tbuckley/cabot-search huggingface dataset:
Emerging Treatment Models in Rheumatology: Challenges for Osteoarthritis Trials
Authors: David T. Felson, Tuhina Neogi
Journal: Arthritis & Rheumatology (2018)

At a time when advancing understanding of osteoarthritis ( OA ) has created opportunities for new treatments, development of treatments has remained considerably behind advances in other rheumatic diseases. We describe elements of trial design and measurements that have inhibited success and offer suggestions that may help break the log jam. Among the problems with trials that include pain as an outcome measure are reliance on a single, non‐optimal pain outcome, overestimation of likely effects of treatments on pain, and failure to identify patient subgroups most likely to respond to specific treatments. With regard to the use of structure modification as an outcome measure, demonstrating structure modification is often highly challenging, even with the use of magnetic resonance imaging. Many OA patients have advanced disease that is unlikely to respond to treatments that prevent cartilage loss. Further, prevention of cartilage loss and reduction of pain correlate weakly at best, and in at least some patients, reduction in pain may actually increase joint damage, making it impossible to demonstrate dual treatment effects on structure and pain in such scenarios. For structure outcomes, treatment effects on pain‐sensitive structures such as bone and synovium may be more achievable than preventing cartilage loss. We suggest that changes in trial design related to some of these issues may increase the chances that new exciting and effective OA treatments will become available.
Development of a patient‐centric food allergy research program: A model for action
Authors: Jennifer J. Bute, S. Brantlee Broome, Jessica N. Marcus, Sandy Mikulcik, Brian Vickery
Journal: Allergy (2018)

Attention to patient perspectives on healthcare and disease burden is the guiding principle of patient-centered outcomes research (1) and is an approach increasingly employed by researchers in allergic disease settings, such as asthma (2) and allergic rhinosinusitis (3) and urticaria (4).Because of the all-encompassing impact of food allergies on daily living, including social and economic effects, the food allergy context is especially suited for an approach to research designed to account for the lived experiences of food allergic patients and their families.Despite recent advances in understanding the effects of food allergy on quality of life, gaps still exist in key areas like participation in clinical trials, access to safe foods and epinephrine and public understanding of food allergies (4 5).Outcomes research offers the opportunity to examine the lives of those impacted by food allergies to determine the wide range of issues that are most important to those directly affected and to address these gaps (5 6).The goal of this letter is to describe a model for engaging key stakeholders in the development of a patient-centric food allergy research agenda.
Why is there shamanism? Developing the cultural evolutionary theory and addressing alternative accounts
Authors: Manvir Singh
Journal: Behavioral and Brain Sciences (2018)

The commentators endorse the conceptual and ethnographic synthesis presented in the target article, suggest extensions and elaborations of the theory, and generalize its logic to explain apparently similar specializations. They also demand clarity about psychological mechanisms, argue against conclusions drawn about empirical phenomena, and propose alternative accounts for why shamanism develops. Here, I respond.
The Effects of Cannabis Among Adults With Chronic Pain
Authors: Shannon M. Nugent, Devan Kansagara
Journal: Annals of Internal Medicine (2018)

Letters3 April 2018The Effects of Cannabis Among Adults With Chronic PainShannon M. Nugent, PhD and Devan Kansagara, MD, MCRShannon M. Nugent, PhDVA Portland Health Care System, Portland, Oregon (S.M.N., D.K.) and Devan Kansagara, MD, MCRVA Portland Health Care System, Portland, Oregon (S.M.N., D.K.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/L17-0732 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:We were aware of and included all studies that were included in Andreae and associates' patient-level meta-analysis. However, our study-level meta-analysis included 4 additional studies. The studies included in Andreae and associates' meta-analysis had larger effect sizes (for example, a greater proportion of intervention patients experienced clinically significant reductions in pain) than the additional studies that we included, which explains why the odds ratio reported in their meta-analysis differed from ours. Of note, the 5 studies in Andreae and associates' meta-analysis were very short (hours), whereas the additional studies that we included measured effects over weeks.The cannabis ... Author, Article, and Disclosure InformationAffiliations: VA Portland Health Care System, Portland, Oregon (S.M.N., D.K.)Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-0155. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoThe Effects of Cannabis Among Adults With Chronic Pain and an Overview of General Harms Shannon M. Nugent , Benjamin J. Morasco , Maya E. O'Neil , Michele Freeman , Allison Low , Karli Kondo , Camille Elven , Bernadette Zakher , Makalapua Motu'apuaka , Robin Paynter , and Devan Kansagara The Effects of Cannabis Among Adults With Chronic Pain David A. Gorelick Metrics Cited byManagement of Chronic Pain in Nursing Homes: Navigating Challenges to Improve Person-Centered CareMedical Reasons for Marijuana Use, Forms of Use, and Patient Perception of Physician Attitudes Among the US PopulationEffective Opioid Analgesic Alternatives and Approaches to Pain Management 3 April 2018Volume 168, Issue 7Page: 525KeywordsCannabisConflicts of interestDisclosureNeuropathic painObservational studiesPulmonary functionRoutes of administrationSafety ePublished: 3 April 2018 Issue Published: 3 April 2018 PDF downloadLoading ...
Increasing Disparities in Mortality by Socioeconomic Status
Authors: Barry Bosworth
Journal: Annual Review of Public Health (2018)

