tbuckley/cabot-search huggingface dataset:
TMOD-36. DEVELOPMENT OF A PATIENT-DERIVED ORTHOTOPIC XENOGRAFT GLIOBLASTOMA MODEL PHENOTYPICALLY REPRESENTATIVE OF THE CLINICAL FEATURES
Authors: Tavarekere Nagaraja, Ana deCarvalho, Brent Griffith, Stephen Brown, George Divine, Susan Irtenkauf, Robert Knight, Ian Lee, Swayamprava Panda, Glauber Cabral, James Ewing
Journal: Neuro-Oncology (2019)

Abstract In murine models, patient derived orthotopic xenografts (PDOXs) generated from neurosphere cultures of human glioblastomas (GBMs) are unmatched in representing the molecular heterogeneity of the disease. However, intra-axial tumors with blood-brain barrier (BBB) breakdown visible on magnetic resonance imaging (MRI) are rare in these models and, thus, phenotypic recapitulation of human tumors is typically absent. We hypothesized that this absence lay in the interaction between tumor and stroma and that manipulation of the tumor stromal composition might produce a consistent BBB breakdown. Thirty-two athymic nude rats were implanted intracerebrally with one of two neurosphere cell lines (HF2303 or HF3016) derived from the tumors of two GBM patients demonstrating post-gadolinium enhancement on MRI. Neurospheres (3x105 cells in 10μl) were co-injected with a preparation containing either 5μl Matrigel with high (M+) or low (M-) growth factors, or PBS (M0). When the lesion reached 4 to 5 mm in diameter on imaging, MRI with contrast was used to study BBB breakdown. Two animals with only extra-axial tumors were excluded from analysis, and the intra-axial tumors were graded for radiological evidence of BBB breakdown on a scale of 0 to 4, with 0 being no evidence, and 4 being florid enhancement. A two-way ordinal logistic regression model was fit with treatment factors (three levels: M0, M+ and M-) and cell line (two levels: HF2303 and HF3016). A Wilcoxon Rank Sum test analysis within each cell line demonstrated a significant BBB breakdown effect with Matrigel in HF3016 (N=16, p=0.004), but not for HF2303 (N=16, p=0.328). By producing phenotypic conditions closer to the human glioma pathology, a reliable BBB breakdown in PDOX models represents a significant advance in assessing experimental therapies. However, as demonstrated herein, the effect of stromal enhancement is cell-line dependent, and the biological correlates that accompany BBB breakdown still need to be described.
Usefulness of laparoscopic posterior rectopexy for complete rectal prolapse: A cohort study
Authors: Hiroki Hashida, Masato Sato, Yukiko Kumata, Motoko Mizumoto, Masato Kondo, Hiroyuki Kobayashi, Takehito Yamamoto, Hiroaki Terajima, Satoshi Kaihara
Journal: International Journal of Surgery (2019)
Daily Chlorhexidine Gluconate Bathing Reduces the Rate of Bloodstream Infections in Adults Undergoing Inpatient Hematopoietic Stem Cell Transplantation
Authors: Vinay K. Giri, Kristin G. Kegerreis, Yi Ren, Lauren M. Bohannon, Erica Lobaugh-Jin, Julia A. Messina, Anita Matthews, Deborah H. Allen, Yvonne M. Mowery, Jennifer L. Saullo, Sin-Ho Jung, Taewoong Choi, Cristina Gasparetto, Mitchell E. Horwitz, Gwynn D. Long, Richard D. Lopez, David A. Rizzieri, Stefanie Sarantopoulos, Nelson J. Chao, Anthony D. Sung
Journal: Blood (2019)
SCIDOT-37. ASSESSING CEREBROSPINAL FLUID FLOW DYNAMICS IN PEDIATRIC PATIENTS WITH CENTRAL NERVOUS SYSTEM TUMORS
Authors: Kim Kramer, Maria Donzellie, Emmanuela Nwora, Neeta Pandit-Taskar
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The incidence of abnormal CSF flow dynamics in the pediatric population with CNS tumors prior to intraventricular therapy has not been described. METHODS We performed a single-institution, retrospective review of patients with primary or metastatic CNS tumors treated between 2003–2018 (15 years).. Patients underwent 111-indium diethylene triamine pentaacetic acid injection into the CSF intraventricular space followed by nuclear medicine imaging at 90 minutes, 4, 24, and 48 hours (if required). CSF flow was classified as normal, delayed, asymmetric or obstructed. RESULTS 278 CSF flow studies were performed in 224 patients, 202(90%) &lt;18 years of age. 116(52%) patients had metastatic CNS neuroblastoma, 57(25%) had medulloblastoma, and 51(23%) had other CNS histologies. Of the 278 studies, 237(85%) were normal, 9(3%) required neurosurgical intervention, 25(9%) were delayed, and 7(3%) were asymmetric. CONCLUSIONS Abnormal CSF flow and necessity of neurosurgical intervention must be considered when attempting to ensure appropriate intraventricular therapy in the pediatric population.
