tbuckley/cabot-search huggingface dataset:
Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study
Authors: Jonathon W. Senefeld, Patrick W. Johnson, Katie L. Kunze, Evan M. Bloch, Noud van Helmond, Michael A. Golafshar, Stephen A. Klassen, Allan M. Klompas, Matthew A. Sexton, Juan C. Diaz Soto, Brenda J. Grossman, Aaron A. R. Tobian, Ruchika Goel, Chad C. Wiggins, Katelyn A. Bruno, Camille M. van Buskirk, James R. Stubbs, Jeffrey L. Winters, Arturo Casadevall, Nigel S. Paneth, Beth H. Shaz, Molly M. Petersen, Bruce S. Sachais, Matthew R. Buras, Mikolaj A. Wieczorek, Benjamin Russoniello, Larry J. Dumont, Sarah E. Baker, Ralph R. Vassallo, John R. A. Shepherd, Pampee P. Young, Nicole C. Verdun, Peter Marks, N. Rebecca Haley, Robert F. Rea, Louis Katz, Vitaly Herasevich, Dan A. Waxman, Emily R. Whelan, Aviv Bergman, Andrew J. Clayburn, Mary Kathryn Grabowski, Kathryn F. Larson, Juan G. Ripoll, Kylie J. Andersen, Matthew N. P. Vogt, Joshua J. Dennis, Riley J. Regimbal, Philippe R. Bauer, Janis E. Blair, Zachary A. Buchholtz, Michaela C. Pletsch, Katherine Wright, Joel T. Greenshields, Michael J. Joyner, R. Scott Wright, Rickey E. Carter, DeLisa Fairweather
Journal: PLoS Medicine (2021)

The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma.
Environmental factors in declining human fertility
Authors: Niels E. Skakkebæk, Rune Lindahl-Jacobsen, Hagai Levine, Anna-Maria Andersson, Niels Jørgensen, Katharina M. Main, Øjvind Lidegaard, Lærke Priskorn, Stine A. Holmboe, Elvira V. Bräuner, Kristian Almstrup, Luiz R. Franca, Ariana Znaor, Andreas Kortenkamp, Roger J. Hart, Anders Juul
Journal: Nature Reviews Endocrinology (2021)
Queries and Minor Notes
Journal: JAMA (1913)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Evaluation of the 3-Minute Diagnostic Confusion Assessment Method for Identification of Postoperative Delirium in Older Patients
Authors: Jordan Oberhaus, Wei Wang, Angela M. Mickle, Jennifer Becker, Catherine Tedeschi, Hannah R. Maybrier, Ravi T. Upadhyayula, Maxwell R. Muench, Nan Lin, Eva M. Schmitt, Sharon K. Inouye, Michael S. Avidan
Journal: JAMA Network Open (2021)

