Artigos de revistas sobre o tema "Greif Inc"

Abstract Background Several COVID-19 vaccines have been authorized, and the need for rapid, further modification is anticipated. This work uses a Model-Based Meta-Analysis (MBMA) to relate, across species, immunogenicity to peak viral load (VL) after challenge and to clinical efficacy. Together with non-clinical and/or early clinical immunogenicity data (ECID), this enables prediction of a candidate vaccine’s clinical efficacy. The goal of this work was to enable the accelerated development of vaccine candidates by supporting Go/No-Go and study design decisions, and the resulting MBMA can be instrumental in decisions not to progress candidates to late stage development. Methods A literature review with pre-specified inclusion/exclusion criteria enabled creation of a database including nonclinical serum neutralizing titers (SN), peak VL after challenge with SARS-CoV-2 (VL), along with data from several clinical vaccine candidates. Rhesus Macaque (RM) and golden hamster (GH) were selected (due to availability and consistency of data) for MBMA modeling. For both RM and GH, peak post-challenge VL in lung and nasal tissues were used as surrogates for clinical disease and were related to pre-challenge SN via the MBMA. The VL predictions from the RM MBMA were scaled to incidence rates in humans, with a scaling factor between RM and human SN estimated using early Phase 3 efficacy data. This enabled clinical efficacy predictions based on ECID. To qualify the model’s predictive power, efficacies of COVID-19 vaccine candidates were compared to those predicted from the MBMA and their respective Ph1/2 SN data. More recently available clinical data enable building a clinical MBMA; comparing this to the RM MBMA further supports SN as predictive. Results The MBMA analyses identified a sigmoidal decrease in VL (increasing protection) with increase in SN in all three species, with more SN needed (in both RM and GH) for protection in nasal swabs than in BAL (see figure). The comparison between predicted and reported clinical efficacies demonstrated the model’s predictive power across vaccine platforms. RM and GH MBMA Protection Models and Translational Prediction with Observed Efficacies Sizes of circles indicate relative weight of the data in the respective quantitative model. Model and data visualizations have been harmonized (across tissue-types) separately for each of RM and GH using VACHER (Lommerse, et al., CPT:PSP, in press). Conclusion By quantifying adjustments needed between species and assays, translational MBMA can inform development decisions by using nonclinical SN and VL, and ECID to predict protection from COVID-19. Disclosures Anna Largajolli, PhD, Certara (Employee) Nele Plock, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Bhargava Kandala, PhD, Merck & Co., Inc. (Employee, Shareholder) Akshita Chawla, PhD, Merck & Co., Inc. (Employee, Shareholder) Seth H. Robey, PhD, Merck & Co., Inc. (Employee, Shareholder) Kenny Watson, PhD, Certara (Employee, Shareholder) Raj Thatavarti, MS, Certara (Employee, Shareholder) Sheri Dubey, PhD, Merck & Co., Inc. (Employee, Shareholder) S. Y. Amy Cheung, PhD, Certara (Employee, Shareholder) Rik de Greef, MSc, Certara (Employee, Shareholder) Jeffrey R. Sachs, PhD, Merck & Co., Inc. (Employee, Shareholder)

Le devoir de représentation juste édicté par l'article 136.1 du Code protège les membres de l'unité de négociation contre l'arbitraire, la discrimination, la mauvaise foi et aussi la négligence de leur agent négociateur lorsque ces atteintes sont d'une nature patente, apparente et très sérieuse. Par ailleurs, le Conseil n 'accepte pas que, même dans les cas de congédiements, l'agent négociateur se sente obligé à cause de son devoir, de pousser jusqu'à la limite extrême le grief d'un membre, pour la seule raison qu'il paye des cotisations syndicales, et sans tenir compte de la valeur intrinsèque du grief. En effet, imposer une norme de conduite aussi rigide à l'agent négociateur, irait à rencontre de cet autre devoir d'un syndicat qui est celui d'administrer d'une façon raisonnable les ressources mises à sa disposition par les cotisations syndicales de tous ses membres. Dans un pareil contexte, avant de conclure à une violation de l'article 136.1, le Conseil analysera dans chaque dossier, premièrement, la nature de la plainte logée; deuxièmement, la nature de l'agent négociateur; et troisièmement, la démarche de cet agent négociateur dans l'administration de son devoir vis-à-vis le membre plaignant de l'unité de négociation. Après avoir effectué cette analyse, le Conseil a rejeté deux plaintes alléguant que l'article 136.1 avait été violé lors du refus de poursuivre des griefs de congédiement à l'arbitrage. Dans les deux cas, le Conseil a jugé que la preuve ne démontrait pas de l'arbitraire, de la discrimination, de la négligence ou de la mauvaise foi de la part de l'agent négociateur vis-à-vis du membre plaignant. André Cloutier et Union des employés du Transport local et autres, local 931 et Cast North America Ltd. Jean Laplante et Union des employés du Transport local et autres, local 932 et A. & F. Baillargeon Express Inc. Dossiers 745-860 et 745-774; deux décisions du 4 juin 1981 (nos 319 et 320); Panel du Conseil; Me Marc Lapointe, président, Me Paul Emile Chiasson et M. Victor Gannon, membres.

This prospective study investigates informal care networks and their impact on hospice outcomes. Primary caregivers (N = 47) were the main source of data from 2 time points: within a week of enrollment in hospice and bereavement. Data were also collected from 42 secondary caregivers. Intraclass correlation coefficients (ICCs) determined correspondence between primary and secondary caregivers regarding informal care network size. Correlations were used to test associations between variables. Nonparametric paired sample tests were used to analyze change in anger and guilt. The ICC found poor correspondence (−0.13) between primary and secondary caregivers’ network descriptions. Correlational analyses found a strong/moderate negative association between quality of dying (QOD) and grief ( r = −0.605, P < .05). Study participants reported increased anger (0.4, P < .05, range 1-5) and guilt (0.4, P < .05, range 1-5), particularly among caregivers with high levels of support. Findings suggest that improving QOD may facilitate postdeath coping for caregivers.

Poa annua frequently is found as the dominant turfgrass species on golf course putting greens grown in the range of cool-season grasses. While not intentionally established, it is an aggressive weed in stands of bentgrasses (Agrostis spp.). When significant encroachment of P. annua occurs, it often is maintained indefinitely. In May 2003, P. annua putting greens at the Riverside Country Club in Rothesay, New Brunswick, Canada showed signs of an unidentified disease. Putting greens were slow to green up and large chlorotic patches were evident across affected areas. When roots were examined, extensive galling was observed. Galls were slender and often twisted in appearance. Upon dissection of washed galls, hundreds of eggs were exuded into the surrounding water droplet, and mature male and female nematodes were observed. Further morphological examination of males, females, and juvenile nematodes demonstrated that they were Subanguina radicicola (Greef 1872) Paramanov 1967 (1,2). Each P. annua plant had an average of four galls (with a range of two to nine) primarily located within the uppermost centimeter of the soil. Of 18 P. annua putting greens, four were affected by the nematode and displayed the same damage symptoms. S. radicicola has been identified from American beachgrass in Rhode Island and from P. annua in Oregon, but to our knowledge, this is the first report of the nematode affecting P. annua on a golf course in eastern North America. References: (1) W. F. Mai and P. Mullin. Plant-Parasitic Nematodes: A Pictorial Key to Genera. Cornell University Press, Ithaca, New York, 1996. (2) G. Thorne. Principles of Nematology. McGraw-Hill Book Company, Inc., New York, 1961