Thalassaemia in Britain
Authors: R. M. Bannerman, S. T. Callender
Journal: BMJ (1961)

tional in quality.They are in every sense of the term a great success.I find them all intelligent and possessed of a wonderful gift of touch, together with keen enthusittsm for their work.Apart from their qualities as masseurs, I think they have an extraordinarily good psychological effect upon their patients."What he said so long ago is still true as I hear from many medical and lay quarters: though of course all these men now practise electrotherapy in addition to massage.General practitioners may like to know that this service is readily available to help their patients.-Iam, etc
Cost-Effectiveness of a 12-Month Fixed Duration of Venetoclax in Combination with Obinutuzumab in First-Line Chronic Lymphocytic Leukemia in the United States
Authors: Matthew S. Davids, Anuja Chatterjee, Arliene Ravelo, Sheila Shapouri, Beenish S Manzoor, Kavita Sail, Gijs Van de Wetering, Michael Hallek
Journal: Blood (2019)
Whooping-cough and Measles
Authors: B. L. Hodge
Journal: BMJ (1948)

work of the late Dr. W. Gordon, of Exeter, who at that time was secretary of the South-Western Branch of the Association.Such was the strong line he took within the Parliamentary Bills Committee on the subject of reform of the Army Medical Service that a special subcommittee was formed; and a letter from him as chairman of this subcommittee was addressed to the Secretary of
Altered expression of β-catenin and UDP-glucose dehydrogenase in normal appearing acini of cancer-bearing prostate glands, detected by quantitative fluorescence imaging analysis
Authors: D. Huang, G. P. Casale, N. K. Wehbi, J. Tian, G. P. Hemstreet
Journal: Journal of Clinical Oncology (2006)

14540 Background: Expression of β-catenin and UDP-glucose dehydrogenase (UGDH) is markedly altered in prostate adenocarcinomas. The objective of this work was to evaluate expression of these proteins in normal appearing acini (NAA) of cancer-bearing prostate glands, as potential biomarkers of PC field disease. Methods: Archived core biopsies of 42 pairs of PC cases and controls were labeled for β-Catenin, and a tissue microarray of 10 prostatectomy specimens of cancer cases and controls were labeled for UGDH. A fluorophore-conjugated secondary antibody was incorporated into the staining protocol. Fluorescence in prostatic acini was measured with an automated Leica microscope and Image Pro Plus software and expressed as mean pixel intensity (MPI) per acinus and average MPI (AMPI) per case or control. Results: Mean AMPI of β-catenin in NAA of 33 cases (545 ± 93) was lower (p &lt; 0.01) than that of normal acini (NA) in age-matched controls (684 ± 90), whereas mean AMPI of NAA in the remaining 9 cases (712 ± 111) was higher (p = 0.003) than that of the matched controls (634 ± 95). Twelve cases under-expressing β-catenin in NAA had AMPIs below the lowest AMPI (506 ± 83) of all controls. Mean AMPI of UGDH in NAA of 7 cases (372 ± 169) was lower (p &lt; 0.05) in comparison to both NA (558 ± 119) and cancerous acini (CA) (645 ± 88). The difference between CA and NA did not achieve statistical significance. Conclusions: Reduced expression of β-catenin is a cancer-associated event in NAA. A cut-off AMPI (506) for β-catenin detected 29% of PC cases with 100% specificity. Altered expression of UGDH in NAA is a potential biomarker of PC. Funded by DoD grant DAMD17–02–1-0121. No significant financial relationships to disclose.
