tbuckley/cabot-search huggingface dataset:
A Comparative Analysis of Pulmonary and Critical Care Medicine Guideline Development Methodologies
Authors: Noah C. Schoenberg, Alan F. Barker, John Bernardo, Robin R. Deterding, Jerrold J. Ellner, Dean R. Hess, Neil R. MacIntyre, Fernando J. Martinez, Kevin C. Wilson
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

The Institute of Medicine (IOM) standards for guideline development have had unintended negative consequences. A more efficient approach is desirable.To determine whether a modified Delphi process early during guideline development discriminates recommendations that should be informed by a systematic review from those that can be based upon expert consensus.The same questions addressed by IOM-compliant pulmonary or critical care guidelines were addressed by expert panels using a modified Delphi process, termed the Convergence of Opinion on Recommendations and Evidence (CORE) process. The resulting recommendations were compared. Concordance of the course of action, strength of recommendation, and quality of evidence, as well as the duration of recommendation development, were measured.When 50% agreement was required to make a recommendation, all questions yielded recommendations, and the recommended courses of action were 89.6% concordant. When 70% agreement was required, 17.9% of questions did not yield recommendations, but for those that did, the recommended courses of action were 98.2% concordant. The time to completion was shorter for the CORE process (median, 19.3 vs. 1,309.0 d; P = 0.0002).We propose the CORE process as an early step in guideline creation. Questions for which 70% agreement on a recommendation cannot be achieved should go through an IOM-compliant process; however, questions for which 70% agreement on a recommendation can be achieved can be accepted, avoiding a lengthy systematic review.
Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial
Authors: Bente L Langdahl, Cesar Libanati, Daria B Crittenden, Michael A Bolognese, Jacques P Brown, Nadia S Daizadeh, Eva Dokoupilova, Klaus Engelke, Joel S Finkelstein, Harry K Genant, Stefan Goemaere, Lars Hyldstrup, Esteban Jodar-Gimeno, Tony M Keaveny, David Kendler, Peter Lakatos, Judy Maddox, Jorge Malouf, Fabio E Massari, Jose Fernando Molina, Maria Rosa Ulla, Andreas Grauer
Journal: The Lancet (2017)
07.03 Behçet’s disease and hla-b51 in ireland
Authors: Fahd Adeeb, Adaeze Ugwoke, Joseph Devlin, Austin Stack, Alexander Fraser
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Behçet's disease (BD) is a type of vasculitis with distinctive clinical manifestations and multifactorial immunopathogenesis. Association of HLA-B51 (which belongs to the HLA-B5/B35 cross-reacting group) is well recognised as the strongest genetic susceptibility gene so far in BD. <h3>Aim</h3> The aim of this study is to determine the association of HLA-B51 in our BD cohort in the Midwest region of Ireland. <h3>Methods</h3> Patients meeting the ISGBD or the ICBD criteria for BD were identified from our institutional database. Medical charts and electronic data were reviewed retrospectively to document the HLA antigen profile of the patients (which were carried out by a same recognised lab in London using Gen-Probe Lifecodes HLA-SSO Typing kits based on Luminex xMAP technology). <h3>Results</h3> 22 patients of Irish descent were identified satisfying the diagnosis for BD, and among them 19 patients (6 males, 13 females) were HLA typed. The HLA-B51 antigen was found in only one of the 19 patients (5.3%) with a higher frequency HLA-B*08, B*44 (6 patients each; 31.6%), B*35, B*57 (5 patients each; 26.3%), B*15 (4 patients; 21%) and B*27 (3 patients; 15.8%). We found no association between HLA-B*51 and our Irish cohort of BD patients compared to control. <h3>Conclusion</h3> The overall frequency of HLA-B51 is not increased in our BD cohort. We acknowledge that the study is subject to several limitations including small sample size. Further study of a larger patient population is needed, which may include combination of BD cohorts throughout the country, which will be important to substantiate, support or refute this finding.
R-Roscovitine simultaneously targets both the p53 and NF-κB pathways and causes potentiation of apoptosis: Implications in cancer therapy
Authors: Anwesha Dey, E. Wong, C. Cheok, V. Tergaonkar, David Lane
Journal: Clinical Cancer Research (2007)