Abstract Background Immunecheckpoint inhibitors are effective in early and advanced TNBC, however only aminority of patients benefit making precision immune-oncology a major unmetneed. Imaging mass cytometry (IMC) enables high dimensional tissue imaging atsubcellular resolution for assessment of TNBC ecosystems, providing informationon cell type composition, functional status, and spatial organisation. Methods InNeoTRIP patients with TNBC were randomized to eight cycles ofnab-paclitaxel/carbo (CT) with/without atezolizumab (CTA). Forty-four proteinsspanning cancer cells and the tumor microenvironment (TME) were assessed onpre-treatment biopsies (n=243/280; 86.8% evaluable after QC). FFPE samples werelabelled with antibodies conjugated to isotopically pure rare earth metalreporters and profiled at one micron resolution by IMC. For each sample, wehave generated three high dimensional images that encompass the tumor,tumor-stroma interface and adjacent stroma. We investigated the association ofprotein expression assessed separately for epithelial and TME cells, cellphenotypes, and spatial architectures with PD-L1 status (Ventana SP142),stromal TILs, TNBC types and pathological complete response (pCR). 237 patients(84.6%) have both IMC and RNA-seq available allowing for comparison with genesignatures derived from HALLMARK,ConsensusTME immune cell types, and Nanostring. Results Across243 samples we identify just over one million single cells. By supervised clustering,we defined 37 robust cell phenotypes. PD-L1-positive tumors, high stromal TILsand TNBC type were characterized by extreme heterogeneity and unique cell-type andspatial TME composition. Severalbiomarkers demonstrated a significant test for interaction. Considering proteinexpression, GATA3 and CD20 on TME, HLA-DR in epithelial cells and Ki67 assessedboth in epithelial and TME, had a significant test for interaction (p &lt;0.05). For all these biomarkers, high expression (above median) was associatedwith an increase of pCR of &gt;10% in favour of atezolizumab, whereas lowerexpression group demonstrated a similar pCR rate among arms.Two cellphenotypes, PD-L1+IDO+ antigen presenting cells (APCs) and CD56+ neuroendocrine(NE) epithelial cells, had a significant test for interaction. Higherexpression of these biomarkers was associated with higher likelihood of pCR in CTAarm, but not in CT arm. For example, PD-L1+IDO+APCs in the CTA arm wereassociated with pCR proportions of 64.6% and 24.6% for above- and below-mediangroups respectively (OR4.5 [2.01-10.1], p&lt;0.001).Mostof these tests of interaction retained significance after adjustment by PD-L1status and stromal TILs. Notably, none among 61 gene-expression basedimmune-related pathways and 7 proliferation-related signatures demonstrated a significant test ofinteraction. Resultsof systematic multi-tiered image analysis at the levels of cell-cellinteractions and recurrent higher order multicellular complexes defining TNBC ecosystemsidentified by graph-based methods will be presented at the meeting. Conclusions Imaging mass cytometry provides a morecomprehensive overview of TNBC heterogeneity at a single-cell level withspatial resolution. Bulk protein or gene expression might deliver limitedpredictive information because it does not consider the cell compartment ofexpression. Precise cell phenotyping highlights the predictive role ofPD-L1+IDO+APCs and CD56+NE epithelial cells. Overall, we demonstrated that IMCis feasible in a large, randomized trial and provides independent predictiveinformation on immune checkpoint inhibitors benefit to PD-L1, TILs and gene-expressionprofiles. Citation Format: Giampaolo Bianchini, Xiao Qian Wang, Esther Danenberg, Chiun-Sheng Huang, Daniel Egle, Maurizio Callari, Begoña Bermejo, Claudio Zamagni, Marc Thill, Anton Anton, Matteo Dugo, Stefania Zambelli, Stefania Russo, Eva Maria Ciruelos, Richard Greil, Vladimir Semiglazov, Marco Colleoni, Catherine Kelly, Gabriella Mariani, Lucia Del Mastro, Balázs Győrffy, Olivia Biasi, Pinuccia Valagussa, Giuseppe Viale, Luca Gianni, H Raza Ali. Single-cell spatial analysis by imaging mass cytometry and immunotherapy response in triple-negative breast cancer (TNBC) in the NeoTRIPaPDL1 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-00.

Abstract Background: The current standard of care for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is R CHOP; however, approximately 40% of patients are not cured. The CD79b-targeting antibody-drug conjugate, polatuzumab vedotin, is approved in relapsed/refractory DLBCL in combination with bendamustine and rituximab, and has also demonstrated promising first line activity and safety when combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) in a Phase Ib/II study (Tilly, et al. Lancet Oncol 2019). Thus, in the Phase III POLARIX study (NCT03274492) we compared pola-R-CHP with R-CHOP in patients with previously untreated DLBCL. Methods: In this double-blind, placebo-controlled, international study, patients with previously untreated DLBCL and an International Prognostic Index (IPI) of 2-5 were randomized 1:1 to receive six cycles of pola-R-CHP (with a vincristine placebo) or R-CHOP (with a polatuzumab vedotin placebo); all patients also received two additional cycles of rituximab. Patients received polatuzumab vedotin 1.8mg/kg or vincristine 1.4mg/m² administered on Day 1, plus intravenous rituximab 375mg/m2, cyclophosphamide 750mg/m², doxorubicin 50mg/m², and placebo on Day 1, and oral prednisone 100mg once daily on Days 1-5. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included investigator-assessed event-free survival (EFS), independent review committee-assessed complete response (CR) rate at the end of treatment by positron emission tomography-computed tomography (PET-CT), disease-free survival (DFS), overall survival (OS), and safety. Results: Overall, 879 patients were randomized, 440 to pola-R-CHP and 439 to R-CHOP. Median age was 65 (range 19-80) years, and the majority of patients had IPI 3-5 (62.0%). At the data cut-off of June 28, 2021, and after a median follow-up of 28.2 months, PFS was superior with pola-R-CHP vs R CHOP (hazard ratio [HR] 0.73; 95% confidence interval [CI]: 0.57-0.95; P&lt;0.02). The 2-year PFS rate was 76.7% (95% CI: 72.7-80.8) with pola-R-CHP vs 70.2% (95% CI: 65.8-74.6) with R-CHOP. EFS favored pola-R-CHP compared with R-CHOP (HR 0.75; 95% CI: 0.58-0.96; P=0.02). The end-of-treatment PET-CT CR rate was not significantly different with pola-R-CHP vs R-CHOP (78.0% vs 74.0%; P=0.16); however, DFS suggested responses were more durable with pola-R-CHP than with R-CHOP (HR 0.70; 95% CI: 0.50-0.98). There was no difference in OS between treatment arms (HR 0.94; 95% CI: 0.65-1.37; P=0.75). At the time of data cut-off, 99 (23%) and 133 (30%) patients in the pola-R-CHP and R-CHOP arms, respectively, had received at least one subsequent anti-lymphoma therapy. Fewer patients in the pola-R-CHP than the R-CHOP arm received subsequent anti-lymphoma treatments (radiotherapy, 9.3% vs 13.0%; stem cell transplantation, 3.9% vs 7.1%; chimeric antigen receptor T-cell therapy, 2.0% vs 3.6%). The safety profile was comparable for pola-R-CHP vs R-CHOP, including rates of grade 3-4 adverse events (AEs; 57.7% vs 57.5%), serious AEs (34.0% vs 30.6%), grade 5 AEs (3.0% vs 2.3%), and AEs leading to dose reduction (9.2% vs 13.0%), respectively. The frequency and severity of peripheral neuropathy were similar for pola-R-CHP vs R-CHOP (any grade, 52.9% vs 53.9%; grade 3-4, 1.6% vs 1.1%). Conclusion: The pola-R-CHP combination demonstrated a 27% reduction in the relative risk of disease progression, relapse, or death compared with R-CHOP, with a similar safety profile in the first-line treatment of patients with DLBCL. Disclosures Tilly: Karyopharm: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Meeting attendance and travel, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Morschhauser: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Genentech, Inc.: Consultancy; Janssen: Honoraria; Genmab: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees. Sehn: Novartis: Consultancy; Genmab: Consultancy; Debiopharm: Consultancy; Teva: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; AbbVie: Consultancy; Acerta: Consultancy; Amgen: Consultancy; Apobiologix: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Incyte: Consultancy; Janssen: Consultancy; Kite: Consultancy; Karyopharm: Consultancy; Lundbeck: Consultancy; Merck: Consultancy; Morphosys: Consultancy; Sandoz: Consultancy; Seattle Genetics: Consultancy; Takeda: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy. Friedberg: Bayer: Membership on an entity's Board of Directors or advisory committees; Acerta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Trněný: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria. Sharman: AbbVie: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Bristol-Myers Squibb: Consultancy; Lilly: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; TG Therapeutics: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Velos: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Herbaux: Takeda: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria; Janssen: Honoraria. Burke: Verastem: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; Adaptive Biotechnologies: Consultancy; Epizyme: Consultancy; Kura: Consultancy; AbbVie: Consultancy; BeiGene: Consultancy, Speakers Bureau; Kymera: Consultancy; Bristol-Myers Squibb: Consultancy; X4 Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Gilead: Consultancy; Genentech, Inc.: Consultancy. Matasar: Memorial Sloan Kettering Cancer Center: Current Employment; Merck Sharp & Dohme: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; IGM Biosciences: Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Rocket Medical: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Honoraria. Rai: Chugai Pharmaceutical Co., Ltd: Speakers Bureau; ONO Pharmaceutical Co., Ltd: Speakers Bureau; Janssen Pharmaceutical: Speakers Bureau; Eisai Co., Ltd: Speakers Bureau. Izutsu: AbbVie: Honoraria; Allergan Japan: Honoraria; AstraZeneca: Honoraria, Research Funding; Bayer: Research Funding; BeiGene: Research Funding; Celgene: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Genmab: Honoraria, Research Funding; Huya Biosciences: Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; MSD: Research Funding; Novartis: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Pfizer: Research Funding; Solasia: Research Funding; Symbio: Honoraria; Takeda: Honoraria, Research Funding; Yakult: Research Funding. Mehta-Shah: C4 Therapeutics: Consultancy; Kiowa Hakko Kirin: Consultancy; Karyopharm: Consultancy; Ono Pharmaceuticals: Consultancy; Secura Bio: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; AstraZeneca: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding; Roche/Genentech: Research Funding; Corvus Pharmaceuticals: Research Funding; Verastem: Research Funding. Oberic: Celgene: Honoraria; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; Janssen: Honoraria, Other: Support for attending meetings and/or travel; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; AbbVie: Other: Support for attending meetings and/or travel; Incyte: Membership on an entity's Board of Directors or advisory committees. Jurczak: Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment; Jagiellonian University: Ended employment in the past 24 months. Greil: Sandoz: Honoraria, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding. Pinto: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; MSD: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau. Abrisqueta Costa: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hirata: Genentech, Inc.: Current Employment; Genentech/Roche: Current holder of stock options in a privately-held company. Jiang: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Yan: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Lee: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Flowers: AbbVie: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Epizyme: Consultancy; Roche/Genentech: Consultancy, Research Funding; Genmab: Consultancy; Gilead: Consultancy, Research Funding; Karyopharm: Consultancy; Pharmacyclics/Janssen: Consultancy; Seattle Genetics: Consultancy; Spectrum: Consultancy; 4D: Research Funding; Acerta: Research Funding; Adaptimmune: Research Funding; Allogene: Research Funding; Amgen: Research Funding; Cellectis: Research Funding; EMD: Research Funding; Guardant: Research Funding; Iovance: Research Funding; Janssen: Research Funding; Kite: Research Funding; Morphosys: Research Funding; Nektar: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Pharmacyclics: Research Funding. Salles: Bayer: Honoraria; AbbVie: Consultancy, Honoraria; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Debiopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ipsen: Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Loxo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Consultancy; Morphosys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rapt: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Velosbio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allogene: Consultancy. OffLabel Disclosure: Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b on malignant B-cells. Polatuzumab vedotin in combination with bendamustine and rituximab (pola-BR) improved complete response rate and overall survival compared with BR alone in patients with relapsed/refractory diffuse large B-cell lymphoma. Pola-BR is approved for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, after at least two prior therapies.