This review focuses on the widening disparities in death rates by socioeconomic class. In recent years, there has been a major increase in the availability of data linking mortality risk and measures of socioeconomic status. The result has been a virtual explosion of new empirical research showing not only the existence of large inequities in the risk of death between those at the top and those at the bottom of the socioeconomic distribution, but also that the gaps have been growing. This assessment of the empirical research finds a consistent pattern of growing disparities within the United States. However, this widening gap in death rates does appear to be a uniquely American phenomenon, as the disparities by socioeconomic class appear to be stable or even declining in Europe and Canada.
Germline pharmacogenomics of DPYD*9A (c.85T&gt;C) variant in patients with gastrointestinal malignancies treated with fluoropyrimidines.
Authors: Moh'd M. Khushman, Girijesh K. Patel, Peter Joel Hosein, Javier Laurini, Daniel Cameron, David Roland Clarkson, Thomas Wayne Butler, Carole Norden, Wilma Baliem, Vanessa Jones, Sanjyot Bhadkamkar, Cindy Nelson, Frances Lee, Ajay Singh, William R. Taylor
Journal: Journal of Clinical Oncology (2018)

598 Background: The correlation between DPYD*9A (c.85T &gt; C) genotype and dihydropyrimidine dehydrogenase (DPD) deficiency clinical phenotype is controversial. Reference laboratories either did not perform DPYD*9A genotyping or have stopped DPYD*9A genotyping and limited genotyping to high-risk variants (DPYD*2A, DPYD*13 and DPYD*9B) only. This study explored DPYD*9A genotype and clinical phenotype correlation in patients with gastrointestinal (GI) malignancies treated with fluoropyrimidines. Methods: Between 2011 and 2017, 67 patients with GI malignancies were genotyped for DPYD variants. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). Fisher’s exact test was used for statistical analysis. Results: DPYD variants were identified in 17 out of 67 (25%) patients. One patient was homozygous for DPYD*9A variant and one patient was double heterozygous for DPYD*9A and DPYD*9B variants. 13/17 (76%) patients had DPYD*9A variant, 3/17 (18%) patients had DPYD*2A variant and 2/17 (12%) patient had DPYD*9B variant. Only patients genotyped prior to 2015 were genotyped for DPYD*9A variant (N = 28). Of those, 13/28 patients (46%) had DPYD*9A variant. Grade 3-4 diarrhea was associated with DPYD*9A variant in patients treated with full dose fluoropyrimidines (P = 0.0055). Conclusions: In our cohort, DPYD*9A variant was the most common diagnosed variant. The correlation between DPYD*9A genotype and DPD deficiency clinical phenotype was noticeable in patients who received full dose fluoropyrimidines as they all experienced grade 3-4 toxicities (diarrhea).
Adoptive Immunotherapy Using PRAME-Specific T Cells in Medulloblastoma
Authors: Domenico Orlando, Evelina Miele, Biagio De Angelis, Marika Guercio, Iolanda Boffa, Matilde Sinibaldi, Agnese Po, Ignazio Caruana, Luana Abballe, Andrea Carai, Simona Caruso, Antonio Camera, Annemarie Moseley, Renate S. Hagedoorn, Mirjam H.M. Heemskerk, Felice Giangaspero, Angela Mastronuzzi, Elisabetta Ferretti, Franco Locatelli, Concetta Quintarelli
Journal: Cancer Research (2018)