A38   The p53 and NF-κB pathways are two critical transcriptional regulatory networks deregulated in various human ailments including cancer and there has been a lot of evidence of cross-talk between these two pathways. Activation of p53 is associated with cell cycle arrest and apoptosis while NF-κB activation is associated with cell survival. Hence the cross talk between these pathways must be finely tuned and regulated. Seliciclib (CYC202, R-Roscovitine) is a 2, 6, 9-substituted purine analogue that is currently in phase II clinical trials as an anticancer agent. We show in this study that R-Roscovitine can downregulate NF-κB activation in response to TNFα and IL1. Activation of p53 dependent transcription is not compromised when R-Roscovitine is combined with TNFα. We characterize the molecular mechanism governing NF-κB repression and show that R-Roscovitine inhibits the IKK kinase activity which leads to defective IκBα phosphorylation, degradation and hence nuclear function of NF-κB. We further show that the downregulation of the NF-κB pathway is also at the level of p65 modification and that the phosphorylation of p65 at Ser 536 is repressed by R-Roscovitine. Consistent with repression of canonical IKK signaling pathway, the induction of NF-κB target genes MCP-1, ICAM-1, Cox-2 and IL-8 is also inhibited by R-Roscovitine. We further show that treatment of cells with TNFα and R-Roscovitine causes potentiation of cell death. Based on these results, we suggest the potential use of R-Roscovitine as a bitargeted anti-cancer drug which functions by simultaneously causing p53 activation and NF-κB suppression. This study also provides mechanistic insight into the molecular mechanism of action of R-Roscovitine thereby possibly explaining its anti-inflammatory properties.
An antigen-specific semi-therapeutic treatment with local delivery of tolerogenic factors through a dual-sized microparticle system blocks experimental autoimmune encephalomyelitis
Authors: Jonathan J. Cho, Joshua M. Stewart, Theodore T. Drashansky, Maigan A. Brusko, Ashley N. Zuniga, Kyle J. Lorentsen, Benjamin G. Keselowsky, Dorina Avram
Journal: Biomaterials (2017)
Use of FLIM histology-based HER2-HER3 heterodimer quantification and a Bayesian latent class proportional hazards model to predict cetuximab response in the COIN and new EPOC trials.
Authors: Tony Ng, Gregory Weitsman, Paul Barber, Katherine Lawler, Mark Rowley, Gabrielle Elshtein, Manuel Rodriguez-justo, Bharat Jasani, Sian Alexandra Pugh, John A. Bridgewater, John Neil Primrose, David Fisher, Richard A. Adams, Tim Maughan, Boris Vojnovic, Anthonius Coolen
Journal: Journal of Clinical Oncology (2015)

e14535 Background: Up-regulation of the EGFR-HER3 dimer may limit the efficacy of anti-EGFR treatment in breast cancerand may constitute a pathway of resistance to Cetuximab in colorectal cancer. The question of whether the HER receptor dimers (in different configurations), may account for the poor response to Cetuximab is insufficiently explored in the clinical context. Methods: We developed a new fluorescence lifetime imaging (FLIM)-based histology assay for accurately quantifying the HER2-3 heterodimer in FFPE patient tissues (with FLIM being the gold standard for measuring FRET within the < 10nm protein proximity range). A Bayesian latent class proportional hazards model was used to carry out the multivariate analysis on the prediction of survival in two published patients cohorts: [i] advanced/metastatic colorectal cancer patients in the COIN trial (N = 144) and [ii] patients with KRAS wild-type resectable colorectal liver metastases in a neo-adjuvant chemotherapy study (new EPOC) (N = 126). Results: Previous analysis using Cox’s multivariate model showed no benefit of adding cetuximab to oxaliplatin and fluoropyrimidine chemotherapy. Using a Bayesian latent class proportional hazards model, an HR of 0.13 for adding cetuximab treatment to oxaloplatin-containing chemotherapy was observed for a subset of patients (20% of total). The FLIM histology-based HER2-HER3 dimer assay (measured on the primary tumour samples) generated predictive parameters for patient survival that are independent of the cetuximab effect. There are also two distinct subgroups of new EPOC patients according to the Bayesian subclassification but neither subclass was associated with a significant beneficial HR by adding cetuximab treatment to chemotherapy. Conclusions: A subgroup of advanced colorectal cancer patients from the COIN but not the New EPOC studies may benefit from Cetuximab with chemotherapy. These data are consistent with the published neutral and negative outcomes of these studies. Our analyses also revealed the potential synergistic effect of targeting HER3 in this patient subclass.
The melanoma risk loci as determinants of melanoma prognosis.
Authors: Justin Rendleman, Shulian Shang, Christine Brocia, Michelle W. Ma, Richard L. Shapiro, Russell S. Berman, Anna C. Pavlick, Yongzhao Shao, Iman Osman, Tomas Kirchhoff
Journal: Journal of Clinical Oncology (2012)

