tbuckley/cabot-search huggingface dataset:
PF427 FOSTAMATINIB, A SPLEEN TYROSINE KINASE INHIBITOR, FOR THE TREATMENT OF WARM ANTIBODY AUTOIMMUNE HEMOLYTIC ANEMIA: INITIAL RESULTS OF THE OPEN‐LABEL EXTENSION PERIOD OF THE SOAR PHASE 2 STUDY
Authors: D. Kuter, A. Richy, M. Boxer, C. Broome, D. Arnold, J. Field, I. Murakhovskaya, K. Rogers, A. Lowe, R. Numerof, H. Zayed, S. Tong, A.‐M. Duliege
Journal: HemaSphere (2019)

Background: Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare and often serious disease resulting from antibody‐mediated destruction of red blood cells (RBCs). The SYK inhibitor, fostamatinib, markedly improved Hgb levels in patients with wAIHA during a phase 2, open‐label, multicenter study, in which 9 of 21 (43%) met the primary endpoint (Hgb &gt;10 g/dL with an increase of ≥2 g/dL from baseline by Week 24 without rescue therapy or RBC transfusion). Aims: We report the results of the ongoing extension period of the study. Methods: Adults with primary or secondary wAIHA had to have failed ≥1 prior treatment for wAIHA, have hemoglobin (Hgb) &lt;10 g/dL, an IgG‐positive direct antiglobulin test, haptoglobin &lt;10 mg/dL, and lactate dehydrogenase (LDH) &gt;ULN. Fostamatinib 150 mg BID was taken orally with no food restriction (dose reduction permitted based on tolerability). To enter the extension, patients had to meet the primary endpoint OR show a marked improvement in Hgb and had to have tolerated study drug. Results: Nine patients who completed the initial treatment phase entered the extension: 7 patients met the primary endpoint, 1 was a late responder, and 1 had a beneficial trend during the initial treatment phase. For baseline characteristics, see table. Median Hgb levels increased over the study. Five of 9 patients have an ongoing response to fostamatinib as of July 2018, and none have had rescue therapy or an RBC transfusion. Six of 9 patients are still on the study, and 3 discontinued due to lack of response plus AE (1), consent withdrawn (1), and unknown (1). Nine patients had ≥1 AE, 6 with treatment‐related AEs. AEs were mostly mild to moderate, and the most common AEs were diarrhea and upper respiratory tract infection. Three Grade 3 AEs were reported in 2 patients. AEs resulted in dose reduction in 2 patients, dose interruption in 2, and study drug withdrawn in 1. Summary/Conclusion: Fostamatinib markedly improved Hgb levels in 9 of 21 (43%) patients with wAIHA during a phase 2, open‐label, multicenter study. Adverse events (AE) were manageable and consistent with those previously reported for fostamatinib in other conditions. A randomized, placebo‐controlled, Phase 3 trial is underway. image
AB0071 SERUM S100A8/A9 (CALPROTECTIN) IN FAMILIAL MEDITERRANEAN FEVER DOES NOT CORRELATE WITH DISEASE ACTIVITY
Authors: Ruth J. Pepper, Mathew Hutchinson, S.R. Henderson, S.K. Todd, Alan D. Salama, Philip N. Hawkins, Helen J. Lachmann
