increased from 780 [423–1351] to 1000 [658–1566] cells/mm<sup>3</sup> (p=0.01). Total <i>naïve</i> CD4 +increased in percentage (33 [18–56] vs 40 [20–61]% of CD4+; p=0.02) and in absolute number (257 [82–568] vs 344 [62–689] cells/mm<sup>3</sup>; p=0.03). In parallel, the number of <i>RTE</i> increased in percentage (10.6 [2–26] vs 11.6 [3–25]% of CD4+; p=0.04) and in absolute number (51 [15–194] vs 110 [23–271] cells/mm<sup>3</sup>; p=0.01). The <i>central naïve</i> counterpart did not show significant variations in percentage (29 [23–40] vs 27 [20–38]% of CD4+; p=0.20) nor in absolute number (191 [41–404] vs 242 [76–526] cells/mm<sup>3</sup>; p=0.20). No correlation was found between age and RTE number at baseline. <h3>Conclusions</h3> The number of total <i>naïve</i> T cells increases after therapy with ABA together with the number of <i>RTE</i>, suggesting a thymic output boost. Besides the peripheral effect in reducing the number of effector T cells which was showed by previous studies,<sup>4</sup> ABA could have a role in promoting the immune reconstitution at the early stage of T cell development. <h3>References</h3> . Wagner UG, et al. <i>PNAS</i>1998. . Imberti L, et al. J Transl Med2015. . Kohler S, et al. Blood2009. . Airò P, et al. Trends Mol Med2013. <h3>Disclosure of interest</h3> None declared
NOVEL PROTHROMBOTIC AND GENETIC RISK FACTORS IN ACUTE MYOCARDIAL INFARCTION: IMPLICATIONS FOR MID- AND LONG-TERM SECONDARY PREVENTION
Authors: Mercè Roqué, Barbara Carbonell, Sara Vazquez, Joaquim Bobi, Victoria Martin-Yuste, Ana Paula Dantas, Maribel Diaz-Ricart, Dolors Tassies, Ander Regueiro, Xavier Freixa, Salvatore Brugaletta, Monica Masotti, Manel Sabate, Juan Carlos Reverter, Gines Escolar
Journal: Journal of the American College of Cardiology (2018)
Speaking up for the majority
Authors: Tom Moberly
Journal: BMJ (2014)

For many years women have outnumbered men at medical school and in medical training. They also now outnumber men further down the career path in areas such as general practice. However, there are still relatively few women pursuing careers in a number of specialties, and women are particularly poorly represented in surgery. Just 11% of general surgeons and 5% of trauma and orthopaedic surgeons are women.

The Royal …
Multicentre determination of rezafungin (CD101) susceptibility of Candida species by the EUCAST method
Authors: M.C. Arendrup, J. Meletiadis, O. Zaragoza, K.M. Jørgensen, L.J. Marcos-Zambrano, L. Kanioura, M. Cuenca-Estrella, J.W. Mouton, J. Guinea
Journal: Clinical Microbiology and Infection (2018)

