tbuckley/cabot-search huggingface dataset:
Abstract PD8-12: Mutational processes, genome evolution and outcome in metastatic breast cancers
Authors: A Patsouris, T Filleron, A Jacquet, A Goncalves, H Bonnefoi, C Letourneau, T Bachelot, M Jimenez, F Andre
Journal: Cancer Research (2018)

Abstract Background: to determine the distribution and evolution of mutational processes in metastatic breast cancers (mBC), together with their clinical relevance Methods: Whole exome sequencing (Hi-Seq, Illumina) and determination of copy number alterations (CNA) (CGH array / SNP6.0) were performed in 240 and 692 metastatic breast cancers respectively. Mutational processes were defined according to Alexandrov (Nature, 2013). Homologous Recombination Deficiency (HRD) was determined by genome wide assessment of loss-of-heteroygosity (LOH) on SNP6.0 (n = 210). Finally, genomic instability was assessed by the % of genome altered assessed by CGH / SNP6.0 Results: Whole exome sequencing showed that HR+/Her2- metastatic breast cancer presented an increased contribution of APOBEC-related signatures, as compared to early breast cancer (TCGA) (58% of the mutations vs 31%, p &amp;lt; 0.0001). Twelve percent of the HR+/Her2- mBC acquired an hypermutator genotype ( &amp;gt; 200 non-synonymous mutations). This acquisition of an hypermutator genotype was confirmed in five paired primary-metastatic samples. An operational APOBEC-related signature 13 was associated with a poor outcome in a multivariate analysis (HR: 1.75, 95%CI: 1.1-2.7, p = 0.017). High LOH score (HRD) was observed in 30% of HR+/Her2- mBC as compared to 13% of early HR+/Her2- early BC (p &amp;lt; 0.0001). The opposite was observed in TNBC (43% in mTNBC versus 58% in early TNBC ,p = 0.032). High LOH score was associated with a trend for poor outcome in HR+/Her2- mBC (multivariate 1.67, 95%CI: 0.949-2.951, p = 0.075).The % of genome altered was associated with a poor outcome in multivariate analyses both in the overall and HR+/Her2- mBC (HR / 10 increase:1.144, 95%CI:1.038-1.261, p = 0.007 and HR:1.18, 95%CI:1.037-1.344, p = 0.012 respectively). Copy number analyses identified 143 genes that are more frequently amplified as compared to early breast cancers (FDR &amp;lt; 0.01) Conclusions: metastatic HR+/Her2- metastatic breast cancer present an increased in APOBEC-related mutational burden and in LOH score as compared to early breast cancers. APOBEC-related signature 13 and genome instability are associated with a poor outcome and could be used in the future to better stratify metastatic breast cancer patients. Citation Format: Patsouris A, Filleron T, Jacquet A, Goncalves A, Bonnefoi H, Letourneau C, Bachelot T, Jimenez M, Andre F. Mutational processes, genome evolution and outcome in metastatic breast cancers [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 PD8-12.
National Football League Head, Neck and Spine Committee’s Concussion Diagnosis and Management Protocol: 2017-18 season
Authors: Richard G Ellenbogen, Hunt Batjer, Javier Cardenas, Mitchel Berger, Julian Bailes, Elizabeth Pieroth, Robert Heyer, Nicholas Theodore, Wellington Hsu, Elizabeth Nabel, Joe Maroon, Robert Cantu, Ronnie Barnes, James Collins, Margot Putukian, Russell Lonser, Gary Solomon, Allen Sills
Journal: British Journal of Sports Medicine (2018)

One of the National Football League's (NFL) Head, Neck and Spine Committee's principal goals is to create a 'best practice' protocol for concussion diagnosis and management for its players. The science related to concussion diagnosis and management continues to evolve, thus the protocol has evolved contemporaneously. The Fifth International Conference on Concussion in Sport was held in Berlin in 2016, and guidelines for sports concussion diagnosis and management were revised and refined. The NFL Head, Neck and Spine Committee has synthesised the most recent empirical evidence for sports concussion diagnosis and management including the Berlin consensus statement and tailored it to the game played in the NFL. One of the goals of the Committee is to provide a standardised, reliable, efficient and evidence-based protocol for concussion diagnosis and management that can be applied in this professional sport during practice and game day. In this article, the end-of-season version of the 2017-18 NFL Concussion Diagnosis and Management Protocol is described along with its clinical rationale. Immediate actions for concussion programme enhancement and research are reviewed. It is the Committee's expectation that the protocol will undergo refinement and revision over time as the science and clinical practice related to concussion in sports crystallise.
Genetics, Lifestyle, and Low-Density Lipoprotein Cholesterol in Young and Apparently Healthy Women
Authors: Jan-Willem Balder, Antoine Rimbert, Xiang Zhang, Martijn Viel, Roan Kanninga, Freerk van Dijk, Peter Lansberg, Richard Sinke, Jan Albert Kuivenhoven
Journal: Circulation (2018)