Abstract Background The identification of biomarkers for optimization of immune checkpoint inhibitors (ICI) treatment is an unmet clinical need. In the Phase III randomized trial, NeoTRIPaPDL1, a post-hoc analysis of whole transcriptome RNA-Seq data, previously showed that the 27-gene IO score is a potential predictive biomarker of increased pathological complete response with the addition of atezolizumab to carboplatin/nab-paclitaxel (Bianchini G ESMO 2021). However, the laboratory implementation of gene-expression signatures measured using RNA-seq is challenging. Therefore, we further assessed the predictive value of the IO score using a twenty-seven gene RT-qPCR assay on NeoTRIP samples, and compared to the previously reported RNA-Seq version of the assay. Methods The NeoTRIP study randomized patients to eight cycles of carboplatin/nab-paclitaxel (CT) with or without atezolizumab (CT/A). 258 patients were evaluable for pCR (breast and nodes) as Per-Protocol Population. We assessed the IO score as binary and continuous variables using the CAP/CLIA validated DetermaIO qPCR test (Saltman et al 2021) on pre-treatment core biopsies (n=220/258; 85.3%), all of which have RNA-Seq data available. We evaluated the association between IO score defined by RT-qPCR and RNA-Seq, and the association of the IO score defined by RT-qPCR test with PD-L1 IHC (Ventana SP142), stromal TILs (sTILs), and pCR. Results Comparison of continuous IO scores between the RT-qPCR assay and the RNA-Seq algorithm had a Pearson’s correlation of 0.94 (p &lt; 0.0001). High agreement between categorical IO scores was also observed (Cohens’ kappa = 0.84; 95% confidence interval [CI] = 0.77-0.91; p &lt; 0.0001). RT-qPCR IO score was balanced in the two arms (p = 0.65) with 44% and 40% positive patients in the CT and CT/A arms, respectively. The RT-qPCR IO score was correlated with both PD-L1 (Pearson’s r = 0.64; p &lt; 0.0001) and sTILs (Pearson’s r = 0.67; p &lt; 0.0001). Continuous IO score was significantly predictive of pCR in CT/A (Odds ratio [OR] = 3.12; 95% CI = 1.20-8.10; p&lt;0.019), but not CT arm (OR = 1.28; 95% CI = 0.54-3.01; p = 0.578). Considering the binary IO score, OR were 2.87 [1.27-6.47] (p = 0.011) and 0.91 [0.43-1.93] (p = 0.812), in CT/A and CT, respectively (interaction test p = 0.043). The pCR rate for CT/A vs CT was 69.8% vs 46.9% in IO score positive [+22.9%, p = 0.046, Chi-squared test] and 44.6% vs 49.2% [-4.6%, p = 0.73] in IO score negative. A significant interaction was found between continuous PD-L1 and continuous IO-score (p = 0.006). Among PD-L1-neg, 9 patients were IO score positive (10.1%). The pCR rate in this group was 3/4 (75%) in the CT/A arm and 1/5 (20%) in CT arm. The predictive value of IO score by RT-qPCR was similar to RNA-Seq. Conclusions We observed a high level of agreement and concordance between IO scores assessed by RT-qPCR and RNA-Seq, indicating that the 27-gene IO assay and algorithm is robust and the choice of platform has limited impact. This finding also demonstrates the high quality of NeoTRIP RNA-Seq data. In this post-hoc analysis, IO score assessment by this CLIA validated RT-qPCR test was confirmed to be predictive of atezolizumab benefit over CT alone in a randomized trial. Citation Format: Matteo Dugo, Chiun-Sheng Huang, Daniel Egle, Begoña Bermejo, Claudio Zamagni, Robert S. Seitz, Tyler J. Nielsen, Marc Thill, Antonio Anton, Stefania Russo, Eva Maria Ciruelos, Brock L. Schweitzer, Douglas T. Ross, Barbara Galbardi, Richard Greil, Vladimir Semiglazov, Balázs Gyorffy, Marco Colleoni, Catherine Kelly, Gabriella Mariani, Lucia Del Mastro, Pinuccia Valagussa, Giuseppe Viale, Maurizio Callari, Luca Gianni, Giampaolo Bianchini. Predictive value of RT-qPCR 27-gene IO score and comparison with RNA-Seq IO score in the NeoTRIPaPDL1 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD10-06.

This study examines psycholinguistic structure of autobiographical and traumatic narratives representing positive emotional and stressful traumatic life events. The research applied the cross sectional, between subjects design utilizing the independent variables of external agent they, space and time and dependent variable of word number in traumatic narratives for multiple regression analysis. The approval letter to recruit the participants through SONA system in 2015–2016 academic year was obtained from Institutional Review Board of Oklahoma State University (USA). 64 undergraduates of nonclinical setting, females (n=37), males (n=27), mean age was 19.43 (SD=1.37) were recruited. PTSD-8: A Short PTSD Inventory assesses PTSD, the Linguistic Inquiry and Word Count (LIWC) analyzes traumatic and autobiographical narratives in terms of linguistic units and psychological meaningful categories. The results indicate that there are significant differences between pronoun they as external agent of proposition and psychological categories of negative emotions and anxiety in traumatic and autobiographical narratives. The frequency of these categories is higher in traumatic narratives compared with autobiographical narratives. External agent they, category of time and space taken together significantly contribute to word number in traumatic narrative. There is a negative correlation between focus on the past and word count, and positive correlation between social category and word count in traumatic narrative in nonclinical sample. To sum up, propositional structure of traumatic memory of individuals without PTSD is represented by external agent and context (place and time) taken together. Considering time as a significant negative predictor of creating traumatic narrative, temporal processing without overestimation of time is an important factor of avoiding PTSD. 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Background: In early unfavorable Hodgkin Lymphoma (HL), long-term tumor control with 4xABVD and 30Gy involved field radiotherapy (IFRT) is approximately 80%. To improve these results, the GHSG HD14 trial compared an intensified chemotherapy regimen consisting of 2xBEACOPPescalated plus 2xABVD (2+2) to 4xABVD. All patients received 30Gy IFRT. Due to a progression-free survival (PFS) difference of 6.2% at five years in favor of the intensified treatment, 2+2 plus 30Gy RT is the current GHSG standard and is a treatment option in the NCCN guidelines for early unfavorable HL. However, there was no overall survival (OS) difference between 2+2 and 4xABVD at the final analysis of HD14 and the potential long-term toxicity of 2+2 is debated. We therefore performed a long-term follow up analysis of HD14. Patients and Methods: Between January 2003 and July 2008, 1,550 patients with early unfavorable HL ≤60 years were randomized and treated with 4xABVD or 2+2, followed by 30Gy IFRT in all patients. Randomization was discontinued after the third planned interim analysis showed a significant advantage of 2+2 in terms of the primary endpoint freedom from treatment failure (FFTF, difference 7.2% at 5 years). Accrual to the 2+2 arm continued from July 2008 to December 2009 and 339 additional qualified patients were treated with 2+2 plus 30Gy IFRT. These patients were not reported in the initial report and are added to all analyses of this long-term follow-up. Time-to-event end points were compared between groups using the Kaplan-Meier method as well as univariate and multivariate Cox regression models. Results: After a median observation time of 97 months, 10.2% (79 of 777) and 3.4% (38 of 1112) of patients treated with 4xABVD and 2+2, respectively, had progression or relapse. The 10-year PFS was 85.6% for 4xABVD (95%-CI 82.9% to 88.4%) and 91.2% for 2+2 (95%-CI 89.0% to 93.4%) accounting for a significant PFS difference of 5.6% (95%-CI 2.1% to 9.1%) in favor of 2+2 (Figure 1). Two or more relapses were experienced by 21 of 777 (2.7%) and 10 of 1112 (0.9%) patients who had received 4xABVD or 2+2 as first-line treatment, respectively. However, there was still no OS difference between the two groups (OS 94.1% [95%-CI 92.3% to 96%] and 94% [95%-CI 92.3% to 95.8%] for 4xABVD and 2+2, respectively; difference at 10 years -0.1% [95%-CI -2.6% to 2.4%], median observation time for OS 104 months). In a multivariate regression analysis adjusting for age, B-symptoms, infra-diaphragmatic disease, and the 4 GHSG risk factors (elevated ESR, involvement of ≥3 lymph node areas, extranodal disease, and large mediastinal tumor) as predictive factors for PFS, age ≥50 (HR 2.260, 95%-CI 1.543 to 3.309), presence of infra-diaphragmatic disease (HR 1.766, 95%-CI 1.055 to 2.955), or of a large mediastinal tumor (HR 1.811, 95%-CI 1.226 to 2.675) and treatment with 4xABVD (HR 1.929, 95%-CI 1.423 to 2.614) were significant predictors of PFS. Slightly more patients in the 4xABVD group died from toxicity of salvage therapy as compared to 2+2 patients (1% [8 of 777] versus 0.6% [7 of 1112]) whereas there were relatively more deaths due to study therapy in the 2+2 group as compared to 4xABVD patients (0.6% [7 of 1112] versus 0.1% [1 of 777]), leading to a similar OS in both groups. There were no apparent differences in other causes of death including HL (5 of 777 [0.6%] versus 9 of 1112 [0.8%]) and second neoplasms (12 of 777 [1.5%] versus 16 of 1112 [1.4%]) between 4xABVD and 2+2, respectively. A total of 95 second malignancies corresponding to 10-year cumulative second malignancy incidences of 4.7% and 6.4% were reported for 4xABVD and 2+2, respectively, without a difference between the two groups (p=0.86). Standardized incidence ratios (SIR) showed elevation compared to the general German population and no significant difference between 4xABVD (2.3 [95%-CI 1.6 to 3.2]) and 2+2 (2.6 [95%-CI 2.0 to 3.4]). Conclusions: This long-term analysis confirms the superior tumor control of 2+2 as compared to 4xABVD in patients ≤60 with early unfavorable HL. However, this does not translate into an OS difference. At longer follow-up, there is no difference regarding second primary malignancies between the groups. In comparison to 4xABVD, the 2+2 regimen spares a significant number of patients from the burden of cancer recurrence and additional treatment without increased long-term toxicity. Therefore, 2+2 remains the GHSG standard for patients with early unfavorable HL ≤60. Disclosures Greil: Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Ratiopharm: Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Eisai: Honoraria; Boehringer Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Sandoz: Honoraria; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Sanofi Aventis: Honoraria; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Merck: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding. Topp:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Zijlstra:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Borchmann:Novartis: Honoraria, Research Funding. von Tresckow:Takeda: Consultancy, Honoraria, Other: Travel and congress funding, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel and congress funding, Research Funding; Pfizer: Honoraria; Amgen: Honoraria; Roche: Honoraria; MSD: Consultancy, Honoraria, Other: Travel and congress funding, Research Funding.