Delirium is a common postoperative complication in older patients that often goes undetected and might lead to worse outcomes. The 3-Minute Diagnostic Confusion Assessment Method (3D-CAM) might be a practical tool for routine clinical diagnosis of delirium.To assess the 3D-CAM for detecting postoperative delirium compared with the long-form CAM used for research purposes.This cohort study of older patients enrolled in ongoing clinical trials between 2015 and 2018 was conducted at a single tertiary US hospital. Included participants were aged 60 years or older undergoing major elective surgical procedures that required at least a 2-day hospital stay. Data were analyzed between February and April 2019.Surgical procedures of at least 2 hours in length requiring general anesthesia with planned extubation.Patients were concurrently assessed for delirium using the 3D-CAM assessment and the long-form CAM, scored based on a standardized cognitive assessment. Agreement between these 2 methods was tested using Cohen κ with repeated measures, a generalized linear mixed-effects model, and Bland-Altman analysis.Sixteen raters conducted 471 concurrent CAM and 3D-CAM interviews including 299 patients (mean [SD] age, 69 [6.5] years), the majority of whom were men (152 [50.8%]), were White (263 [88.0%]), and had noncardiac operations (211 [70.6%]). Both instruments had good intraclass correlation (0.84 for the CAM and 0.98 for the 3D-CAM). Cohen κ demonstrated good overall agreement between the CAM and 3D-CAM (κ = 0.71; 95% CI, 0.58 to 0.83). According to the mixed-effects model, there was statistically significant disagreement between the 3D-CAM and CAM (estimated difference in fixed effect, -0.68; 95% CI, -1.32 to -0.05; P = .04). Bland-Altman analysis showed the probability of a delirium diagnosis with the 3D-CAM was more than twice the probability of a delirium diagnosis with the CAM (probability ratio, 2.78; 95% CI, 2.44 to 3.23).The 3D-CAM instrument demonstrated agreement with the long-form CAM and might provide a pragmatic and sensitive clinical tool for detecting postoperative delirium, with the caveat that the 3D-CAM might overdiagnose delirium.
Clonal hematopoiesis is associated with improved survival in patients with metastatic colorectal cancer from the FIRE-3 trial
Authors: Christopher Maximilian Arends, Savvina Dimitriou, Arndt Stahler, Raphael Hablesreiter, Paulina M. Strzelecka, Catarina M. Stein, Marlon Tilgner, Ryunosuke Saiki, Seishi Ogawa, Lars Bullinger, Dominik P. Modest, Sebastian Stintzing, Volker Heinemann, Frederik Damm
Journal: Blood (2021)
Performance of Machine Learning Algorithms for Predicting Progression to Dementia in Memory Clinic Patients
Authors: Charlotte James, Janice M. Ranson, Richard Everson, David J. Llewellyn
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Machine learning algorithms could be used as the basis for clinical decision-making aids to enhance clinical practice. <h3>Objective</h3> To assess the ability of machine learning algorithms to predict dementia incidence within 2 years compared with existing models and determine the optimal analytic approach and number of variables required. <h3>Design, Setting, and Participants</h3> This prognostic study used data from a prospective cohort of 15 307 participants without dementia at baseline to perform a secondary analysis of factors that could be used to predict dementia incidence. Participants attended National Alzheimer Coordinating Center memory clinics across the United States between 2005 and 2015. Analyses were conducted from March to May 2021. <h3>Exposures</h3> 258 variables spanning domains of dementia-related clinical measures and risk factors. <h3>Main Outcomes and Measures</h3> The main outcome was incident all-cause dementia diagnosed within 2 years of baseline assessment. <h3>Results</h3> In a sample of 15 307 participants (mean [SD] age, 72.3 [9.8] years; 9129 [60%] women and 6178 [40%] men) without dementia at baseline, 1568 (10%) received a diagnosis of dementia within 2 years of their initial assessment. Compared with 2 existing models for dementia risk prediction (ie, Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk Score, and the Brief Dementia Screening Indicator), machine learning algorithms were superior in predicting incident all-cause dementia within 2 years. The gradient-boosted trees algorithm had a mean (SD) overall accuracy of 92% (1%), sensitivity of 0.45 (0.05), specificity of 0.97 (0.01), and area under the curve of 0.92 (0.01) using all 258 variables. Analysis of variable importance showed that only 6 variables were required for machine learning algorithms to achieve an accuracy of 91% and area under the curve of at least 0.89. Machine learning algorithms also identified up to 84% of participants who received an initial dementia diagnosis that was subsequently reversed to mild cognitive impairment or cognitively unimpaired, suggesting possible misdiagnosis. <h3>Conclusions and Relevance</h3> These findings suggest that machine learning algorithms could accurately predict incident dementia within 2 years in patients receiving care at memory clinics using only 6 variables. These findings could be used to inform the development and validation of decision-making aids in memory clinics.
Prospective Identification of Subclinical Interstitial Lung Disease in a Rheumatoid Arthritis Cohort Is Associated with the <i>MUC5B</i> Promoter Variant
Authors: Scott M. Matson, Kevin D. Deane, Anna L. Peljto, Tami J. Bang, Peter B. Sachs, Avram D. Walts, Christopher Collora, Shuyu Ye, M. Kristen Demoruelle, Stephen M. Humphries, David A. Schwartz, Joyce S. Lee
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