Atherosclerosis starts in childhood but low-density lipoprotein cholesterol (LDL-C), a causal risk factor, is mostly studied and dealt with when clinical events have occurred. Women are usually affected later in life than men and are underdiagnosed, undertreated, and understudied in cardiovascular trials and research. This study aims at a better understanding of lifestyle and genetic factors that affect LDL-C in young women.We randomly selected for every year of age 8 women with LDL-C ≤1st percentile (≤50 mg/dL) and 8 women with LDL-C ≥99th percentile (≥186 mg/dL) from 28 000 female participants aged between 25 to 40 years of a population-based cohort study. The resulting groups include 119 and 121 women, respectively, of an average 33 years of age. A gene-sequencing panel was used to assess established monogenic and polygenic origins of these phenotypes. Information on lifestyle was extracted from questionnaires. A healthy lifestyle score was allocated based on a recently developed algorithm.Of the women with LDL-C ≤1st percentile, 19 (15.7%) carried mutations that are causing monogenic hypocholesterolemia and 60 (49.6%) were genetically predisposed to low LDL-C on the basis of an extremely low weighted genetic risk score. In comparison with control groups, a healthier lifestyle was not associated with low LDL-C in women without genetic predispositions. Among women with LDL-C ≥99th percentile, 20 women (16.8%) carried mutations that cause familial hypercholesterolemia, whereas 25 (21%) were predisposed to high LDL-C on the basis of a high-weighted genetic risk score. The women in whom no genetic origin for hypercholesterolemia could be identified were found to exhibit a significantly unfavorable lifestyle in comparison with controls.This study highlights the need for early assessment of the cardiovascular risk profile in apparently healthy young women to identify those with LDL-C ≥99th percentile for their age: first, because, in this study, 17% of the cases were molecularly diagnosed with familial hypercholesterolemia, which needs further attention; second, because our data indicate that an unfavorable lifestyle is significantly associated with severe hypercholesterolemia in genetically unaffected women, which may also need further attention.
Mini C-arm fluoroscopic x ray equipment
Authors: Chang-Bon Man, Olivier A Branford
Journal: BMJ (2010)

This course, run by the Pulvertaft Hand Centre at the Royal Derby Hospital, is highly recommended for surgeons wishing to use the mini C-arm in theatres or with outpatients. At the time of writing, it was the only course available that fulfils the criteria for the Ionising Radiation (Medical Exposure) Regulations 2000.

The course is aimed mainly at plastic and orthopaedic surgeons who wish to use the mini C-arm for imaging extremities. However, there were many colleagues from allied specialties, including rheumatology and radiology, who wanted a safe grounding in the theoretical use of the …
Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis
Authors: Tom T.P. Seijkens, Claudia M. van Tiel, Pascal J.H. Kusters, Dorothee Atzler, Oliver Soehnlein, Barbara Zarzycka, Suzanne A.B.M. Aarts, Marnix Lameijer, Marion J. Gijbels, Linda Beckers, Myrthe den Toom, Bram Slütter, Johan Kuiper, Johan Duchene, Maria Aslani, Remco T.A. Megens, Cornelis van ‘t Veer, Gijs Kooij, Roy Schrijver, Marten A. Hoeksema, Louis Boon, Francois Fay, Jun Tang, Samantha Baxter, Aldo Jongejan, Perry D. Moerland, Gert Vriend, Boris Bleijlevens, Edward A. Fisher, Raphael Duivenvoorden, Norbert Gerdes, Menno P.J. de Winther, Gerry A. Nicolaes, Willem J.M. Mulder, Christian Weber, Esther Lutgens
Journal: Journal of the American College of Cardiology (2018)