Abstract Background Rapid induction of remission is a favorable factor in pts with Hodgkin's disease and DLBCL. In MM, only few data are available on the impact of response kinetics on outcome in newly diagnosed transplant ineligible MM pts. Recently, (Abstract EP971, EHA 2021) we described a significant correlation between time to response and progression-free survival (PFS) and overall survival in this patient population. Response and time to response depend on several factors such as the biology of the underlying myeloma clone(s), the activity of the treatment regimen, and on the composition of the bone marrow immune environment. Here, we evaluated possible interconnections between the bone marrow immune environment at baseline and the time to response to therapy in a series of pts randomized to either 9 cycles KRd or KTd induction therapy followed by a second randomization to carfilzomib maintenance or observation. Patients and Methods Composition of the immune environment at baseline was analyzed in 55 pts with newly diagnosed transplant ineligible MM enrolled in a randomized phase II trial (AGMT_MM 02). Median age: 74 years (range: 58-84 years), ISS I: 21.8%, ISS II: 41.8%, and ISS III: 36.4%, cytogenetics: 30.9% high risk, 40% standard risk, 29.1% unknown, ECOG Status 0: 54.5%, 1: 45.6%. Treatment: Carfilzomib : Cycle 1 day 1+2: 20mg/m 2, days 8+9 and 15+16: 27 mg/m 2 ; Cycle 2 day 1,2,8,9,15 + 16: 27 mg/m 2 Cycle 3-9: 56mg/m 2 on days 1, 8 and 15. Lenalidomide: 25mg p.o. on days 1-21/cycle or thalidomide: 100 mg p.o. on days 1-28; in pts ≥75 years of age 50mg p.o. on days 1-28, dexamethasone: 40 mg p.o. on days 1, 8, 15, 22 (± 1 day), in pts ≥ 75 years of age 20 mg p.o. this treatment was administered for nine cycles. Thereafter, pts were randomized to carfilzomib maintenance at last tolerated dose on days 1+15 or to observation for 12 cycles. BM samples were stained with 3 different antibody combinations for the analysis of T, B and NK cells (T cells: CD45RA, CD127, CD8, TCRgd, CD25, CD197, CD4, CD3, B/NK cells: CD57, CCR7, CD314, CD85j, CD62L, CD3, CD16, CD56, CD335, HLADR, CD337). We used a semi-automated pipeline to unveil full cellular diversity based on unbiased clustering. The median and range of each cellular subgroup was calculated and compared between pts with short or longer time to response (&lt; or ≥119 days (median)). Statistical significance of these comparisons was calculated using the Wilcoxon test. Results Median FU was 20.5 months. Twenty of the 55 pts achieved a CR (36.7%) and 16 (57.1%) of the 28 who had MRD testing were shown to be MRD negative at a sensitivity of 10 -6. Twenty-three pts achieved a VGPR (41.8%), while only 12 pts achieved a PR (21.8%). Pts were subdivided into two groups according to time to best response. Group A (n=26), median time 56 (26-112) days, group B (n=29), 265 (119-675) days. PFS was significantly longer in group B (19.1 months vs not reached, p=0.007), while for OS only a trend for better survival was noted for group B pts (median survival not reached, p=0.129). High numbers of total CD3 + cells (p=0.033) and CD4 T cells with a CD 197 loCD45RA -CD127 + phenotype (p=0.022) were associated with longer time to best response and longer PFS. An opposite result was noted for the following T cell subsets, which correlated with a shorter time to best response and shorter PFS: CD56 + T cells with (p=0.01) or without (p=0.024) HLADR and CD8 Naïve CD127 + T cells (p=0.041). Diverse results were noted when the NK cell compartment was analyzed. Higher levels of circulatory CD314 - (p&lt;0.0001) and circulatory CD314 + (p=0.049) NK cells correlated with longer time to best response and longer PFS. By contrast, lower levels of cytotoxic HLADR + NK cells (p=0.044) were associated with better outcome. Conclusion Our data show significant correlations between the composition of bone marrow immune cells at start of therapy with time to best response and PFS in newly diagnosed transplant ineligible MM pts uniformly treated with carfilzomib-based therapy. High numbers of total lymphocytes CD3 and CD4 Tcells with a CD197 loCD45RA -CD127 + phenotype correlated with significantly longer PFS and longer time to response. Furthermore, higher numbers of specific NK subsets such as those with a circulatory phenotype, correlated with better outcome. These results highlight the prognostic potential of immune monitoring and the interconnection between specific subsets of the immune environment with the course of the disease. Figure 1 Figure 1. Disclosures Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. Podar: Amgen Inc.: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Roche Pharmaceuticals: Research Funding; Celgene: Consultancy, Honoraria. Petzer: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Saegen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zojer: Celgene-BMS, Amgen, Takeda, Sanofi, Janssen: Consultancy, Speakers Bureau. Schreder: BMS-Celgene, Amgen: Consultancy. Melchardt: Abbvie, Celgene, Novartis: Honoraria. Knop: BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Janssen: Consultancy; Oncopeptides: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy. Paiva: Bristol-Myers Squibb-Celgene, Janssen, and Sanofi: Consultancy; Adaptive, Amgen, Bristol-Myers Squibb-Celgene, Janssen, Kite Pharma, Sanofi and Takeda: Honoraria; Celgene, EngMab, Roche, Sanofi, Takeda: Research Funding. Ludwig: Janssen, Celgene-BMS, Sanofi, Seattle Genetics: Consultancy, Speakers Bureau; Amgen, Takeda: Consultancy, Research Funding, Speakers Bureau. OffLabel Disclosure: Carfilzomib in first-line therapy