Abstract Medulloblastoma is the most frequent malignant childhood brain tumor with a high morbidity. Identification of new therapeutic targets would be instrumental in improving patient outcomes. We evaluated the expression of the tumor-associated antigen PRAME in biopsies from 60 patients with medulloblastoma. PRAME expression was detectable in 82% of tissues independent of molecular and histopathologic subgroups. High PRAME expression also correlated with worse overall survival. We next investigated the relevance of PRAME as a target for immunotherapy. Medulloblastoma cells were targeted using genetically modified T cells with a PRAME-specific TCR (SLL TCR T cells). SLL TCR T cells efficiently killed medulloblastoma HLA-A*02+ DAOY cells as well as primary HLA-A*02+ medulloblastoma cells. Moreover, SLL TCR T cells controlled tumor growth in an orthotopic mouse model of medulloblastoma. To prevent unexpected T-cell–related toxicity, an inducible caspase-9 (iC9) gene was introduced in frame with the SLL TCR; this safety switch triggered prompt elimination of genetically modified T cells. Altogether, these data indicate that T cells genetically modified with a high-affinity, PRAME-specific TCR and iC9 may represent a promising innovative approach for treating patients with HLA-A*02+ medulloblastoma. Significance: These findings identify PRAME as a medulloblastoma tumor-associated antigen that can be targeted using genetically modified T cells. Cancer Res; 78(12); 3337–49. ©2018 AACR.
The impact of lung and bone metastases on prognosis in advanced PDAC.
Authors: Grainne M. O'Kane, Adriana Fraser, Stephanie Moignard, Anna Dodd, Sean Creighton, Hao-Wen Sim, Kyaw Lwin Aung, Ayelet Borgida, Steven Gallinger, Jennifer J. Knox
Journal: Journal of Clinical Oncology (2018)

494 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a highly fatal disease inherently resistant to cytotoxic treatment. Despite the prevalence of liver and peritoneal metastases, subsets of patients also develop lung and bone metastases highlighting phenotypic heterogeneity. We reviewed the prognostic implications of metastatic sites on survival. Methods: This retrospective cohort study included all patients with PDAC who received surgical or oncological treatment at the University Health Network from September 2012 until December 2016. Clinical and pathological variables were obtained from patient electronic records. Radiological images and pathology reports were reviewed to ascertain sites of metastatic disease. The Kaplan-Meier method for survival and multivariable cox regression analysis identified prognostic factors. Results: 1153 patients were reviewed and 985 were included. 55% were male and the median age at diagnosis was 67 years. 287 (29%) completed curative surgery and 698 (71%) had locally advanced or metastatic disease; the median survival was 22 months and 9 months respectively. Lung and bone metastases were present in 18% (N = 180) and 6% (N = 58) of patients. In multivariable analysis increasing age and stage at diagnosis correlated with inferior survival (p &lt; 0.0001) and the presence of any lung (HR 0.77; 95% CI 0.63-0.94, p = 0.01) or bone metastases (HR 0.74; 95% CI 0.54-1.0, p = 0.05) resulted in improved outcomes. Liver and peritoneal disease were not prognostic. Sex and family history of PDAC did not associate with survival. There was no association between site of metastases and sex however patients with bone metastases were significantly younger at first diagnosis (median age 63yrs, p &lt; 0.01). Conclusions: Patients with advanced PDAC and metastases to lung or bone may represent distinct biological subtypes of PDAC. Molecular profiling of available tissue is ongoing.
Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation
Authors: Thomas Vogl, Athanasios Stratis, Viktor Wixler, Tom Völler, Sumita Thurainayagam, Selina K. Jorch, Stefanie Zenker, Alena Dreiling, Deblina Chakraborty, Mareike Fröhling, Peter Paruzel, Corinna Wehmeyer, Sven Hermann, Olympia Papantonopoulou, Christiane Geyer, Karin Loser, Michael Schäfers, Stephan Ludwig, Monika Stoll, Tomas Leanderson, Joachim L. Schultze, Simone König, Thomas Pap, Johannes Roth
Journal: Journal of Clinical Investigation (2018)

Autoimmune diseases, such as psoriasis and arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals, such as danger-associated molecular patterns (DAMPs), are indispensable for manifestation of local inflammation. S100A8/S100A9 complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP activities are barely understood. We now unravel for the first time, to our knowledge, a mechanism of autoinhibition in mice and humans restricting S100-DAMP activity to local sites of inflammation. Combining protease degradation, pull-down assays, mass spectrometry, and targeted mutations, we identified specific peptide sequences within the second calcium-binding EF-hands triggering TLR4/MD2-dependent inflammation. These binding sites are free when S100A8/S100A9 heterodimers are released at sites of inflammation. Subsequently, S100A8/S100A9 activities are locally restricted by calcium-induced (S100A8/S100A9)2 tetramer formation hiding the TLR4/MD2-binding site within the tetramer interphase, thus preventing undesirable systemic effects. Loss of this autoinhibitory mechanism in vivo results in TNF-α-driven fatal inflammation, as shown by lack of tetramer formation in crossing S100A9-/- mice with 2 independent TNF-α-transgene mouse strains. Since S100A8/S100A9 is the most abundant DAMP in many inflammatory diseases, specifically blocking the TLR4-binding site of active S100 dimers may represent a promising approach for local suppression of inflammatory diseases, avoiding systemic side effects.
Financial alchemists and financial shamans
Authors: Samuel G. B. Johnson
Journal: Behavioral and Brain Sciences (2018)