"Prospective Identification of Subclinical Interstitial Lung Disease in a Rheumatoid Arthritis Cohort Is Associated with the MUC5B Promoter Variant." American Journal of Respiratory and Critical Care Medicine, 205(4), pp. 473–476
Publisher Correction: Multi-omic analysis of selectively vulnerable motor neuron subtypes implicates altered lipid metabolism in ALS
Authors: Hojae Lee, Jae Jin Lee, Na Young Park, Sandeep Kumar Dubey, Taeyong Kim, Kai Ruan, Su Bin Lim, Seong-Hyun Park, Shinwon Ha, Irina Kovlyagina, Kyung-tai Kim, Seongjun Kim, Yohan Oh, Hyesoo Kim, Sung-Ung Kang, Mi-Ryoung Song, Thomas E. Lloyd, Nicholas J. Maragakis, Young Bin Hong, Hyungjin Eoh, Gabsang Lee
Journal: Nature Neuroscience (2021)
Association of Stage Shift and Population Mortality Among Patients With Non–Small Cell Lung Cancer
Authors: Raja Flores, Parth Patel, Naomi Alpert, Bruce Pyenson, Emanuela Taioli
Journal: JAMA Network Open (2021)

Early detection by computed tomography and a more attention-oriented approach to incidentally identified pulmonary nodules in the last decade has led to population stage shift for non-small cell lung cancer (NSCLC). This stage shift could substantially confound the evaluation of newer therapeutics and mortality outcomes.To investigate the association of stage shift with population mortality among patients with NSCLC.This retrospective cohort study was performed from October 2020 to June 2021 and used data from the Surveillance, Epidemiology, and End Results (SEER) registries to assess all patients from 2006 to 2016 with NSCLC.Incidence-based mortality was evaluated by year-of-death. To assess shifts in diagnostic characteristics, clinical stage and histology distributions were examined by year using χ2 tests. Trends were assessed using the average annual percentage change (AAPC), calculated with JoinPoint software. Kaplan-Meier survival analysis assessed overall survival according to stage and compared those missing any stage with those with a reported stage.The final sample contained 312 382 patients; 166 657 (53.4%) were male, 38 201 (12.2%) were Black, and 249 062 (79.7%) were White; the median (IQR) age was 68 (60-76) years; 163 086 (52.2%) had adenocarcinoma histology. Incidence-based mortality within 5 years of diagnosis decreased from 2006 to 2016 (AAPC, -3.7; 95% CI, -4.1 to -3.4). When assessing stage shift, there was significant association between year-of-diagnosis and clinical stage, with stage I/II diagnosis increasing from 26.5% to 31.2% (AAPC, 1.5; 95% CI, 0.5 to 2.5); and stage III/IV diagnosis decreasing significantly from 70.8% to 66.1% (AAPC, -0.6; 95% CI, -1.0 to -0.2). Missing staging information was not associated with year-of-diagnosis (AAPC, -1.6; 95% CI, -7.4 to 4.5). Year-of-diagnosis was significantly associated with tumor histology (χ2 = 8990.0; P < .001). There was a significant increase in adenocarcinomas: 42.9% in 2006 to 59.0% in 2016 (AAPC, 3.4; 95% CI, 2.9 to 3.9). Median (IQR) survival for stage I/II was 57 months (18 months to not reached); stage III/IV was 7 (2-19) months; and missing stage was 10 (2-28) months. When compared with those with known stage, those without stage information had significantly worse survival than those with stage I/II, with survival between those with stage III and stage IV (log-rank χ2 = 87 125.0; P < .001).This cohort study found an association between decreased mortality and a corresponding diagnostic shift from later to earlier stage. These findings suggest that studies investigating the effect of treatment on lung cancer must take into account stage shift and the confounding association with survival and mortality outcome.
Anti-CD38 therapy impairs SARS-CoV-2 vaccine response against alpha and delta variants in patients with multiple myeloma
Authors: Soledad Henriquez, Jérémie Zerbit, Timothée Bruel, Amani Ouedrani, Delphine Planas, Paul Deschamps, Isabelle Staropoli, Jérôme Hadjadj, Bruno Varet, Natalia Ermak, Didier Bouscary, Lise Willems, Guillemette Fouquet, Justine Decroocq, Patricia Franchi, Benedicte Deau-Fischer, Benjamin Terrier, Jérôme Tamburini, Lucienne Chatenoud, Olivier Schwartz, Marguerite Vignon
Journal: Blood (2021)
ANTIVACCINATION AND INTERNAL VACCINATION.
Journal: JAMA (1904)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Using artificial intelligence-based models to predict the risk of mucormycosis among COVID-19 survivors: An experience from a public hospital in India
Authors: Shabbir Syed-Abdul, A. Shoban Babu, Raja Shekhar Bellamkonda, Ramaiah Itumalla, GVRK Acharyulu, Surya Krishnamurthy, Y. Venkat Santosh Ramana, Naresh Mogilicharla, Shwetambara Malwade, Yu-Chuan Li
Journal: Journal of Infection (2021)
Slow degrading Mg-based materials induce tumor cell dormancy on an osteosarcoma-fibroblast coculture model
Authors: Philipp Globig, Regine Willumeit-Römer, Fernanda Martini, Elisa Mazzoni, Bérengère J.C. Luthringer-Feyerabend
Journal: Bioactive Materials (2021)