Abstract Background Several therapies are recommended by NCCN/ESMO guidelines for autologous stem cell transplant (ASCT)-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). In the single-arm, Phase II L-MIND study (NCT02399085), the chemotherapy-free regimen tafasitamab + lenalidomide (LEN) demonstrated efficacy for this patient population. In the absence of randomized clinical trial data, RE-MIND2 (NCT04697160), an observational, retrospective cohort study, compared patient outcomes from L-MIND with matched patient populations treated with NCCN/ESMO recommended therapies for ASCT-ineligible patients with R/R DLBCL. Methods Data were retrospectively collected between 1 April and 13 November 2020 from academic and public hospitals, as well as private practices in North America, Europe and Asia Pacific. To ensure consistency with L-MIND I/E criteria, patients aged ≥18 years with histologically confirmed DLBCL and who had received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy) were enrolled. For the main analysis, patients from the L-MIND tafasitamab + LEN cohort were matched with patients from the RE-MIND2 observational cohort using estimated propensity score-based 1:1 nearest neighbor matching, balanced for six baseline characteristics: age (&lt;70 vs ≥70 years), refractoriness to last line of therapy (yes vs no), number of prior lines of therapy (1 vs 2/3), history of primary refractoriness (yes vs no), prior ASCT (yes vs no), and Eastern Cooperative Oncology Group performance status (0-1 vs ≥2). A sensitivity analysis was performed using an inverse probability of treatment weighting method calculating the average effect of the treatment on the treated, to generate balanced cohorts based on nine baseline characteristics: age, refractoriness to last line of therapy, number of previous lines of therapy, history of primary refractoriness, prior ASCT, Ann Arbor Stage (I/II vs III/IV), elevated LDH (yes vs no), neutropenia (yes vs no), and anemia (yes vs no). Additional sensitivity analyses accounting for missing baseline characteristics using multiple imputation technique were performed. Data are presented for tafasitamab + LEN versus polatuzumab vedotin + bendamustine + rituximab (pola-BR), rituximab + LEN (R2), and CD19 CAR-T therapies (CAR-T). The primary endpoint was overall survival (OS). Secondary endpoints included objective response rate (ORR), complete response rate, progression-free survival and duration of response. Results Of 3,454 patients enrolled from 200 sites, 106, 106, and 149 patients were treated with pola-BR, R2, and CAR-T, respectively. For the comparative analysis, matched patient pairs were created using 1:1 nearest neighbor matching with a caliper. Matched pairs consisted of: tafasitamab + LEN vs pola-BR, n=24 pairs; vs R2, n=33 pairs; and vs CAR-T, n=37 pairs. A significant OS benefit was associated with tafasitamab + LEN compared to pola-BR (HR: 0.44, 95% confidence interval [CI]: 0.20-0.96; p=0.038) and R2 (HR=0.44, 95% CI: 0.22-0.84; p=0.014) (Figure 1A-B). There was no significant difference in OS benefit between tafasitamab + LEN and CAR-T (HR=0.95, 95% CI: 0.47-1.91; p=0.891) (Figure 1C). ORR was 62.5% (15/24) for tafasitamab + LEN vs 58.3% (14/24) for pola-BR (p=1.000), 63.6% (21/33) vs 30.3% (10/33) for R2 (p=0.013), and 59.5% (22/37) vs 75.7% (28/37) for CAR-T (p=0.214). Improved outcomes were also observed with tafasitamab + LEN for other secondary endpoints (Table 1). Results are consistent with those obtained in the sensitivity analyses. Conclusions The results of this retrospective cohort analysis suggest that the novel tafasitamab + LEN combination may significantly improve health outcomes, with a prolonged survival benefit for ASCT-ineligible R/R DLBCL patients, relative to NCCN/ESMO recommended therapies. Tafasitamab + LEN improved survival outcomes compared with pola-BR and R2 in closely matched patient populations. Comparable outcomes were observed for tafasitamab + LEN vs CAR-T. Although based on limited patient numbers, these data may be clinically relevant in the context of emerging therapies for R/R DLBCL. While this study design does not replace randomized data, it remains more rigorous than inter-trial comparison. The limitations of comparing clinical trial and matched retrospective real-world data will be discussed. Funding: MorphoSys AG. Figure 1 Figure 1. Disclosures Nowakowski: Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, NanoString Technologies, MorphoSys: Research Funding. Joffe: AstraZeneca. Epizyme: Consultancy. Fleury: Abbvie, Astrazeneca, BMS, Celgene, Janssen, Kite-Gilead, Merck, Novartis, Roche, Seattle Genetics: Other: conference and advisory role. Peters: AbbVie, Incyte: Consultancy, Honoraria. Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. Ku: Roche: Consultancy; Antegene: Consultancy; Genor Biopharma: Consultancy. Marks: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Meeting attendance; Kite/Gilead: Honoraria; Merck: Consultancy. Kim: AstraZeneca: Research Funding. Zinzani: BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trotman: Beigene: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Roche: Research Funding; Janssen: Research Funding; PCYC Pharmacyclics: Research Funding. Sabatelli: Incyte: Current Employment, Current equity holder in publicly-traded company. Huang: MorphoSys: Current Employment. Waltl: MorphoSys: Current Employment. Winderlich: MorphoSys: Current Employment, Current equity holder in publicly-traded company. Ambarkhane: MorphoSys: Current Employment, Other: Support for attending meetings/travel. Kurukulasuriya: MorphoSys: Current Employment, Current equity holder in publicly-traded company, Other: Support for attending meetings/travel. Cordoba: Pfizer: Research Funding; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADCTherapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hess: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead/Kite: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; EUSA: Honoraria, Membership on an entity's Board of Directors or advisory committees. Salles: Miltneiy: Consultancy; Novartis: Consultancy; Morphosys: Consultancy, Honoraria; Janssen: Consultancy; Genentech/Roche: Consultancy; Kite/Gilead: Consultancy; Regeneron: Consultancy, Honoraria; Velosbio: Consultancy; Takeda: Consultancy; Allogene: Consultancy; Ipsen: Consultancy; Loxo: Consultancy; Rapt: Consultancy; Genmab: Consultancy; Incyte: Consultancy; Epizyme: Consultancy, Honoraria; Debiopharm: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria.