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Familial Mediterranean Fever (FMF) is caused by mutations in MEFV. The protein product pyrin is expressed in monocytes, neutrophils and eosinophils. Acute inflammatory attacks are accompanied by a dramatic hepatic acute phase response. S100A8/A9 is damage associated molecular pattern and a TLR4 ligand expressed in neutrophils, monocytes and early infiltrating macrophages. We aimed to investigate S100A8/A9 in 39 patients with FMF, 45 healthy carriers and wild type controls. <h3>Objectives</h3> To measure S100A8/9 in patients with FMF, carriers and healthy controls. <h3>Methods</h3> All patients were genotyped. Patients and healthy controls (HC) serum S100A8/A9 levels, cell surface expression on monocytes and neutrophils as well as intracellular peripheral blood mononuclear cells (PBMC) expression were measured by flow cytometry (FACS). CD14 cells were isolated and following overnight incubation with or without LPS, S100A8/A9 was measured in the supernatants by ELISA. Patient and HC monocyte apoptosis was compared. <h3>Results</h3> Serum levels were measures in 84 samples from 31 patients with homozygous or compound mutations (median 9061ng/ml [range 500-38470], 79 samples from 39 symptomatic patients who were MEFV heterozygotes (median 9394ng/ml [range 1744-38119], 80 samples from 45 individuals with MEFV variants but without clinical features of FMF (median 10939ng/ml [range 2447-&gt;40000]. There was no difference in calprotectin concentrations between the different mutations. All the groups described had significantly higher levels than healthy controls (n=16 median 2836ng/ml [range 1058-6175])(p&lt;0.001).Minimal monocyte and neutrophil cell surface expression was detectable. Following LPS stimulation there was significantly more S100A8/A9 detected in the supernatants in patients than healthy control CD14. There was also a trend to an increased intracellular monocyte S100A8/A9 expression. <h3>Conclusion</h3> Patients with pyrin mutations both with and without clinical disease have greatly elevated serum S100A8/A9 levels without detectable cell surface expression in well-controlled disease with a trend to an increased monocyte intracellular expression. Upon monocyte stimulation with LPS, increased S100A8/A9 is secreted. The exact mechanism by which these patients, especially those with mutations but no clinical disease, demonstrate sustained elevated serum S100A8/A9 remains to be elucidated but does not appear to result in a significant clinical sequelae. <h3>Disclosure of Interests</h3> Ruth J. Pepper: None declared, Mathew Hutchinson: None declared, S.R. Henderson: None declared, S.K. Todd: None declared, Alan D. Salama: None declared, Philip N Hawkins: None declared, Helen J. Lachmann Grant/research support from: SOBI, Novartis, Consultant for: Novartis, Takeda, Speakers bureau: SOBI. Novartis
Abstract 17565: High-Throughput Analysis of Full-Text Cardiac Catheterization Reports Using Open-Source Natural Language Processing and Machine Learning Tools
Authors: Michael G Levin, Aeron M Small, Jay S Giri, Daniel J Rader, Scott M Damrauer
Journal: Circulation (2017)