8557 Background: Genetic risk factors of human cancer emerge as promising markers of clinical outcome. The recent melanoma genome-wide scans (GWAS) have identified loci associated with the disease risk, nevi or UV/pigmentation, but the prognostic potential of these variants is yet to be determined. In this study, we performed the first-to-date systematic evaluation of the association between established melanoma risk loci and melanoma progression. Methods: 891 melanoma patients prospectively accrued and followed up at NYU Medical Center were studied. We examined the association of 108 melanoma susceptibility single nucleotide polymorphisms (SNPs), selected or imputed from recent GWASs on melanoma, nevi or pigmentation, with recurrence-free survival (RFS) and overall survival (OS). The genotyping was performed using Sequenom I-plex. Cox PH model was used to test the association between each SNP and RFS and OS adjusted by age at diagnosis, gender, tumor stage and histological subtype. ROC curves were used to measure predictive utility of SNPs in predicting 3-year recurrence. Results: The strong association was observed for rs7538876 (RCC2) with RFS (HR=2.445, 95% CI 1.57 – 3.8, p=0.0006) and rs9960018 (DLGAP1) with both RFS and OS (HR=4.7, 95% CI=2.11-10.43, p=0.0061, HR=1.55, 95% CI=1.11-2.17, p=0.0094, respectively) using adjusted multivariate analysis. In addition, we identified the classifier with rs7538876 and rs9960018, stage and histological type at primary tumor diagnosis, achieving a higher area under the ROC curve (AUC=84%) compared to the baseline (AUC=78%) in predicting 3-year recurrence. Univariate survival analyses have identified associations of several SNPs with ulceration and/or tumor thickness. Conclusions: Our data revealed an association between specific melanoma susceptibility variants and worse clinicopathological variables at the time of diagnosis as well as worse disease outcome. The strength of associations observed for rs7538876 and rs9960018 suggest biological implication of these loci in melanoma recurrence. The observed predictive patterns of associated variants with clinical outcome provide for the first time evidence for the potential utilization of genetic markers in melanoma prognostication.
Safety Of Non-Bronchoscopic Bronchoalveolar Lavage In Children With Severe Bronchiolitis
Authors: E. R. Barreira, H. H. Shieh, L. F. Darmaros, T. Castilho, L. A. Y. Fernandes, R. H. A. Quinzani, D. C. Souza, A. R. Precioso
Journal: American Journal of Respiratory and Critical Care Medicine (2013)
De-Intensification of the Chemotherapy Did Not Affect the Outcome of Ph-Positive Acute Lymphocytic Leukemia Patients in the Era of Tyrosine Kinase Inhibitors
Authors: Olga A. Gavrilina, Elena N. Parovichnikova, Vera V. Troitskaya, Andrey N. Sokolov, Larisa A. Kuzmina, Galina Baskhaeva, Kseniia Zarubina, Valery G Savchenko
Journal: Blood (2016)
Deaths from chickenpox [3] (multiple letters)
Authors: Marc Brisson, W. John Edmunds, Elizabeth Miller, J. Claire Bramley, Ruby Devi, David Muir, Philip Rice, A. H. Mohsen, M. W. McKendrick, Neil Roberts, Giles J. Peek, Nikki Jones, Richard K. Firmin, Diana Elbourne
Journal: BMJ (2002)
Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial
Authors: Marloes G M Derks, Erik J Blok, Caroline Seynaeve, Johan W R Nortier, Elma Meershoek-Klein Kranenbarg, Gerrit-Jan Liefers, Hein Putter, Judith R Kroep, Daniel Rea, Annette Hasenburg, Christos Markopoulos, Robert Paridaens, Jan B E Smeets, Luc Y Dirix, Cornelis J H van de Velde