Abstract Background: Standard of care (SOC) for second-line (2L) therapy (tx) of relapsed/refractory aggressive B-cell non-Hodgkin lymphomas (R/R aNHL) includes platinum-based chemotherapy (PCT) followed by autologous hematopoietic cell transplantation (aHCT) in responders. Outcomes are poor for patients (pts) with R/R aNHL who experience progression during or within 12 months (mo) of 1L tx. Tisagenlecleucel (tisa-cel) is an autologous chimeric antigen receptor (CAR) T-cell tx targeting CD19 approved for pts with large B-cell lymphoma (LBCL; US) and diffuse LBCL (non-US) after ≥2 lines of tx. BELINDA (NCT03570892) is a Phase III, randomized, global (18 countries) study of tisa-cel vs SOC as 2L tx for R/R aNHL. Methods: Adults with confirmed R/R aNHL within 12 mo after 1L chemo-immunotherapy were eligible. All pts underwent leukapheresis for tisa-cel production and were randomized 1:1 to receive tisa-cel (Arm A) or SOC (Arm B) and stratified by 1L duration of response, International Prognostic Index (IPI), and geographic region. Arm A received optional bridging tx (investigator choice of protocol-defined PCT regimens) followed by lymphodepletion (LD; generally, fludarabine 25 mg/m 2/day [d] + cyclophosphamide 250 mg/m 2/d for 3 d) and followed by a single tisa-cel infusion (0.6-6×10 8 CAR-T cells). Arm B received investigator choice of PCT regimen followed by aHCT in responders or a second PCT in nonresponders. Disease assessments were performed at 6 and 12 weeks (wk), then planned every 3 mo for year (y) 1 and every 6 mo for y 2. The primary endpoint was event-free survival (EFS), defined as time from randomization to stable disease (SD) or progressive disease (PD) at or after wk 12 assessment or death at any time. SD/PD at wk 6 was not considered an event on either Arm. Arm A's wk 6 assessment evaluated disease burden before tisa-cel infusion and after bridging if administered. Arm B's wk 6 assessment determined if response was sufficient for aHCT or if a second PCT regimen was needed prior to aHCT. Results: As of May 6, 2021, 322 pts were randomized: 162 to Arm A and 160 to Arm B. In Arms A and B, 33% and 29% were ≥65 y, and 66% and 67% had primary refractory disease, respectively. Baseline characteristics indicated imbalances with more high-grade B-cell lymphomas (24% vs 17%) and IPI ≥2 (65% vs 58%) in Arm A vs B. In Arm A, 47% received ≥2 cycles of bridging PCT, 36% received 1 cycle, and 17% received 0. In Arm A, 96% received tisa-cel; the median dose was 2.9×10 8 cells. In Arm B, 96% received ≥2 PCT cycles and 54% received ≥2 different PCT regimens; 33% received aHCT, including 10% requiring ≥2 different PCT regimens before aHCT. Median time from randomization to aHCT was 92 d (range, 61-158 d). Median follow-up was 10 mo (range, 2.9-23.2 mo). At wk 6 assessment, 26% had PD in Arm A vs 14% in Arm B. Median EFS in Arms A and B was 3 mo (HR 1.07; 95% CI, 0.82-1.40; P=0.69); Arm A pts with PD at wk 6 had shorter EFS. Overall response rate (ORR) at wk 12 in Arm A was 46% vs 43% in Arm B; complete response rate in both arms was 28%. Some pts responded to tisa-cel after SD/PD at wk 12 without additional tx but were counted as an event in EFS analysis. In Arm B, 81 pts (51%) crossed over to receive tisa-cel, 71 without receiving aHCT. Of 72 crossover pts with response assessment, ORR to tisa-cel was 40%. Overall survival was immature at data cutoff. In Arm A, 84% had a grade ≥3 adverse event (AE; vs 90% in Arm B), including grade ≥3 cytokine release syndrome in 5% (CRS; Lee 2014) and grade ≥3 neurologic events (NE) in 3% (CTCAE v5.0), with no grade 5 CRS/NE. Median times to CRS and NE onset were 4 and 5 d, respectively; median time to resolution was 5 and 9 d. Fifty-two (32%) and 45 (28%) pts in Arms A and B died on study, including 42 (26%) and 32 (20%) deaths due to PD, respectively. Ten pts in Arm A and 13 in Arm B died of AEs. Conclusions: Tisa-cel as 2L tx in R/R aNHL pts did not have a higher EFS vs SOC. Possible contributing factors include study design elements, such as optional PCT bridging tx in Arm A with potential delay of tisa-cel infusion until after wk 6 assessment, allowance of a different PCT regimen to reach aHCT in Arm B after inadequate response to first PCT, and imbalances in relevant pt characteristics. Insights from this randomized Phase III study will inform use of cellular tx in the 2L R/R aNHL setting and the design of future CAR-T trials. Figure 1 Figure 1. Disclosures Bishop: Arcellx, Autolus, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis: Consultancy, Research Funding; Bristol-Myers Squibb and Kite/Gilead: Other: fees for non-CME/CE services . Dickinson: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Research Funding; Celgene: Research Funding; Amgen: Honoraria. Purtill: Novartis: Honoraria; Gilead: Honoraria; BMS Celgene: Honoraria. Barba: Amgen, Celgene, Gilead, Incyte, Jazz Pharmaceuticals, MSD, Novartis, Pfizer and Roche, Jazz Phar,aceuticals: Honoraria; Cqrlos III heqlth Institute, aSOCIACION espanola contra el cancer, PERIS: Research Funding. Santoro: Arqule: Consultancy, Speakers Bureau; Sanofi: Consultancy; Takeda: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; AbbVie: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eli-Lilly: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kato: Abbvie: Consultancy, Research Funding; AstraZeneca: Consultancy; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Dainippon-Sumitomo: Honoraria; Eisai: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; MSD: Honoraria; Mundi: Honoraria; Novartis: Consultancy, Research Funding; Ono: Honoraria, Research Funding. Sureda: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy. Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. Thieblemont: Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Morschhauser: F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Janssen: Honoraria; Genmab: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees. Janz: Janssen: Honoraria, Other: Meeting Fees; Novartis: Honoraria; Takeda: Honoraria, Other: Travel Accommodations, Expenses, Meeting fees; Roche: Honoraria; Gilead: Other: Travel Accommodations, Expenses, Meeting fees. Flinn: Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Seattle Genetics: Research Funding; Sarah Cannon Research Institute: Current Employment; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding. Kwong: Novartis: Consultancy, Honoraria, Research Funding. Kersten: Novartis: Consultancy, Honoraria, Other: Travel support; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Research Funding; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support; BMS/Celgene: Consultancy, Honoraria. Minnema: Janssen: Consultancy, Honoraria; Celgene: Other: Travel expenses; BMS: Consultancy; Kite/Gilead: Consultancy; Alnylam: Consultancy. Holte: Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Nanovector: Membership on an entity's Board of Directors or advisory committees, Other: lectures honorarias; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Nordic: Membership on an entity's Board of Directors or advisory committees. Martinez-Lopez: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maziarz: Novartis: Consultancy, Other: Data and Safety Monitoring board, Research Funding; Incyte Corporation: Consultancy, Honoraria; Bristol-Myers, Squibb/Celgene,, Intellia, Kite: Honoraria; Allovir: Consultancy, Research Funding; Artiva Therapeutics: Consultancy; CRISPR Therapeutics: Consultancy; Intellia: Honoraria; Omeros: Research Funding; Athersys: Other: Data and Safety Monitoring Board, Patents & Royalties; Vor Pharma: Other: Data and Safety Monitoring Board. McGuirk: Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Fresenius Biotech: Research Funding; Astelllas Pharma: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding; Pluristem Therapeutics: Research Funding. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Dreyling: Amgen: Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Gilead Kite: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; AbbVie: Research Funding; BeiGene: Consultancy, Speakers Bureau; Genmab: Consultancy; MorphoSys: Consultancy. Harigae: Bristol Myers Squibb: Honoraria; Novartis Pharma: Honoraria, Research Funding; Chugai Pharma: Honoraria; Janssen Pharma: Honoraria; Ono pharma: Honoraria, Other: Subsidies or Donations; Astellas Pharma: Other: Subsidies or Donations; Kyowakirin: Other: Subsidies or Donations. Bond: Kite/Gilead: Honoraria. Andreadis: Merck: Research Funding; BMS: Research Funding; CRISPR Therapeutics: Research Funding; GenMAB: Research Funding; Novartis: Research Funding; Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Epizyme: Honoraria; Incyte: Honoraria; TG Therapeutics: Honoraria; Kite: Honoraria; Karyopharm: Honoraria; Atara: Consultancy, Honoraria. McSweeney: Kite-Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gamida: Consultancy, Honoraria; TG Theraputics: Consultancy, Honoraria; Autolous Limited: Research Funding; Novartis: Research Funding; NKARTA: Research Funding; Allovir: Research Funding. Newsome: Novartis: Current Employment. Degtyarev: Novartis: Current Employment, Current equity holder in publicly-traded company. Del Corral: Novartis: Current Employment. Andreola: Novartis: Current Employment, Current holder of stock options in a privately-held company. Masood: Novartis: Current Employment, Current holder of stock options in a privately-held company. Schuster: AbbVie, Acerta, Celgene/Juno, DTRM Bio, Genentech, Incyte, Merck, Novartis, Portola, and TG Therapeutics: Research Funding; Acerta, AlloGene, AstraZeneca, BeiGene, Celgene/Juno, Genentech/Roche, LoxoOncology, Novartis, and Tessa Therapeutics: Consultancy; Acerta, AlloGene, AstraZeneca, BeiGene, Celgene, Genentech/Roche, LoxoOncology, Novartis, Nordic Nanovector, Pfizer, and Tessa Therapeutics;: Honoraria; Novartis: Other: Personal fees, Patents & Royalties; AbbVie, Celgene, Novartis, Juno, Nordic Nanovector, and Pfizer: Other: Steering Committee Participation. Jaeger: BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Westin: Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Umoja: Consultancy; Iksuda Therapeutics: Consultancy; Curis: Research Funding; Morphosys: Research Funding; 47 Inc: Research Funding.