Osteosarcoma is one of the most common cancers in young adults and is commonly treated using surgery and chemotherapy. During the past years, these therapy approaches improved but failed to ameliorate the outcomes. Therefore, novel, targeted therapeutic approaches should be established to enhance treatment success while preserving patient's quality of life. Recent studies suggest the application of degradable magnesium (Mg) alloys as orthopedic implants bearing a potential antitumor activity. Here, we examined the influence of Mg-based materials on an osteosarcoma-fibroblast coculture. Both, Mg and Mg-6Ag did not lead to tumor cell apoptosis at low degradation rates. Instead, the Mg-based materials induced cellular dormancy in the cancer cells indicated by a lower number of Ki-67 positive cancer cells and a higher p38 expression. This dormancy-like state could be reversed by reseeding on non-degrading glass slides but could not be provoked by inhibition of the protein kinase R-like endoplasmic reticulum kinase. By investigating the influence of the disjunct surface-near effects of the Mg degradation on cell proliferation, an increased pH was found to be a main initiator of Mg degradation-dependent tumor cell proliferation inhibition.
Risks and Benefits of Cannabis and Cannabinoids in Psychiatry
Authors: Kevin P. Hill, Mark S. Gold, Charles B. Nemeroff, William McDonald, Adrienne Grzenda, Alik S. Widge, Carolyn Rodriguez, Nina V. Kraguljac, John H. Krystal, Linda L. Carpenter
Journal: American Journal of Psychiatry (2021)

Objective: The United States is in the midst of rapidly changing laws regarding cannabis. The increasing availability of cannabis for recreational and medical use requires that mental health clinicians be knowledgeable about evidence to be considered when counseling both patients and colleagues. In this review, the authors outline the evidence from randomized double-blind placebo-controlled trials for therapeutic use of cannabinoids for specific medical conditions and the potential side effects associated with acute and chronic cannabis use. Methods: Searches of PubMed and PsycInfo were conducted for articles published through July 2021 reporting on “cannabis” or “cannabinoids” or “medicinal cannabis.” Additional articles were identified from the reference lists of published reviews. Articles that did not contain the terms “clinical trial” or “therapy” in the title or abstract were not reviewed. A total of 4,431 articles were screened, and 841 articles that met criteria for inclusion were reviewed by two or more authors. Results: There are currently no psychiatric indications approved by the U.S. Food and Drug Administration (FDA) for cannabinoids, and there is limited evidence supporting the therapeutic use of cannabinoids for treatment of psychiatric disorders. To date, evidence supporting cannabinoid prescription beyond the FDA indications is strongest for the management of pain and spasticity. Conclusions: As cannabinoids become more available, the need for an evidence base adequately evaluating their safety and efficacy is increasingly important. There is considerable evidence that cannabinoids have a potential for harm in vulnerable populations such as adolescents and those with psychotic disorders. The current evidence base is insufficient to support the prescription of cannabinoids for the treatment of psychiatric disorders.
TET deficiency perturbs mature B cell homeostasis and promotes oncogenesis associated with accumulation of G-quadruplex and R-loop structures
Authors: Vipul Shukla, Daniela Samaniego-Castruita, Zhen Dong, Edahí González-Avalos, Qingqing Yan, Kavitha Sarma, Anjana Rao
Journal: Nature Immunology (2021)
New Treatments for Migraine—Therapeutic Ratings and Comparative Coverage in the US, Canada, and Europe
Authors: Thomas J. Hwang, Kerstin N. Vokinger, Aaron S. Kesselheim
Journal: JAMA Internal Medicine (2021)