Disrupting the costimulatory CD40-CD40L dyad reduces atherosclerosis, but can result in immune suppression. The authors recently identified small molecule inhibitors that block the interaction between CD40 and tumor necrosis factor receptor-associated factor (TRAF) 6 (TRAF-STOPs), while leaving CD40-TRAF2/3/5 interactions intact, thereby preserving CD40-mediated immunity.This study evaluates the potential of TRAF-STOP treatment in atherosclerosis.The effects of TRAF-STOPs on atherosclerosis were investigated in apolipoprotein E deficient (Apoe-/-) mice. Recombinant high-density lipoprotein (rHDL) nanoparticles were used to target TRAF-STOPs to macrophages.TRAF-STOP treatment of young Apoe-/- mice reduced atherosclerosis by reducing CD40 and integrin expression in classical monocytes, thereby hampering monocyte recruitment. When Apoe-/- mice with established atherosclerosis were treated with TRAF-STOPs, plaque progression was halted, and plaques contained an increase in collagen, developed small necrotic cores, and contained only a few immune cells. TRAF-STOP treatment did not impair "classical" immune pathways of CD40, including T-cell proliferation and costimulation, Ig isotype switching, or germinal center formation, but reduced CD40 and β2-integrin expression in inflammatory monocytes. In vitro testing and transcriptional profiling showed that TRAF-STOPs are effective in reducing macrophage migration and activation, which could be attributed to reduced phosphorylation of signaling intermediates of the canonical NF-κB pathway. To target TRAF-STOPs specifically to macrophages, TRAF-STOP 6877002 was incorporated into rHDL nanoparticles. Six weeks of rHDL-6877002 treatment attenuated the initiation of atherosclerosis in Apoe-/- mice.TRAF-STOPs can overcome the current limitations of long-term CD40 inhibition in atherosclerosis and have the potential to become a future therapeutic for atherosclerosis.
Review: Cell Death, Nucleic Acids, and Immunity
Authors: Keith B. Elkon
Journal: Arthritis & Rheumatology (2018)

Cells of the innate immune system are rigged with sensors that detect nucleic acids derived from microbes, especially viruses. It has become clear that these same sensors that respond to nucleic acids derived from damaged cells or defective intracellular processing are implicated in triggering diseases such as lupus and arthritis. The ways in which cells die and the concomitant presence of proteins and peptides that allow nucleic acids to re-enter cells profoundly influence innate immune responses. In this review, we briefly discusses different types of programmed necrosis, such as pyroptosis, necroptosis, and NETosis, and explains how nucleic acids can engage intracellular receptors and stimulate inflammation. Host protective mechanisms that include compartmentalization of receptors and nucleases as well as the consequences of nuclease deficiencies are explored. In addition, proximal and distal targets in the nucleic acid stimulation of inflammation are discussed in terms of their potential amenability to therapy for the attenuation of innate immune activation and disease pathogenesis.
HCN4 AND GATA5 PREVIOUSLY UNDESCRIBED VARIANTS IN A LARGE KINDRED WITH FAMILIAL ATRIAL FIBRILLATION
Authors: Alfonso Fraile Sanz, Raquel Casado Alvarez, Ricardo Caballero, Eva Delpon, Jesus Perea Egido, Blanca Alcon Duran, Belen Gil-Fournier, Soraya Ramiro, Israel Thuissard, Juan Tamargo, Marisa Lefort, Joaquin Alonso Martin, Francisco Cosio
Journal: Journal of the American College of Cardiology (2018)
Cutaneous squamous cell carcinomas are associated with basal proliferating actinic keratoses
Authors: L. Schmitz, T. Gambichler, C. Kost, G. Gupta, M. Stücker, E. Stockfleth, T. Dirschka
Journal: British Journal of Dermatology (2018)

In addition to the extent of atypical keratinocytes throughout the epidermis, actinic keratoses (AKs) are histologically characterized by downward‐directed basal‐layer expansion. It is not known whether this growth pattern correlates with the risk of developing invasive squamous cell carcinoma (iSCC). To characterize the prevalence of downward‐directed basal‐layer expansion of AKs adjacent to iSCC. The epidermis overlying and adjacent to iSCCs was assessed histologically. We determined the histological grade (AK I–III), basal growth pattern (PRO I–III) and accompanying parameters such as adnexal involvement. Among 307 lesions, 52·4% of AKs were histologically classified as AK grade I, 38·1% as AK II and 6·8% as AK III (χ2‐test, P < 0·001). Only 2·6% of adjacent epidermal samples did not show any atypical keratinocytes. The epidermis adjacent to iSCCs was classified as having a PRO I basal growth pattern in 25·7%, PRO II in 31·9% and PROIII in 39·4% of cases. Only 2·9% of AKs showed no basal growth (χ2‐test, P < 0·001). In total 118 AKs (48·8%) showed extension into adnexal structures. These AKs were graded as PRO I in 18·6% of cases, PRO II in 30·5% and PRO III in 50·8%. The epidermis above iSCCs could be assessed only for upwards‐directed growth and showed no significant differences in the three AK grades (P = 0·42). Basal proliferative AKs, as well as atypical keratinocytes restricted to the lower third of the epidermis, are most commonly seen adjacent to iSCC, with less evidence for full‐thickness epidermal dysplasia. Our study supports the important role of dysplastic keratinocytes in the epidermal basal layer and their potential association with iSCC.
Hyperammonemia After Blood Transfusion
Authors: Stephen M. Picca
Journal: Annals of Internal Medicine (2018)