Impact of Donor-Derived CD34+ Infused Cell Dose on Outcomes of Patients Undergoing Allo-HCT Following Reduced Intensity Regimen for Myelofibrosis:a Study from the Chronic Malignancies Working Party of the EBMT
Authors: Tomasz Czerw, Vittoria Malpassuti, Simona Iacobelli, Linda Koster, Nicolaus Kröger, Marie Robin, Johan Maertens, Patrice Chevallier, Stephan Mielke, Xavier Poire, John A Snowden, Eefke J. Petersen, Ram Malladi, Didier Blaise, Péter Reményi, Virginie Gandemer, Jörg Cammenga, Marie Thérèse Rubio, Sébastien Maury, Eric Deconinck, Damian Finnegan, Patrick Hayden, Juan Carlos Hernandez Boluda, Donal P. McLornan, Ibrahim Yakoub-Agha
Journal: Blood (2019)
The Prognostic Significance of Blast Aberrancies By Flow Cytometry in Low/Int Risk MDS
Authors: Kristen M Corrao, Alexandra M. Harrington, Steven H. Kroft, Laura C. Michaelis, Karen-Sue B. Carlson, Lyndsey Runaas, Ehab L. Atallah, Sameem Abedin
Journal: Blood (2019)
IMMU-18. IMMUNOGENOMIC RESPONDER PHENOTYPE FROM A PHASE I TRIAL OF ANTI-LAG3 OR ANTI-CD137 ALONE AND IN COMBINATION WITH ANTI-PD-1 IN PATIENTS WITH RECURRENT GBM
Authors: Christina Jackson, John Choi, JiaJia Zhang, Anna Piotrowski, Tobias Walbert, Arati Desai, Manmeet Ahluwalia, Burt Nabors, Xiaobu Ye, Serena Desideri, Joy Fisher, Patrick Wen, Stuart Grossman, Kellie Smith, Drew Pardoll, Michael Lim
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Immune checkpoint inhibitors (ICIs) are not uniformly effective in glioblastoma treatment. Immunogenomic determinants may identify patients who are most likely to benefit from these therapies. Therefore, we compared the immunogenomic phenotype of a responder to combination anti-LAG-3 and anti-PD-1 therapy to non-responders. METHODS We performed T cell receptor (TCR) sequencing and gene expression analysis on pre-treatment, post-chemoradiation, and post-immunotherapy tumor specimens of glioblastoma patients treated with anti-LAG3 in combination with anti-PD-1 after first recurrence (NCT02658981, ongoing). We evaluated T cell clonotypes and immunophenotype of serially collected peripheral blood mononuclear cells (PBMCs) during treatment using multi-parametric flow cytometry. RESULTS To date, six patients have been enrolled in the initial anti-LAG-3 and anti-PD-1 cohort. One patient demonstrated complete response, one had stable disease, and four had progressive disease by radiographic evaluation. The responder demonstrated substantially higher TCR clonality in the resected tumor at initial diagnosis compared to non-responders (mean 0.028 vs. 0.005). Shared tumor infiltrating clonotypes with pre-immunotherapy PBMCs exhibited an increase in frequency from initial resection (6.8%) to resection at recurrence (20%). The responder’s tumor at initial resection exhibited increased gene signatures of PD1low CD8+ T cells, chemokine signaling, and interferon gamma pathways. On PBMC phenotypic analysis, the responder demonstrated significantly higher percentages of CD137+ CD8+T cells (median 8.38% vs 3.24%, p=0.02) and lower percentages of Foxp3+CD137+ CD4+T cells compared to non-responders (median 18.5% vs. 38.5%, p=0.006). Interestingly, dynamic analysis of PBMCs showed that the responder demonstrated a lower percentage of PD1+ CD8+ T cells pre-immunotherapy (median 2.5% vs.12.4%, p=0.002), with persistent decrease over the course of treatment while non-responders showed no consistent pattern. CONCLUSION Our preliminary results demonstrate significant differences in tumor and peripheral blood immunogenomic characteristics between responder and non-responders to anti-LAG3 and anti-PD-1 therapy. These immunogenomic characteristics may help stratify patients’ response to combination ICIs.