Introduction: Cardiac catheterization reports are rich sources of clinical data, but their unstructured format makes large-scale analysis time- and effort-intensive. Natural Language Processing (NL...
Association of Infectious Diseases Consultation With Long-term Postdischarge Outcomes Among Patients With <i>Staphylococcus aureus</i> Bacteremia
Authors: Michihiko Goto, Michael P. Jones, Marin L. Schweizer, Daniel J. Livorsi, Eli N. Perencevich, Kelly Richardson, Brice F. Beck, Bruce Alexander, Michael E. Ohl
Journal: JAMA Network Open (2020)

<h3>Importance</h3> <i>Staphylococcus aureus</i>bacteremia (SAB) is common and associated with poor long-term outcomes. Previous studies have demonstrated an association between infectious diseases (ID) consultation and improved short-term (ie, within 90 days) outcomes for patients with SAB, but associations with long-term outcomes are unknown. <h3>Objective</h3> To investigate the association of ID consultation with long-term (ie, 5 years) postdischarge outcomes among patients with SAB. <h3>Design, Setting, and Participants</h3> This cohort study included all patients (N = 31 002) with a first episode of SAB who were discharged alive from 116 acute care units of the nationwide Veterans Health Administration where ID consultation was offered. Data were collected from January 2003 to December 2014, with follow-up through September 30, 2018. Data analysis was conducted from February to December 2019. <h3>Exposures</h3> Infectious diseases consultation during the index hospital stay. <h3>Main Outcomes and Measures</h3> The primary outcome was time to development of a composite event of all-cause mortality or recurrence of SAB within 5 years of discharge. As secondary outcomes, SAB recurrence and all-cause mortality with and without recurrence were analyzed while accounting for semicompeting risks. <h3>Results</h3> The cohort included 31 002 patients (30 265 [97.6%] men; median [interquartile range] age at SAB onset, 64.0 [57.0-75.0] years). Among 31 002 patients, there were 18 794 (60.6%) deaths, 4772 (15.4%) SAB recurrences, and 20 414 (65.8%) composite events during 5 years of follow-up; 12 773 deaths (68.0%) and 2268 recurrences (47.5%) occurred more than 90 days after discharge. Approximately half of patients (15 360 [49.5%]) received ID consultation during the index hospital stay; ID consultation was associated with prolonged improvement in the composite outcome (adjusted hazard ratio at 5 years, 0.71; 95% CI, 0.68-0.74;<i>P</i> &lt; .001). Infectious diseases consultation was also associated with improved outcomes when all-cause mortality without recurrence and SAB recurrence were analyzed separately (all-cause mortality without recurrence: adjusted hazard ratio at 5 years, 0.77; 95% CI, 0.74-0.81;<i>P</i> &lt; .001; SAB recurrence: adjusted hazard ratio at 5 years, 0.68; 95% CI, 0.64-0.72;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> Having an ID consultation during the index hospital stay among patients with SAB was associated with improved postdischarge outcomes for at least 5 years, suggesting that contributions of ID specialists to management during acute infection may have a substantial influence on long-term outcomes. Further investigations of the association of ID consultation with outcomes after<i>S aureus </i>should include long-term follow-up.
One-pot synthesis of a microporous organosilica-coated cisplatin nanoplatform for HIF-1-targeted combination cancer therapy
Authors: Xiaojuan Zhang, Chuanchuan He, Xiaoguang Liu, Yan Chen, Pengxuan Zhao, Chen Chen, Ruicong Yan, Minsi Li, Ting Fan, Bouhari Altine, Tan Yang, Yao Lu, Robert J. Lee, Yongkang Gai, Guangya Xiang
Journal: Theranostics (2020)

Nanoparticle formulations have proven effective for cisplatin delivery. However, the development of a versatile nanoplatform for cisplatin-based combination cancer therapies still remains a great challenge. Methods: In this study, we developed a one-pot synthesis method for a microporous organosilica shell-coated cisplatin nanoplatform using a reverse microemulsion method, and explored its application in co-delivering acriflavine (ACF) for inhibiting hypoxia-inducible factor-1 (HIF-1). Results: The resulting nanoparticles were tunable, and they could be optimized to a monodisperse population of particles in the desired size range (40-50 nm). In addition, organic mPEG2000-silane and tetrasulfide bond-bridged organosilica were integrated into the surface and silica matrix of nanoparticles for prolonged blood circulation and tumor-selective glutathione-responsive degradation, respectively. After reaching the tumor sites, cisplatin induced cancer cell death and activated HIF-1 pathways, resulting in acquired drug resistance and tumor metastasis. To address this issue, ACF was co-loaded with cisplatin to prevent the formation of HIF-1α/β dimers and suppress HIF-1 function. Hence, the efficacy of cisplatin was improved, and cancer metastasis was inhibited. Conclusion: Both in vitro and in vivo results suggested that this core-shell nanostructured cisplatin delivery system represented a highly efficacious and promising nanoplatform for the synergistic delivery of combination therapies involving cisplatin.
USPSTF recommends screening for asymptomatic bacteriuria in pregnant women but not nonpregnant adults
Authors: Dennis G. Maki
Journal: Annals of Internal Medicine (2020)