Letters20 February 2018Hyperammonemia After Blood TransfusionStephen M. Picca, MDStephen M. Picca, MDNassau University Medical Center, East Meadow, New York (S.M.P.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L17-0640 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:In their case report describing the development of hyperammonemia after blood transfusion, Rossfeld and Wright (1) state that the lethargic patient was intubated “without sedation beyond 100 mg of rocuronium.” Rocuronium is a nondepolarizing muscle relaxant without sedative properties. As described, the patient was paralyzed for the intubation but received no sedation. The authors then note that he received hydromorphone 15 minutes later and “stopped moving spontaneously.” This response was probably a continued effect of the rocuronium, which would be unlikely to wear off spontaneously in such a short amount of time after a full intubating dose.... Reference1. Rossfeld ZM, Wright NR. Hyperammonemia after blood transfusion. Ann Intern Med. 2017;167:143-4. [PMID: 28605806]. doi:10.7326/L17-0093 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Nassau University Medical Center, East Meadow, New York (S.M.P.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L17-0640. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoHyperammonemia After Blood Transfusion Zachary M. Rossfeld and Nathan R. Wright Hyperammonemia After Blood Transfusion Zachary M. Rossfeld and Nathan R. Wright Hyperammonemia After Blood Transfusion Bertrand Hermann , Dominique Thabut , and Nicolas Weiss Metrics 20 February 2018Volume 168, Issue 4Page: 305KeywordsBlood transfusionConflicts of interestDisclosureIntubationMusclesSedationSedatives ePublished: 20 February 2018 Issue Published: 20 February 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Doctors are confused and cynical about purpose of revalidation
Authors: Abi Rimmer
Journal: BMJ (2014)

Doctors are confused and cynical about the purpose of revalidation, and many believe that the process was introduced to “catch a Shipman,” research by the King’s Fund has found.

Earlier this month the King’s Fund published a report, commissioned by the NHS’s Revalidation Support Team, on its qualitative assessment of the impact that revalidation has had on doctors’ behaviour.1 Researchers assessed the effects of revalidation at seven sites, including …
A phase 3, randomized, open-label study of first-line durvalumab (MEDI4736) ± tremelimumab versus standard of care (SoC; EXTREME regimen) in recurrent/metastatic (R/M) SCCHN: KESTREL.
Authors: Tanguy Y. Seiwert, Jared Weiss, Shrujal S. Baxi, Myung-Ju Ahn, Jerome Fayette, Maura L. Gillison, Jean-Pascal H. Machiels, Shunji Takahashi, Giovanni Melillo, April Franks, Ugochi Emeribe, David Raben, Michael McDevitt, Amanda Psyrri
Journal: Journal of Clinical Oncology (2016)

TPS6101 Background: Current therapies for pts with R/M SCCHN achieve poor survival, so more effective and better tolerated treatments are needed. Tumors can evade immune detection by exploiting inhibitory immune checkpoints such as programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), commonly expressed in SCCHN. Durvalumab (D) is a selective, high affinity, engineered human IgG1 mAb that blocks binding of programmed cell death ligand-1 (PD-L1) to PD-1 and CD80. Tremelimumab (T) is a selective human IgG2 mAb inhibitor of CTLA-4. Targeting both PD-L1 and CTLA-4 pathways has potential for synergistic antitumor effects. In a Phase 1b study in pts with advanced NSCLC (NCT2000947), D+T combination regimens demonstrated clinical activity and manageable tolerability profiles. The Phase 3 KESTREL study (NCT02551159) compares D ± T with SoC EXTREME regimen for first-line treatment of R/M SCCHN. Methods: KESTREL is an open-label, multicenter, global study of pts with R/M SCCHN (oral cavity, oropharynx, hypopharynx or larynx) who have received no prior systemic chemotherapy (unless part of multimodality treatment for locally advanced disease). Pts (n = 628) will be stratified by PD-L1 status, smoking history, tumor location, and then HPV status (oropharyngeal cancer) and randomized (2:1:1) to receive flat-doses of T 75 mg q4w (max 4 doses) + D 1500 mg q4w; D 1500 mg q4w; or SoC EXTREME regimen (carboplatin or cisplatin + 5FU + cetuximab), all until PD. The D+T combination will be assessed vs SoC in terms of co-primary endpoints PFS and OS. D+T vs SoC will be further assessed in terms of ORR; DoR; proportion of pts alive and progression free at 12 months; OS at 24 months; secondary progression; safety and tolerability; pharmacokinetics; immunogenicity; and HRQoL. The efficacy of D monotherapy vs both D+T and SoC will also be tested. Exploratory endpoints include blinded independent central review of antitumor activity (immune-related RECIST v1.1) and potential biomarkers of progression/response. Pts are enrolled from USA, Canada, Taiwan, South Korea, Greece and Spain (total of: 23 countries, 191 sites planned). Clinical trial information: NCT02551159.
“Exploited” doctors are keeping overstretched NHS going, says GP leader
Authors: Gareth Iacobucci
Journal: BMJ (2018)