Abstract Background: Zanubrutinib (zanu) is a selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimize off-target effects (Guo, J Med Chem 2019;62:7923-40). In a phase 1/2 study, zanu demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes and was associated with durable clinical responses in patients (pts) with CLL/SLL (Tam, Blood 2019;134:851-9). Here, we present interim results for the phase 3 SEQUOIA (BGB-3111-304; NCT03336333) trial, which evaluated the efficacy and safety of zanu vs BR in TN pts with CLL/SLL. Methods: SEQUOIA is an open-label, global phase 3 study that randomized TN pts with CLL/SLL without del(17p) to receive zanu 160 mg twice daily until progressive disease or unacceptable toxicity, or bendamustine 90 mg/m 2 on day 1 and 2 and rituximab 375 mg/m 2 in cycle 1, 500 mg/m 2 in cycles 2-6 for 6 × 28-day cycles. Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Hallek, Blood 2008;111:5446-56) were eligible if they were either ≥65 y or unsuitable for treatment with fludarabine, cyclophosphamide and rituximab. Central verification of del(17p) status by fluorescence in situ hybridization was required. Pts were stratified by age (&lt;65 y vs ≥65 y), Binet Stage (C vs A/B), IGHV mutational status, and geographic region. The primary endpoint was independent review committee (IRC)-assessed progression-free survival (PFS) for zanu vs BR. Secondary endpoints included PFS by investigator assessment (INV), overall response rate (ORR; by IRC and INV), overall survival (OS), and safety. Responses for CLL and SLL were assessed per modified iwCLL criteria (Hallek, Blood 2008;111:5446-56; J Clin Oncol 2012;30:2820-2) and Lugano criteria (Cheson, J Clin Oncol 2014;32:3059-68), respectively. Adverse events (AEs) were recorded until disease progression to support safety evaluation over an equivalent time period. Results: From 31 Oct 2017-22 Jul 2019, 479 pts without del(17p) were randomized to zanu (n=241) and BR (n=238). Treatment groups were well balanced for demographic and disease characteristics (zanu vs BR): median age, 70.0 y vs 70.0 y; unmutated IGHV, 53.4% (125/234) vs 52.4% (121/231); and del(11q), 17.8% vs 19.3%. At median follow-up (26.2 mo), PFS by IRC was significantly prolonged with zanu vs BR (HR 0.42, 95% CI 0.28-0.63, 1-sided and 2-sided P&lt;0.0001; Figure); similar results were observed by INV (HR 0.42, 95% CI 0.27-0.66, 1-sided P&lt;0.0001, 2-sided P=0.0001). Treatment benefit for zanu was observed across subgroups for age, Binet stage, bulky disease, and del(11q) status. Treatment benefit was also observed for pts with unmutated IGHV (HR 0.24, 1-sided and 2-sided P&lt;0.0001), but not for mutated IGHV (HR 0.67, 1-sided P=0.0929). Estimated 24-mo PFS (IRC) for zanu vs BR was 85.5% (95% CI 80.1%- 89.6%) vs 69.5% (95% CI 62.4%-75.5%). ORR by IRC for zanu vs BR was 94.6% (95% CI 91.0%-97.1%) vs 85.3% (95% CI 80.1%-89.5%). Complete response rate was 6.6% with zanu and 15.1% with BR. ORR by INV for zanu vs BR was 97.5% (95% CI 94.7%-99.1%) vs 88.7% (95% CI 83.9%-92.4%) Estimated 24-mo OS for zanu vs BR was 94.3% (95% CI 90.4%-96.7%) and 94.6% (95% CI 90.6%-96.9%). The most common AEs are shown in the Table. AEs of interest occurring during the full reporting period (pooled terms, zanu vs BR) included atrial fibrillation (any grade [gr]: 3.3% vs 2.6%), bleeding (any gr/gr≥3: 45.0%/3.8% vs 11.0%/1.8%), hypertension (any gr: 14.2% vs 10.6%), infection (any gr/gr≥3: 62.1%/16.3% vs 55.9%/18.9%), and neutropenia (any gr/gr≥3: 15.8%/11.7% vs 56.8%/51.1%). Treatment discontinuation due to AEs occurred in 20 pts (8.3%) receiving zanu vs 31 pts (13.7%) receiving BR; 85.5% of pts receiving zanu remain on treatment. AEs leading to death occurred in 11 pts (4.6%) receiving zanu vs 12 pts (5.3%) receiving BR. No sudden deaths were reported. Conclusions: In this global registrational trial, zanu demonstrated statistically significant improvement in PFS compared to BR as assessed by IRC. Superiority was also observed in PFS by INV as well as ORR by both IRC and INV. Zanu was generally well tolerated, with low rates of atrial fibrillation consistent with those observed in the phase 3 ASPEN (Tam, Blood 2020;136:2038-2050) and ALPINE studies (Hillmen, EHA 2021 #LB1900). These data support the potential utility of zanu in the frontline management of pts with TN CLL/SLL. Figure 1 Figure 1. Disclosures Tam: AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Honoraria; Novartis: Honoraria; Loxo: Consultancy; Roche: Consultancy, Honoraria. Giannopoulos: Polish Myeloma Consortium, Next Generation Hematology Association: Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Honoraria; Pfizer: Honoraria; Teva: Honoraria; TG Therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria, Research Funding; Bei-Gene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi-Genzyme: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Jurczak: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Bayer: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celtrion: Research Funding; Celgene: Research Funding; Debbiopharm: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Šimkovič: Janssen, Gilead, Roche, AstraZeneca, and AbbVie: Other: consultancy fees, advisory board participation fees, travel grants, and honoraria; University Hospital Hradec Kralove: Current Employment; AbbVie: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Merck: Current equity holder in publicly-traded company; Eli Lilly: Current equity holder in publicly-traded company; J&J: Current equity holder in publicly-traded company; Gilead: Other: Travel, Accommodations, Expenses. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Österborg: BeiGene: Research Funding; Gilead: Research Funding. Laurenti: Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Gilead: Honoraria; Roche: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Honoraria. Walker: BeiGene: Consultancy; Acerta: Consultancy. Opat: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Sandoz: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Monash Health: Current Employment. Chan: AbbVie: Membership on an entity's Board of Directors or advisory committees; Eusa: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel, Accommodations, Expenses; Celgene: Other: Travel, Accommodations, Expenses; Roche: Speakers Bureau. Ciepluch: Copernicus Wojewodzkie Centrum Onkologii: Current Employment. Greil: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding. Trněný: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; AstraZeneca: Honoraria. Brander: Verastem: Consultancy; ArQule: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; MEI Pharma: Research Funding; Novartis: Research Funding; LOXO: Research Funding; Ascentage: Research Funding; AstraZeneca: Research Funding; BeiGene: Research Funding; DTRM: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel; NCCN: Other: panel member; ArQule/Merck: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Flinn: Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Verner: Janssen-Cilag Pty Ltd: Research Funding. Brown: Janssen: Consultancy; MEI Pharma: Consultancy; Rigel: Consultancy; Bristol-Myers Squib/Juno/Celegene: Consultancy; Novartis: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; TG Therapeutics: Research Funding; Abbvie: Consultancy; Acerta/Astra-Zeneca: Consultancy; Beigene: Consultancy; Catapult: Consultancy; Loxo/Lilly: Research Funding; Sun: Research Funding; Nextcea: Consultancy; Gilead: Research Funding; SecuraBio: Research Funding; Eli Lilly and Company: Consultancy; Genentech/Roche: Consultancy; Pfizer: Consultancy; Morphosys AG: Consultancy. Kahl: AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy; AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding. Ghia: Sunesis: Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Celgene/Juno/BMS: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Tian: BeiGene: Current Employment; AbbVie: Ended employment in the past 24 months. Marimpietri: BeiGene USA: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Paik: BeiGene USA, Inc.: Current Employment, Current equity holder in publicly-traded company. Cohen: BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: Travel, Accommodations, Expenses. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Robak: Biogen, Abbvie, Octapharma, Janssen: Honoraria, Other: Advisory board; AstraZeneca, Abbvie, Janssen, Octapharma, Gilead,Oncopeptides AB, Pharmacyclics, Pfizer, GlaxoSmithKline, Biogen: Research Funding; Medical University of Lodz: Current Employment. Hillmen: Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; AstraZeneca: Honoraria; SOBI: Honoraria; BeiGene: Honoraria; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not been approved for TN CLL/SLL without del(17p) in the US

BackgroundA child’s death is the most stressful event and the most complex grief that families face. The process of psychological adaptation to the illness and death of a child is difficult due to a variety of emotional reactions. Parental grief had received the attention of researchers only in recent years when it became clear that this reality differs substantially from the general grief process.ObjectiveThis work aims to highlight the needs of bereaved parents; increase the specificity and effectiveness of the therapeutic approach to prevent complications in the process of loss-making; and find the recurrent thematic nuclei in the development of bereavement present in a therapeutic group of parents who have lost their child to an onco-hematological disease.MethodBetween 2011 and 2016, five therapeutic groups for the grief elaboration were made. The sample included a total of 50 parents of children who died from cancer between the ages of 0 and 21 years.Content analysis was carried out as a qualitative analysis method. The SAS® Text Miner software (SAS Institute Inc, 2004) was used to read, interpret, classify and integrate the data from numerous sources.ResultsThe development and consecutive interpretation of the 5 clusters have been carried out to analyze the related topics using the node “Topic Analysis” and requesting the subdivision into five topics. Four topics have been well defined. Clear topics are reducible to categories of emotional relief, tools, legacy, and unfinished business. The topic analysis provides interesting indications about the different interpretive journeys of the bereavement situation and offers ideas regarding the different types of social responses.ConclusionsAfter reviewing the existing bibliography, we have confirmed the lack of specific literature on the problem of grief in parents whose children have died from cancer. Much research has shown that parents who lose a child to cancer want support, and there are still few studies on the most effective interventions for this group.

Aims: Poor glycemic control may contribute to the very high mortality rate in patients with type 2 diabetes (T2D) receiving hemodialysis (HD) . Whether analogue compared to human insulin therapy associates with different outcomes is unknown. Methods: Incident HD patients with T2D on insulin treatment enrolled at one of the 288 Fresenius Medical Care facilities across 7 European countries between 2007-20were identified using an established administrative data algorithm. All patients were censored after 3 years of observation. Following multiple imputation, inverse probably weighting (IPW) and instrumental variable (IV; using country) analyses were used to generate Cox-proportional hazards to estimate analogue compared to human insulin hazard ratios for all-cause mortality (ACM) , MACE, hospitalization, and confirmed hypoglycemia (&lt;3.0 mmol/L during a dialysis session) . Results: About 713 analogue users were compared to 733 subjects treated with human insulin. Significant variation in prescription by country was observed. IPW hazard ratios [95% confidence intervals] for patients on analogue compared to human insulin were 0.8[0.659-0.991] for ACM (p=0.042) , 0.817 [0.679-0.983] for MACE (p=0.033) , 0.757 [0.665-0.861] for hospitalization (p&lt;0.001) , and 1.6[1.1419-2.268] for hypoglycemia (p=0.008) . Consistent strength and direction of the associations were observed in the IV analysis and across sensitivity analyses. Conclusions: In this large, multinational cohort of patients with T2D on HD, compared to human insulins, analogue insulins were associated with better clinical outcomes, although hypoglycemia rates were increased. Whether analogue insulins represent the preferred therapy in this group requires confirmatory evidence from a clinical trial. Disclosure T. Ebert: Consultant; Sanofi, Santis. Research Support; AstraZeneca, Novo Nordisk. N. Sattar: None. M. Greig: None. C. Lamina: None. K. Eckardt: Consultant; Akebia Therapeutics, Inc. Research Support; Bayer AG, Evotec International GmbH, Fresenius Medical Care. Speaker's Bureau; AstraZeneca, Bayer AG, Otsuka Pharmaceutical Co., Ltd. J. Floege: Other Relationship; Novo Nordisk A/S. F. Kronenberg: Advisory Panel; Amgen Inc., Novartis AG. P. Stenvinkel: Advisory Panel; AstraZeneca, Baxter, Fresenius Medical Care, Reata Pharmaceuticals, Inc., Vifor Pharma Management Ltd. Speaker's Bureau; Astellas Pharma Inc., Bayer AG, Novo Nordisk. D.C. Wheeler: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., GlaxoSmithKline plc., Janssen Global Services, LLC, Merck Sharp & Dohme Corp., Mundipharma, Tricida, Inc., Vifor Pharma Management Ltd. Consultant; AstraZeneca. Speaker's Bureau; Amgen Inc., Astellas Pharma Inc. J. Fotheringham: Advisory Panel; Novartis Pharmaceuticals Corporation. Speaker's Bureau; Fresenius Medical Care, Novartis Pharmaceuticals Corporation, Vifor Pharma Management Ltd. Funding Amgen (Europe) GmbH- Rotkreuz, Switzerland- Swedish Research Council (grant 2009-1068) - Swedish Heart and Lung Foundation (20160384) - Njurfonden- Westmans Foundation- Novo Nordisk (Postdoctoral fellowship program run inpartnership with Karolinska Institutet, Stockholm,Sweden) - Karolinska Institutet Research Foundation - EFSD (EFSD Mentorship Programme supported by AstraZeneca) - German Research Foundation (SFB TRR 219, projects C1 and M1) - National Institute for Health Research (UK) (Clinician Scientist Award)