In primary care, CRP testing reduced antibiotic use in COPD exacerbations without worsening health
Authors: Henry S. Sacks
Journal: Annals of Internal Medicine (2019)

ACP Journal Club19 November 2019In primary care, CRP testing reduced antibiotic use in COPD exacerbations without worsening healthHenry S. Sacks, PhD, MDHenry S. Sacks, PhD, MDIcahn School of Medicine at Mount Sinai, New York, New York, USA (H.S.S.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJ201911190-051 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationButler CC, Gillespie D, White P, et al. C-reactive protein testing to guide antibiotic prescribing for COPD exacerbations. N Engl J Med. 2019;381:111-20. https://pubmed.ncbi.nlm.nih.gov/31291514Clinical Impact RatingsGIM/FP/GP: Pulmonology: References1 Anzueto A, Miravitlles M. Chronic obstructive pulmonary disease exacerbations: a need for action. Am J Med. 2018;131:15-22. [PMID: 29777660] Google Scholar2 Vollenweider DJ, Frei A, Steurer-Stey CA, Garcia-Aymerich J, Puhan MA. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2018;10:CD010257. [PMID: 30371937] Google Scholar Author, Article, and Disclosure InformationAffiliations: Icahn School of Medicine at Mount Sinai, New York, New York, USA (H.S.S.)This article was published at Annals.org on 5 November 2019. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byComparison of Immediate and Sequential Withdrawal of a Systemic Glucocorticoid in the Treatment of Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Multicenter, Randomized, Double-Blind, Parallel-Controlled, Open-Label Study 19 November 2019Volume 171, Issue 10Page: JC51KeywordsAntibiotic resistanceAntibioticsC-reactive proteinsChronic obstructive pulmonary diseasePatientsPrimary care physiciansPulmonary medicineQuestionnairesResearch assessmentSputum ePublished: 19 November 2019 Issue Published: 19 November 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
CTNI-38. PAMIPARIB IN COMBINATION WITH RADIATION THERAPY (RT) AND/OR TEMOZOLOMIDE (TMZ) IN PATIENTS WITH NEWLY DIAGNOSED (ND) OR RECURRENT/REFRACTORY (R/R) GLIOBLASTOMA (GBM); PHASE 1B/2 STUDY UPDATE
Authors: Anna Piotrowski, Vinay Puduvalli, Patrick Wen, Howard Colman, Jian Campian, Michael Pearlman, Nicholas Butowski, Timothy Cloughesy, James Battiste, Jon Glass, David Schiff, Martin van den Bent, Tobias Walbert, Manmeet Ahluwalia, Michael Badruddoja, Amandeep Kalra, Robert Pelham, Kathy Zhang, Katie Wood, Michael Weller, Kent Shih
Journal: Neuro-Oncology (2020)

Abstract Pamiparib, an investigational, oral PARP 1/2 inhibitor, demonstrated preclinical brain penetration and synergistic cytotoxicity with TMZ. We report updated safety and antitumor data for pamiparib plus RT and/or TMZ in ND-GBM or R/R-GBM (SNO 2019, ACTR-39). This dose-escalation/expansion study includes three arms: A, pamiparib (2, 4, or 6 weeks) plus RT (6–7 weeks) in ND-GBM with unmethylated MGMT promoter (unmethylated-GBM); B, pamiparib (6 weeks) plus RT and increasing TMZ doses in Weeks 1 and 5 of RT in unmethylated ND-GBM; and C, pamiparib plus increasing TMZ doses in methylated/unmethylated R/R-GBM. Most patients in Arms A (expansion) and B received maintenance pamiparib plus TMZ after post-RT rest period at Arm C expansion. As of April 10, 2020, enrollment was complete (N=116; A, n=60; B, n=9; C, n=47). Median study follow-up was 11.3 mo (A/B) and 7.1 mo (C). Common grade ≥3 AEs were anemia (10%) in Arm A; decreased neutrophil and white blood cell count (each 22%) in B; anemia, fatigue, and decreased lymphocyte count (each 11%) in C. Brain edema (A) and pneumonia (C) (n=1 each) were fatal treatment-unrelated AEs. In ND-GBM, modified disease control rate (DCR following post-RT rest period) was 69.8% (95% CI, 55.7–81.7) overall, 68.8% (50.0–83.9) in A, and 80.0% (28.4–99.5) in B. Median duration of response was 5.1 mo (overall), 3.8 mo (A), and NE (B). In Arms A/B, median progression-free survival (PFS) and median overall survival (OS) were 4.4 mo and 12.7 mo, respectively; 12-mo OS rate, 54% (95% CI, 40–66). In R/R-GBM (Arm C), confirmed ORR was 9.1% (95% CI, 2.5–21.7); median PFS and OS were 1.9 mo and 7.3 mo, respectively; 6-mo PFS rate, 19% (95% CI, 9–32). These results showed a manageable safety profile for pamiparib +/- RT +/-TMZ; response and survival results support further evaluation of these combinations in GBM.