Abstract Professional money management appears to require little skill, yet its practitioners command astronomical salaries. Singh's theory of shamanism provides one possible explanation: Financial professionals are the shamans of the global economy. They cultivate the perception of superhuman traits, maintain grueling initiation rituals, and rely on esoteric divination rituals. An anthropological view of markets can usefully supplement economic and psychological approaches.
Findings Linking Mismatch Repair Mutation With Age at Endometrial and Ovarian Cancer Onset in Lynch Syndrome
Authors: Manon Suerink, Sanne W. ten Broeke, Maartje Nielsen
Journal: JAMA Oncology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
ACPA IgG galactosylation associates with disease activity in pregnant patients with rheumatoid arthritis
Authors: Albert Bondt, Lise Hafkenscheid, David Falck, T Martijn Kuijper, Yoann Rombouts, Johanna M W Hazes, Manfred Wuhrer, Radboud J E M Dolhain
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> Patients with autoantibody-positive rheumatoid arthritis (RA) are less likely to experience pregnancy-induced improvement of RA disease activity (DAS28-C reactive protein (CRP)) compared with patients with autoantibody-negative RA. Anti-citrullinated protein antibodies (ACPAs) are the most specific autoantibodies for RA. We previously demonstrated that disease improvement is associated with changes in total IgG glycosylation, which regulate antibody effector function. Therefore, we sought to analyse the ACPA-IgG glycosylation profile during pregnancy with the aim to understand the lower change of pregnancy-induced improvement of the disease in patients with autoantibody-positive RA. <h3>Methods</h3> ACPA-IgGs were purified from ACPA-positive patient sera (n=112) of the Pregnancy-induced Amelioration of Rheumatoid Arthritis cohort, a prospective study designed to investigate pregnancy-associated improvement of RA. The fragment crystallisable (Fc)glycosylation profile of ACPA-IgGs was characterised by mass spectrometry and compared with that of total IgG derived from the same patients or from ACPA-negative patients. <h3>Results</h3> All ACPA-IgG subclasses display significant changes in the level of galactosylation and sialylation during pregnancy, although less pronounced than in total IgG. The pregnancy-induced increase in ACPA-IgG galactosylation, but not sialylation, associates with lower DAS28-CRP. In ACPA-positive patients, no such association was found with changes in the galactosylation of total IgG, whereas in ACPA-negative patients changes in disease activity correlated well with changes in the galactosylation of total IgG. <h3>Conclusions</h3> In ACPA-positive RA, the pregnancy-induced change in galactosylation of ACPA-IgG, and not that of total IgG, associates with changes in disease activity. These data may indicate that in ACPA-positive patients the galactosylation of ACPA-IgG is of more pathogenic relevance than that of total IgG.
Developing core elements and checklist items for global hospital antimicrobial stewardship programmes: a consensus approach
Authors: C. Pulcini, F. Binda, A.S. Lamkang, A. Trett, E. Charani, D.A. Goff, S. Harbarth, S.L. Hinrichsen, G. Levy-Hara, M. Mendelson, D. Nathwani, R. Gunturu, S. Singh, A. Srinivasan, V. Thamlikitkul, K. Thursky, E. Vlieghe, H. Wertheim, M. Zeng, S. Gandra, R. Laxminarayan
Journal: Clinical Microbiology and Infection (2018)
LncRNAs regulate the cytoskeleton and related Rho/ROCK signaling in cancer metastasis
Authors: Yanyan Tang, Yi He, Ping Zhang, Jinpeng Wang, Chunmei Fan, Liting Yang, Fang Xiong, Shanshan Zhang, Zhaojian Gong, Shaolin Nie, Qianjin Liao, Xiayu Li, Xiaoling Li, Yong Li, Guiyuan Li, Zhaoyang Zeng, Wei Xiong, Can Guo
Journal: Molecular Cancer (2018)

Some of the key steps in cancer metastasis are the migration and invasion of tumor cells; these processes require rearrangement of the cytoskeleton. Actin filaments, microtubules, and intermediate filaments involved in the formation of cytoskeletal structures, such as stress fibers and pseudopodia, promote the invasion and metastasis of tumor cells. Therefore, it is important to explore the mechanisms underlying cytoskeletal regulation. The ras homolog family (Rho) and Rho-associated coiled-coil containing protein serine/threonine kinase (ROCK) signaling pathway is involved in the regulation of the cytoskeleton. Moreover, long noncoding RNAs (lncRNAs) have essential roles in tumor migration and guide gene regulation during cancer progression. LncRNAs can regulate the cytoskeleton directly or may influence the cytoskeleton via Rho/ROCK signaling during tumor migration. In this review, we focus on the regulatory association between lncRNAs and the cytoskeleton and discuss the pathways and mechanisms involved in the regulation of cancer metastasis.