Journal: The Lancet Oncology (2017)
THU0468 Diagnostic experience of patients with fibromyalgia – a systematic synthesis of qualitative studies
Authors: AM Mengshoel, J Sim, B Ahlsen, S Madden
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> In recent years, the evidence-based practice (EBP) movement has become embraced by clinicians and scientists world-wide. A guiding principle of the EBP is that the best evidence available should inform clinical practice. At the same time, patients9 experiences should be taken into consideration in the clinical disicion-making. Over the years, the diagnosis of fibromyalgia (FM) has been subject to numerous debates among scientists and clinicians. Despite that a diagnosis may lead to a biographical disruption, be a starting point for patients to make sense of their illness, and shape expectations for the future, the diagnostic debates have not been appreciably informed by how patients themselves perceive the diagnosis. <h3>Objectives</h3> To examine how individuals experience the process and consequences of receiving a diagnosis of fibromyalgia <h3>Methods</h3> A systematic literature search of qualitative studies up to May 2016 was performed. A systematic search was carried out in Medline (<i>n</i>=562), PsychInfo (n=430), Cinahl, AMED (<i>n</i>=95), and Social Science Citation Index (<i>n</i>=486) up to May 2016, supplemented by items from the authors9 knowledge of the literature. Duplicates, quantitative studies, studies addressing chronic pain with no specification of diagnosis or including patients with other diagnoses, editorials, reviews, conference reports and dissertations were excluded. After this reading 93 qualitative studies of patients9 experience were read to identify whether they included information about patients9 diagnostic experience. Twenty-six papers, one book and a book chapter were included. Information about diagnostic experiences were extracted and subjected to an interpretive analysis in accordance with principles of meta-ethnography. <h3>Results</h3> Years were normally spent consulting specialists in an attempt to confirm the reality of symptoms and make sense of the illness. In this process, the reality of the illness was questioned. Great relief was expressed at finally achieving the FMS diagnosis. However, relief waned when therapies proved ineffective. Health professionals and others again questioned whether individuals were genuinely ill, that the illness had a psychological nature, and whether they were doing their best to recover. For the patients, the diagnosis did not provide a meaningful explanation of their suffering and had limited power to legitimate illness. The patients felt blamed for their failure to recover which meant their personal credibility and moral identity were put at stake. <h3>Conclusions</h3> The FMS diagnosis has limitations in validating and making sense of patients9 illness experiences and in providing social legitimation of their illness. Social relationships are strained during the diagnostic process and in the course of ineffective therapies. <h3>Disclosure of Interest</h3> None declared
microRNA-7 upregulates death receptor 5 and primes resistant brain tumors to caspase-mediated apoptosis
Authors: Deepak Bhere, Kaoru Tamura, Hiroaki Wakimoto, Sung Hugh Choi, Benjamin Purow, Jeremy Debatisse, Khalid Shah
Journal: Neuro-Oncology (2017)