Dyspnoea symptom intensity and impact on health-related quality of life in patients with cardiovascular or pulmonary diseases: a longitudinal observational study
Authors: Nasser S. Ahmadi, Ulf Lindblad, Jörgen Månsson
Journal: Clinical Cardiology and Cardiovascular Interventions (2019)

Introduction: Dyspnoea is a prevalent symptom associated with significantly reduced health-related quality of life (HRQoL). Accurate estimates of the severity and intensity of dyspnoea using standard tools in the clinic are important for the assessment of the severity of symptoms at later follow ups. Objectives: The current study had two aims. First, we sought to determine one-year changes in dyspnoea and health-related quality of life in patients with cardiac or respiratory diseases. Second, we sought to analyse the long-term associations between one-dimensional measurement methods and a generic instrument reflecting the multi-dimensionality of dyspnoea using the Short-Form Health Survey (SF-36). Methods: We prospectively recruited adult dyspnoeic patients in a rural primary health care centre. Participants were assessed for demographics, symptoms, medications, and N-terminal B-Type natriuretic pro-peptide (Nt-proBNP) level, and underwent spirometry and echocardiography. Results were analysed at baseline and one-year after enrolment. Based on the assessment results, we categorized the patients into one of three groups as the underlying disorder for dyspnoea: cardiovascular, pulmonary or psychiatric disease. Results: The ordinal scales [New York Heart Association (NYHA), modified Medical Research Council (mMRC) and Verbal Rating Scale (VRS)] indicated a slight but not significant decrease in dyspnoea severity, whereas the VAS showed a significant reduction in dyspnoea severity (p = 0.001) overall as well as in the cardiovascular group. By contrast, patients with pulmonary disease showed no improvement. HRQoL, as determined by the eight domains of SF-36, was unchanged, and dyspnoea severity had no impact on the worsening of health status. The correlation coefficient by test-re-test (reliability) of values at baseline and at the end of the study was highly significant. Conclusion: As appropriate measurements for the assessment of dyspnoea using one-dimensional scales, both mMRC and VAS should be considered for measuring changes in dyspnoea severity. VAS should be considered particularly for long-term changes in dyspnoeic patients with cardiovascular disorders. Changes in the different domains of the SF-36 were not seen after one year.