ACP Journal Club18 February 2020USPSTF recommends screening for asymptomatic bacteriuria in pregnant women but not nonpregnant adultsDennis G. Maki, MD, MACPDennis G. Maki, MD, MACPUniversity of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA (D.G.M.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJ202002180-014 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationOwens DK, Davidson KW, Krist AH, et al. Screening for asymptomatic bacteriuria in adults: US Preventive Services Task Force recommendation statement. JAMA. 2019;322:1188-94. https://pubmed.ncbi.nlm.nih.gov/31550038Clinical Impact RatingsInfectious Disease: Public Health: References1 Schito GC, Naber KG, Botto H, et al. The ARESC study: an international survey on the antimicrobial resistance of pathogens involved in uncomplicated urinary tract infections. Int J Antimicrob Agents. 2009;34:407-13. [PMID: 19505803] Google Scholar2 Nicolle LE, Gupta K, Bradley SF, et al. Clinical practice guideline for the management of asymptomatic bacteriuria: 2019 update by the Infectious Diseases Society of America. Clin Infect Dis. 2019;68:1611-15. [PMID: 31506700] Google Scholar3 Flokas ME, Andreatos N, Alevizakos M, et al. Inappropriate management of asymptomatic patients with positive urine cultures: a systematic review and meta-analysis. Open Forum Infect Dis. 2017;4:ofx207. [PMID: 29226170] Google Scholar4 Nace DA, Perera SK, Hanlon JT, et al. The Improving Outcomes of UTI Management in Long-Term Care Project (IOU) consensus guidelines for the diagnosis of uncomplicated cystitis in nursing home residents. J Am Med Dir Assoc. 2018;19:765-9.e3. [PMID: 30037743] Google Scholar Author, Article, and Disclosure InformationAffiliations: University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA (D.G.M.)Disclosures: The commentator has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-3039.This article was published at Annals.org on 4 February 2020. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 18 February 2020Volume 172, Issue 4Page: JC14KeywordsAntimicrobialsCathetersElderlyJoint replacement surgeryOutpatient clinicsPopulation statisticsPregnancySpinal cord injurySystematic reviewsTreatment guidelines ePublished: 18 February 2020 Issue Published: 18 February 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Understanding the Role of Comparative Clinical Studies in the Development of Oncology Biosimilars
Authors: Justin Stebbing, Paul N. Mainwaring, Giuseppe Curigliano, Mark Pegram, Mark Latymer, Angel H. Bair, Hope S. Rugo
Journal: Journal of Clinical Oncology (2020)

Biosimilars have the potential to broaden patient access to biologics and provide cost savings for health care systems. During the development of a biosimilar, data that directly compare the proposed biosimilar with the reference product are required. Such comparative data are generated in a stepwise hierarchical process that begins with extensive laboratory-based structural analyses and functional assays. This initial analytical phase serves as the foundation for the demonstration of biosimilarity and is followed by nonclinical in vivo testing (if required) and then clinical evaluation, including a comparative pharmacokinetics/pharmacodynamics study that is usually conducted in healthy volunteers. The development program typically culminates with a comparative clinical efficacy study. The aim of this study is to confirm clinical equivalence of the potential biosimilar and reference product on the basis of prespecified margins, using a study population and efficacy end point that are sufficiently sensitive for detecting potential product-related differences. Such studies also include detailed analyses of safety as well as evaluation of immunogenicity. As biosimilars become more widely available in oncology, especially with recent regulatory approvals of rituximab, trastuzumab, and bevacizumab biosimilars, it is critically important that clinicians understand how the comparative clinical study differs from a traditional phase III efficacy and safety study in the development of a novel biologic originator product. Here, we review the role of comparative clinical studies in biosimilar development, with a focus on trials conducted to support approved trastuzumab biosimilars. We discuss the study populations and end points used, extrapolation of indications, and the confirmatory nature of these studies within the totality of evidence supporting biosimilarity.
BMJ Awards: finalists announced for 12th annual event
Authors: Jacqui Wise
Journal: BMJ (2020)

The race to recognise the most innovative and inspirational teams working in UK healthcare is almost over, with this week’s announcement of the 85 teams shortlisted for the 12th BMJ Awards.

This year’s awards attracted 281 submissions across 14 categories, which for the first time include environmental sustainability and climate action, women’s health, and work and wellbeing. There will also be two special recognition awards for outstanding contribution to health and for the UK research paper of the year.