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 Internal Medicine 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 Internal Medicine journal
Abstract 13747: Targeting Urokinase-Type Plasminogen Activator (uPA) and the uPA Receptor, Reduces Vascular Inflammation and Lung Hemorrhage in Systemic Lupus and SARS CoV2 Infection in Mouse Models of Respiratory Distress Syndromes
Authors: Liqiang Zhang, Jordan R Yaron, Lauren Schutz, Emily Aliskevich, Kyle Browder, Nicholas Saldevar, Isabela R Zanetti, Nora Elmadbouly, Honor Glenn, Yize Li, Karen Kibler, Brenda Hogue, Grant McFadden, Alexandra R Lucas
Journal: Circulation (2021)

Introduction: Acute respiratory distress syndromes with vascular inflammation and alveolar hemorrhage have high mortality and limited treatment. Autoimmune disease and severe viral infection cause vascular inflammation and hemorrhage. Serine protease coagulation pathways increase inflammatory cell activation and damage. Viruses have evolved highly effective immune modulating ser ine p roteinase in hibitors, serpins . Myxomavirus Serp-1 improves survival and reduces inflammation, vasculitis and lung hemorrhage in MHV68 gamma herpes infections (P &lt; 0.01). Serp-1 also reduces Lupus alveolar hemorrhage (DAH) and proved safe and effective in a randomized, blinded, dose escalating trial in patients with coronary stent implant. Hypothesis: We hypothesize that treatment with PEGylated Serp-1 (PEGSerp-1) will reduce hemorrhage and inflammatory vasculitis in autoimmune and infectious lung disease. Methods: Pristane induced DAH and SARS-CoV-2 virus infections were treated with PEGSerp-1 in mouse models. Results: Serp-1 and PEGSerp-1 given daily IP for 14 days significantly reduced pristane induced DAH (N = 30 C57Bl/6 mice; P &lt; 0.05) at 14 days follow up. PEGSerp-1 also reduced lung hemorrhage given for 7days treatment (N = 6 mice; P &lt;0.01) or when given 7 days after pristane induction of DAH (N = 6 mice; P &lt; 0.01). Macrophage invasion (P &lt; 0.01), Prussian blue staining for hemosiderosis, C5b-9 complex deposition and soluble uPAR (suPAR) were significantly reduced with PEGSerp-1 treatment. PEGSerp-1 given daily after SARS-CoV-2 infection (48hrs, BALB/c mice, N = 16) also significantly reduced lung inflammation; decreased F4/80+ and iNOS+ macrophage staining (P &lt; 0.02). Virus titer was also reduced in TMPRS2+ Vero cells (10μg/mL), and in SARS infected lungs. PEG Serp-1 homes to areas of pristane lung damage, but not normal lungs, indicating targeting of protease activation. No adverse effects were detected. Conclusion: Treatment for vascular inflammation and hemorrhage in severe autoimmune and virus induced respiratory distress syndromes is very limited. Targeting thrombolytic and inflammatory serine protease uPA/ uPAR complex activation provides a new therapeutic approach to severe respiratory distress in autoimmune disease and viral infection.
Successful removal of a toothpick penetrating the sigmoid colon by low-pressure endoscopy using the gel immersion method
Authors: Yohei Funayama, Tomonori Yano, Masafumi Kitamura, Hiroki Nagai, Shigeru Ono, Alan Kawarai Lefor, Hironori Yamamoto
Journal: Endoscopy (2021)

Foreign bodies with sharp edges such as toothpicks in the gastrointestinal tract may cause injury [1]. Foreign bodies in the colon are preferably removed by colonoscopy, but bowel preparation should be avoided with suspected penetration. Gel immersion endoscopy can provide a clear view even without bowel preparation [2] while maintaining low intraluminal pressure [3] [4].