Doctors across the NHS are being exploited by a system that is relying on their goodwill and “toleration of the unacceptable” to keep it functioning, the UK’s most senior GP has said.

Richard Vautrey, chair of the BMA’s General Practitioners Committee, urged ministers to end a decade of “excuses” and commit themselves to an urgent increase in funding for general practice.

In a keynote speech at the annual UK conference …
Abstract 13503: Efficacy of Subcutaneous Implantable Cardioverter Defibrillator Defibrillation Testing in Hypertrophic Cardiomyopathy Patients at High Risk of Sudden Cardiac Death
Authors: Niccolo’ Maurizi, Ilaria Tanini, Iacopo Olivotto, Ernesto Amendola, Giuseppe Limongelli, Antonio Rapacciuolo, Francesca Esposito, Stefano Viani, Giuseppe Allocca, Nadir Sitta, Giovanni Battista Perego, Giuseppe Ricciardi, Paolo Pieragnoli, Paolo De Filippo, Paola Ferrari, Giovanni Quarta, Maria Grazia Bongiorni, Franco Cecchi
Journal: Circulation (2016)

Introduction: Subcutaneous ICD (S-ICD) is a promising option for Hypertrophic Cardiomyopathy (HCM) patients at high-risk of Sudden Cardiac Death (SCD). However, its efficacy in terminating ventricular arrhythmias in HCM is yet unresolved. Hypothesis: To determine the efficacy of post-implantation S-ICD defibrillation testing (DT) of Ventricular Fibrillation (VF) in HCM patients and assess possible predictors of failure. Methods: Consecutive HCM patients referred for S-ICD implantation at seven Italian Centers from June 2014 to May 2016 were prospectively enrolled. At S-ICD implantation, patients underwent one or two attempts of VF induction by programmed electrical stimulation. Successful conversion was defined as any 65j shock that terminated VF and did not require rescue shocks. Clinical, ECG and Echocardiographic findings were analyzed to study potential predictors of conversion failure. Results: We evaluated 50 HCM patients (34 males, mean age 40±16) with a mean BMI of 25.2±4.4 kg/m 2 [18.1-36]. Two patients (4%) had a history of cardiac arrest, whereas 48 (96%) were implanted in primary prevention. Mean calculated risk of SCD at 5 years by the ESC score was 6.5±3.9% and all patients had at least one major risk factor. Maximal LV wall thickness (LVMWT) was &gt;25 mm in 19 (38%) patients and ≥ 30 mm in 13 (26 %). In 2/50 patients (4%) no arrhythmias were inducible, while in 7 (14%) only polymorphic sustained ventricular tachycardia (SVT) was induced and correctly cardioverted by the S-ICD. In the remaining 41 (82%) patients, 70 VF episodes were induced (2 VF in 29 and 1 VF in 12 patients), all correctly recognized by the device. Of the 70 VFs, 4 (6%) spontaneously converted into sinus rhythm. In 65/66 (98%) the S-ICD performed successful conversions, but failed in 1 (2%) patient, who needed rescue defibrillation. This patient was severely obese, with a BMI 36 kg/m 2 and LVMWT of 25 mm. VF was induced again and successfully converted by 80j shock with inverted polarity. Conclusions: Acute defibrillation testing at 65j shows the efficacy of S-ICD in terminating VF or polymorphic SVT in HCM patients, despite the presence of extreme LV hypertrophy. Severe obesity was possibly responsible for the single failure observed at 65j in our series.
A REAPPRAISAL OF THE EPIDEMIOLOGY OF DILATED AND HYPERTROPHIC CARDIOMYOPATHY IN OLMSTED COUNTY, MINNESOTA
Authors: Akil Sherif, Anwar Chahal, Praise Anene, Keerthi Jaliparthy, Christopher Scott, Alanna Chamberlain, Virend Somers, Bernard Gersh, Peter A. Brady
Journal: Journal of the American College of Cardiology (2018)