ObjectivesRezafungin (CD101) is a new long-acting echinocandin allowing weekly dosing, currently undergoing phase-II clinical trials for invasive candidiasis. The aim of this study was to assess rezafungin's in vitro activity against the most frequent Candida species following the EUCAST methodology.MethodsThe susceptibility of 2018 clinical Candida isolates was determined at four European laboratories. In parallel, six control strains were repeatedly tested. Wild-type upper limits (WT-ULs), defined as the MIC value where the wild-type distribution ends, were determined following the principles for EUCAST ECOFF-setting.ResultsThe lowest rezafungin MICs (geometric MIC (GM-MIC), MIC range (mg/L)) were observed for C. albicans (0.016, 0.002–0.125) and the highest for C. parapsilosis (1.657, 0.063->4). MICs for the remaining species were in between these values (GM-MICs 0.048–0.055). Visual and statistical WT-ULs were identical for C. glabrata (0.125), C. krusei (0.125), C. parapsilosis (4), and C. tropicalis (0.25). If adopting these WT-ULs for classification into WT and non-WT populations, 1/413 C. glabrata, 1/402 C. krusei, 1/398 C. parapsilosis, and 1/402 C. tropicalis isolates were categorized as non-WT, all of which derived from Laboratory 1. For C. albicans unexplained laboratory variation was observed (WT-UL: 0.063–0.125 in Laboratories 1 and 2 versus 0.016 in Laboratories 3 and 4). A similar systematic difference was observed comparing the MICs for the three C. albicans QC strains, specifically, obtained in Laboratories 1and 2 with those in Laboratories 3 and 4.DiscussionRezafungin displayed species-specific activity similar to other echinocandins. Interlaboratory variation was observed for the most susceptible species C. albicans clinical and QC strains, an observation that warrants further investigation.
KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (PBO) + chemo for previously untreated, locally recurrent, inoperable or metastatic triple-negative breast cancer (mTNBC).
Authors: Javier Cortés, Zifang Guo, Vassiliki Karantza, Gursel Aktan
Journal: Journal of Clinical Oncology (2018)

TPS18 Background: In the phase Ib KEYNOTE-012 study, the anti–PD-1 antibody pembro demonstrated promising antitumor activity and acceptable safety as monotherapy in pretreated patients (pts) with PD-L1+ mTNBC. Adding pembro to chemo may enhance antitumor activity. KEYNOTE-355 (NCT02819518) is a global phase III study of pembro+chemo vs PBO+chemo in pts with previously untreated, locally recurrent, inoperable TNBC/mTNBC. Methods: Eligible pts are ≥18 y and have centrally confirmed, locally recurrent, inoperable TNBC or mTNBC not previously treated with chemo (prior chemo in [neo]adjuvant setting is allowed); measurable disease per RECIST v1.1; ECOG PS 0-1; ≥6 mo between definitive surgery or last dose of adjuvant chemo, whichever was last; and first disease recurrence (≥12 mo if prior treatment with same-class agent). Part 1 is an open-label, unblinded safety run-in of ~30 pts in 3 arms (pembro+nab-paclitaxel, pembro+paclitaxel, pembro+gemcitabine/carboplatin). Part 2 is a double-blind, PBO-controlled study of ~828 pts randomized 2:1 to pembro 200 mg every 3 weeks + chemo (nab-paclitaxel 100 mg/m 2 on d 1, 8, and 15 every 28 d; paclitaxel 90 mg/m 2 on d 1, 8, and 15 every 28 d; or gemcitabine 1000 mg/m 2 + carboplatin AUC 2 on d 1 and 8 every 21 d) or PBO+chemo. Crossover is not allowed. Stratification factors are study chemo (taxane vs gemcitabine/carboplatin), tumor PD-L1 expression (+/-), and prior therapy with same-class agent in the (neo)adjuvant setting (yes/no). Treatment will occur for ≤35 administrations (pembro/PBO only) or until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or decision to discontinue. Primary end points are safety in part 1 and PFS (by RECIST v1.1, central radiology review) and OS in part 2; secondary end points include ORR (by RECIST v1.1, central radiology review) and duration of response. AEs will be graded per NCI CTCAE v4.0. Response will be assessed at wk 8, 16, 24, then at 9-wk intervals up to 1 y, and at 12-wk intervals thereafter. Interim safety analysis will occur after pts complete 1 treatment cycle in part 1. Clinical trial information: NCT02819518.
BMA loses legal challenge over clinical excellence awards in Northern Ireland
Authors: Helen Jaques
Journal: BMJ (2012)

The BMA has lost its High Court battle against the government’s decision not to allocate any new clinical excellence awards to consultants in Northern Ireland in 2010-11.

In a consultation in early 2011 Northern Ireland’s Department of Health, Social Services and Public Safety stated that the awards, which are paid on top of basic salary, amounted to a pay rise for those consultants receiving a …