EFS12 Is a Powerful Predictive Tool for Outcomes in Stage I Aggressive Non Hodgkin Lymphoma: A Report from Nationwide Registry in a Resource Limited Country Thai Lymphoma Study Group
Authors: Kitsada Wudhikarn, Udomsak Bunworasate, Jakrawadee Julamanee, Arnuparp Lekhakula, Archrob Khuhapinant, Supachai Ekwattanakit, Lalita Norasetthada, Weerasak Nawarawong, Tontanai Numbenjapon, Kannadit Prayongratana, Chittima Sirijerachai, Kanchana Chansung, Suporn Chuncharunee, Pimjai Niparuck, Nonglak Kanitsap, Somchai Wongkhantee, Tawatchai Suwanban, Nisa Makruasi, Peerapon Wong, Pannee Praditsuktavorn, Tanin Intragumtornchai
Journal: Blood (2019)
The Presence and Possible Role of Virus-Host Chimeric Transcripts in Adult T-Cell Leukemia-Lymphoma
Authors: Hiroo Katsuya, Paola Miyazato, Saiful Islam, Benjy Jek Yang Tan, Yuki Inada, Misaki Matsuo, Takaharu Ueno, Masahito Tokunaga, Hiroyuki Hata, Makoto Yamagishi, Jun-Ichi Fujisawa, Toshiki Watanabe, Kaoru Uchimaru, Atae Utsunomiya, Shinya Kimura, Yorifumi Satou
Journal: Blood (2019)
SCIDOT-20. ADAPTING ENGINEERED CELL THERAPIES TO UNDERSTAND AND OVERCOME GLIOBLASTOMA RESISTANCE USING INTEGRATED IN VIVO AND EX VIVO MODELS
Authors: Andrew Satterlee, Denise Dunn, Scott Floyd, Shawn Hingtgen
Journal: Neuro-Oncology (2019)

Abstract Genetically engineered neural stem cells (NSCs) are a promising therapy for the highly aggressive brain cancer glioblastoma (GBM), yet treatment durability remains a major challenge. We sought to define the events that contribute to dynamic adaption of GBM during NSC treatment and develop strategies to convert initial tumor kill into sustained GBM suppression. Using a unique hybrid tumor model treated with human skin-derived induced NSCs (iNSCs) releasing the pro-apoptotic agent TRAIL, we investigated how spatial distribution of tumor and iNSCs affects GBM adaption throughout recurrence. Serial bioluminescent imaging (BLI) was used to track tumor volumes in vivo, while a subset of mice were sacrificed 6, 13, and 20 days post-treatment to harvest brains and generate living ex vivo tissue slices. Live animal imaging showed iNSC-TRAIL treatment rapidly decreased tumor volumes when delivered into the primary tumor mass; however, minimal impact on tumor growth was observed when cells were delivered into distal regions of the brain. In contrast, high-resolution imaging of living brain sections showed extensive impacts of iNSC-TRAIL therapy that could not be visualized with BLI. The living slices showed iNSC-TRAIL treatment into the primary tumor decreased the solid, but not the invasive, tumor burden. Treatment into the lateral ventricles did impact tumor kill and was more effective at treating the invasive tumor burden and maintaining inhibition than treatment into the contralateral parenchyma. We next utilized the living tissue slices to explore the sensitivity of the recurrent tumors to TRAIL. When therapy was applied to slices harboring recurrent tumor, treatment again significantly reduced tumor volumes, suggesting tumors had not acquired TRAIL resistance. These results informed an additional in vivo survival study and subsequent PCR analysis of untreated and recurrent tumors, and combine the fidelity of in vivo studies with the speed and spatial resolution of living brain slice technology.
Stiff Erythrocyte Subpopulations Biomechanically Induce Endothelial Inflammation in Sickle Cell Disease
Authors: Christina Caruso, Xiao Zhang, Yumiko Sakurai, Wei Li, Meredith E. Fay, Marcus A. Carden, David R. Myers, Robert G. Mannino, Clinton H. Joiner, Michael D. Graham, Wilbur A. Lam
Journal: Blood (2019)
Alliance A041701 - a Randomized Phase 2/3 Study of Conventional Chemotherapy +/- Uproleselan (GMI-1271) in Older Adults with Acute Myeloid Leukemia (AML) Receiving Intensive Induction Chemotherapy
Authors: Geoffrey L. Uy, Jun Yin, Heidi D. Klepin, Shira Dinner, Anthony J. Jaslowski, Stephen A. Strickland, Jane L. Liesveld, John C. Byrd, Richard M. Stone
Journal: Blood (2019)
Induction of a Leukemic Bone Marrow Niche Mediated By TGFB1 of Leukemic Blasts in Pediatric Acute Mekaryoblastic Leukemia: Results of an in Vitro and In Vivo Analysis
Authors: Theresa Hack, Stefanie Bertram, Guntram Büsche, Helmut Hanenberg, Ludger Klein-Hitpass, Nils Von Neuhoff, Dirk Reinhardt, Markus Schneider, Mareike Rasche
Journal: Blood (2019)