MicroRNAs (miRs) are known to play a pivotal role in tumorigenesis, controlling cell proliferation and apoptosis. In this study, we investigated the potential of miR-7 to prime resistant tumor cells to apoptosis in glioblastoma (GBM).
Sedentary time in older adults: a critical review of measurement, associations with health, and interventions
Authors: Jennifer L Copeland, Maureen C Ashe, Stuart JH Biddle, Wendy J Brown, Matthew P Buman, Sebastien Chastin, Paul A Gardiner, Shigeru Inoue, Barbara J Jefferis, Koichiro Oka, Neville Owen, Luís B Sardinha, Dawn A Skelton, Takemi Sugiyama, Shilpa Dogra
Journal: British Journal of Sports Medicine (2017)

Sedentary time (ST) is an important risk factor for a variety of health outcomes in older adults. Consensus is needed on future research directions so that collaborative and timely efforts can be made globally to address this modifiable risk factor. In this review, we examined current literature to identify gaps and inform future research priorities on ST and healthy ageing. We reviewed three primary topics:(1) the validity/reliability of self-report measurement tools, (2) the consequences of prolonged ST on geriatric-relevant health outcomes (physical function, cognitive function, mental health, incontinence and quality of life) and(3) the effectiveness of interventions to reduce ST in older adults. Methods A trained librarian created a search strategy that was peer reviewed for completeness. Results Self-report assessment of the context and type of ST is important but the tools tend to underestimate total ST. There appears to be an association between ST and geriatric-relevant health outcomes, although there is insufficient longitudinal evidence to determine a dose–response relationship or a threshold for clinically relevant risk. The type of ST may also affect health; some cognitively engaging sedentary behaviours appear to benefit health, while time spent in more passive activities may be detrimental. Short-term feasibility studies of individual-level ST interventions have been conducted; however, few studies have appropriately assessed the impact of these interventions on geriatric-relevant health outcomes, nor have they addressed organisation or environment level changes. Research is specifically needed to inform evidence-based interventions that help maintain functional autonomy among older adults. This consensus statement has been endorsed by the following societies: Academy of Geriatric Physical Therapy, Exercise &amp; Sports Science Australia, Canadian Centre for Activity and Aging, Society of Behavioral Medicine, and the National Centre for Sport and Exercise Medicine.
Correlation between tumor mutation burden and response to immunotherapy.
Authors: Ioana Bonta, John Florin Isac, Eyal Meiri, Dacian Bonta, Patricia Rich
Journal: Journal of Clinical Oncology (2017)

e14579 Background: The use of immunotherapy is exponentially increasing in treatment of patients with advanced solid tumors. However, the response rates vary significantly between different tumor types and even within same tumor type (e.g. in lung cancer approx. 1 in 4 patients respond to immunotherapy). In order to better identify patients that will respond to immunotherapy, several markers have been proposed. Tumor mutation burden (TMB) has emerged more recently as a quantitative marker that can help predict responses to immunotherapies across different cancers, including melanoma, lung cancer and bladder cancer. TMB is a measure of the overall number of somatic protein coding mutations occurring in the tumor specimen. Methods: We analyzed 54 consecutive patients treated with immunotherapy at our institution for which we had genomic sequencing (FoundationOne). There were 39 lung cases and 15 non-lung (GI, GU, sarcoma). For 30 cases we had TMB data. Favorable response was defined as stable disease or response to therapy at 3 months. The relationship between TMB and tumor response was explored using ROC analysis. Results: The probability of a favorable response to immunotherapy in our patient dataset was 57% (31/54 patients). Among the patients with known TMB 60% (18/30) had a favorable response (stable disease or response to therapy). The favorable response rate for tumors originating in the lung was 64% (25/39) and for non-lung primary tumors was 40% (6/15). The difference was not statistically significant, with p = 0.12. Higher TMB values were correlated with increased probability of a favorable response. ROC analysis demonstrated an A z of 74% for TMB values in differentiating between patients with and without a favorable response. A TMB cutoff value of 8 mutations/megabase yielded a sensitivity of 95% and a specificity of 58% for predicting favorable response. Conclusions: In our data base 57%of patients with different solid cancers had favorable response to immunotherapy, in second line and beyond .Higher TMB correlated with higher likelihood of response to immunotherapy, independent of the primary site of cancer.
A smoker with joint pain
Authors: Annabel Suarez, Benjamin Faber, Andrew Stanton
Journal: BMJ (2017)

A 45 year old man presented with a 6 month history of painful joints, cough, fever, and weight loss. He had a smoking history of 15 pack years. On examination there was synovitis of the hands, feet, and ankles. Radiographs were taken of the chest, ankle (fig 1⇓), hands, and feet. The chest radiograph and computed tomography image of the thorax showed a lung mass. A biopsy found a poorly differentiated epithelioid …
Treatment of Elastosis Perforans Serpiginosa Using a Fractional Carbon Dioxide Laser
Authors: Awatef Kelati, Sylvie Lagrange, Florence Le Duff, Jean-Philippe Lacour, Thierry Passeron
Journal: JAMA Dermatology (2017)

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