The BMJ awards aim to promote excellence in healthcare, …
Blockade of DC-SIGN+ Tumor-Associated Macrophages Reactivates Antitumor Immunity and Improves Immunotherapy in Muscle-Invasive Bladder Cancer
Authors: Baoying Hu, Zewei Wang, Han Zeng, Yangyang Qi, Yifan Chen, Tao Wang, Jiajun Wang, Yuan Chang, Qi Bai, Yu Xia, Yiwei Wang, Li Liu, Yu Zhu, Bo Dai, Jianming Guo, Le Xu, Weijuan Zhang, Jiejie Xu
Journal: Cancer Research (2020)

Abstract Tumor-associated macrophages (TAM) play an indispensable role in the modulation of the cancer immune microenvironment. Despite the fact that TAMs may exert both antitumor and protumor activities, the molecular mechanisms involved remain poorly understood. Here, we characterized a subpopulation of TAMs expressing dendritic cell–specific C-type lectin (DC-SIGN) and investigated its relevance to the prognosis and immune microenvironment of muscle-invasive bladder cancer (MIBC). DC-SIGN+ TAMs were abundant in a significant proportion of human MIBC specimens. High levels of DC-SIGN+ TAMs were associated with dismal prognosis and unresponsiveness to adjuvant chemotherapy in MIBC. Notably, multiple anti-inflammatory cytokines were enriched in DC-SIGN+ TAMs. RNA-seq analysis revealed that multiple M2-like signaling pathways were significantly upregulated in DC-SIGN+ TAMs. High infiltration of DC-SIGN+ TAMs was associated with CD8+ T-cell tolerance in MIBC. Moreover, abrogating DC-SIGN function using a neutralizing antibody led to impaired expression of anti-inflammatory cytokines and augmented PD-1 inhibitor pembrolizumab-mediated cytotoxic effects of CD8+T cells toward MIBC cells. In summary, these results suggest that DC-SIGN+ TAM infiltration is closely linked to a protumor immune microenvironment and may serve as a promising therapeutic target in the immunotherapy of MIBC. Significance: DC-SIGN+ TAMs have an immunosuppressive and tumor-promoting function and may serve as a prognostic indicator and therapeutic target in MIBC.
Implications of new understandings of gliomas in children and adults with NF1: report of a consensus conference
Authors: Roger J Packer, Antonio Iavarone, David T W Jones, Jaishri O Blakeley, Eric Bouffet, Michael J Fisher, Eugene Hwang, Cynthia Hawkins, Lindsay Kilburn, Tobey MacDonald, Stefan M Pfister, Brian Rood, Fausto J Rodriguez, Uri Tabori, Vijay Ramaswamy, Yuan Zhu, Jason Fangusaro, Stephen A Johnston, David H Gutmann
Journal: Neuro-Oncology (2020)

Abstract Gliomas are the most common primary central nervous system tumors occurring in children and adults with neurofibromatosis type 1 (NF1). Over the past decade, discoveries of the molecular basis of low-grade gliomas (LGGs) have led to new approaches for diagnosis and treatments. However, these new understandings have not been fully applied to the management of NF1-associated gliomas. A consensus panel consisting of experts in NF1 and gliomas was convened to review the current molecular knowledge of NF1-associated low-grade “transformed” and high-grade gliomas; insights gained from mouse models of NF1-LGGs; challenges in diagnosing and treating older patients with NF1-associated gliomas; and advances in molecularly targeted treatment and potential immunologic treatment of these tumors. Next steps are recommended to advance the management and outcomes for NF1-associated gliomas.
体系的鉄ホメオスタシスと鉄-反応性エレメント/鉄-調節蛋白質(IRE/IRP)調節ネットワーク | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: U Muckenthaler Martina, Galy Bruno, W Hentze Matthias
Journal: Annual Review of Nutrition (2008)
Three Problems in Meta-analysis of Prevalence of Obesity in European Children—Reply
Authors: Miriam Garrido-Miguel, Iván Cavero-Redondo, Vicente Martínez-Vizcaíno
Journal: JAMA Pediatrics (2020)

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 Pediatrics 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 Pediatrics journal