Abstract Background Prolonged Grief Disorder (PGD) was newly included in the ICD-11 and DSM-5-TR. It is not yet part of the standard assessments in many healthcare systems, including psychiatric wards. Because disordered grief is associated with suicidality, sleep problems and substance use disorders, an investigation into PGD in psychiatric inpatients is warranted. Method We interviewed N = 101 psychiatric inpatients who were admitted to the open psychiatric wards and the day hospital of a German psychiatric hospital and who had lost a person close to them. Assessments comprised clinical interviews and self-report instruments covering PGD and other mental disorders. We specifically developed the International Interview for Prolonged Grief Disorder according to ICD-11 (I-PGD-11) for the study and examined its psychometric properties. Results The prevalence rate of PGD among bereaved patients according to ICD-11 was 16.83% and according to DSM-5-TR 10.89%. The I-PGD-11 showed good psychometric properties (Mc Donald’s ω = 0.89, ICC = 0.985). Being female, having lost a child or spouse, and unnatural or surprising circumstances of the death were associated with higher PGD scores. Trial registration Approval was obtained by the ethics committee of the of the Goethe University Frankfurt (2021-62, 2023-17) and the Chamber of Hessian Physicians (2021-2730-evBO). The study was preregistered (https://doi.org/10.17605/OSF.IO/K98MF). Limitations We only assessed inpatients of one psychiatric clinic in Germany, limiting the generalizability of our findings. Conclusion The present study underlines the importance of exploring loss and grief in psychiatric inpatients and including PGD in the assessments. Given that a significant minority of psychiatric inpatients has prolonged grief symptoms, more research into inpatient treatment programs is needed.

ZusammenfassungDas gestaltete Gelände einer Modelleisenbahn hat – will der Erbauer als ‚ernsthafter Modellbahner‘, nicht als ‚Spielbahner‘ gelten – mehrere Funktionen: es legitimiert die Bahnanlagen, es schafft eine zeitliche Kontextualisierung für das rollende Material und es kaschiert dem Blick zu entziehende Teile der Modellbahn. Ein wesentliches Medium der Vermittlung von Konventionen der Gestaltung dieses Geländes, auf Grundlage einesCommon SenseVerständnisses von Landschaft, dient Modelleisenbahn bezogene Literatur. Diese wiederum greift häufig auf kartographische Darstellungen zurück. Diese Darstellungen ordnen sich zwischen der Polarität reiner Gleispläne (unter Rückgriff) auf abstrakte Signaturen und topographischen Darstellungen, die zu abstrakten Liniensignaturen für Gleisdarstellungen auf eine konkrete Signaturensprache zurückgreifen. Darüber hinaus vermitteln Blockbilder einen dreidimensionalen Eindruck der darzustellenden Anlage. Insgesamt dominiert eine eher schlichte, intuitiv erschließbare Darstellung, die innerhalb von gewissen Konventionen individuelle Gestaltungsspielräume offenlässt. Dieser Beitrag stellt die Ergebnisse einer explorativen Studie in den Kontext aktueller landschaftstheoretischer Forschung.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no definitive treatment. However, a bioactive lipid mediator, sphingosine-1-phosphate (S1P) has been identified to have a role in the pathogenesis of IPF. S1P is synthesized from sphingosine by iso-enzymes sphingosine kinase (SPHK) 1 & 2. In animal models of IPF, genetic knockout of Sphk1 or inhibition of SPHK1 protected the lungs from fibrosis induced by inciting agents. SPHK1 expression is upregulated in IPF; however, the mechanism(s) of its upregulation remain unclear. Hypothesis In silico analysis can predict transcription factors (TFs) that could bind to the promoter region of mouse Sphk1, upregulating its transcription. This could help predict therapeutic targets for IPF in mouse models. Methods: MatInspector® software tool of Genomatix Inc. (Germany) was used for in silico analysis of TF binding sites in Sphk1. This tool uses the available pool of data for TF binding sites to predict probable binding sites in the DNA nucleotide sequence. Results A search for Sphk1 transcript in mouse using gene ID 20698 with accession numbers GXP_6660985, 9541363 and 10224577 yielded 2,119 matches in chromosome 11. GXP_6660985, with the highest probability of TF binding, was the main transcript. The top 100 TF binding sites were analyzed. Among these, 24 binding sites relevant to lung tissue had a very high probability of binding with matrix similarity of 0.98 to 1.0. The TFs included GREF, STAT, SMAD and FKHD. Among these, seven TFs and their binding sites were not cited in the literature according to MatInspector®. Conclusions: A total of 12 TFs were identified in lung tissue as potential members of transcription initiation complex for Sphk1 gene in mouse.Future direction: In silico analysis of TF binding for human SPHK1 is in progress. Modulation of these TFs could serve as a potential therapeutic tool for IPF. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

It’s a portrait of grief, to be sure, but it puts grief in the air, as a cultural atmospheric, without giving us anything to mourn.—— Tom Junod, “The Man Who Invented 9/11”The nearly decade-long attempt by families of 9/11 victims to reclaim the remains of their relatives involves rhetorics of bodilessness, waste, and virtuality that offer startling illustrations of what might be termed “the poetics of grief.” After combining as the WTC Families for Proper Burial Inc. in 2002, the families sued the city of New York in 2005. They lost and the case has been under appeal since 2008. WTC Families is asking for nearly one million tons of material to be moved from the Fresh Kills landfill on Staten Island in order to sift it for human remains. These remains will then be reclaimed and interred: Proper Burial. But the matter is far less definitive. When a judge hearing the appeal asked how one would prove someone’s identity, the city’s lawyer replied, “You have to be able to particularise and say it’s your body. All that’s left here is a bunch of undifferentiated dust.” The reply “elicited gasps and muttered ‘no’s’ from a crowd whose members wore laminated photos of deceased victims” (Hughes). These laminated displays are an attempt by WTC Families to counteract the notion of the victims as “undifferentiated dust”; the protected, hermetic images are testimony to painful uncertainty, an (always) outmoded relic of the evidentiary self.In the face of such uncertainty, it was not only court audiences who waited for a particular response to the terrorist attacks. Adam Hirsch, reviewer for the New York Sun, claimed that “the writer whose September 11 novel seemed most necessary was Don DeLillo. Mr. DeLillo, more than any other novelist, has always worked at the intersection of public terror and private fear.” DeLillo’s prescience regarding the centrality of terrorism in American culture was noted by many critics in the aftermath of the attack on the World Trade Centre. The novelist even penned an essay for Harper’s in which he reflected on the role of the novelist in the new cultural landscape of the post-9/11 world. In an online book club exchange for Slate, Meghan O’Rourke says, “DeLillo seemed eerily primed to write a novel about the events of September 11. … Rereading some of his earlier books, including the terrorism-riddled Mao II, I wondered, half-seriously, if Mohamed Atta and crew had been studying DeLillo.” If there was any writer who might have been said to have seen it coming it was DeLillo. The World Trade Center had figured in his novels before the 9/11 attacks. The twin towers are a primary landmark in Underworld, gracing the cover of the novel in ghostly black and white. In Players (1977), a Wall Street worker becomes involved in a terrorist plot to bomb the New York Stock exchange and his wife works in the WTC for the “Grief Management Council”—“Where else would you stack all this grief?” (18).ClassificationsAs the WTC Families for Proper Burial Inc. trial demonstrates, the reality of the terrorist attacks of September 11 offered an altogether more macabre and less poetic reality than DeLillo’s fiction had depicted. The Fresh Kills landfill serves in Underworld as a metaphor for the accumulated history of Cold War America in the last half-century. Taking in the “man-made mountain,” waste management executive Brian Glassic thinks, “It was science fiction and prehistory”; seeing the World Trade Center in the distance, “he sensed a poetic balance between that idea and this one” (Underworld 184). But the poetic balance DeLillo explores in the 1997 novel has been sundered by the obliteration of the twin towers. Fresh Kills and the WTC are now united by a disquieting grief. The landfill, which closed in 2001, was forced to reopen when the towers collapsed to receive their waste. Fresh Kills bears molecular witness to this too-big collective trauma. “‘They commingled it, and then they dumped it,’ Mr. Siegel [lawyer for WTC Families] said of the remains being mixed with household trash, adding that a Fresh Kills worker had witnessed city employees use that mixture to fill potholes” (Hughes). The revelation is obscene: Are we walking and driving over our dead? The commingling of rubble and human remains becomes a collective (of) contamination too toxic, too overwhelming for conventional comprehension. “You can’t even consider the issue of closure until this issue has been resolved,” says the lawyer representing WTC Families (Hartocollis).Nick Shay, Underworld’s main character, is another waste executive who travels the world to observe ways of dealing with garbage. Of shopping with his wife, Nick says, “Marion and I saw products as garbage even when they sat gleaming on store shelves, yet unbought. We didn’t say, What kind of casserole will that make? We said, What kind of garbage will that make?” (121). This attests to the virtuality of waste, a potentiality of the products – commercial, temporal, biological – that comprise the stuff of contemporary American culture. Synecdoche and metonymy both, waste becomes the ground of hysteron proteron, the rhetorical figure that disorders time and makes the future always present. Like (its) Fresh Kills, waste is science fiction and prehistory.Repeating the apparent causal and temporal inversion of hysteron proteron, Nick’s son Jeff uses his home computer to access a simultaneous future and past that is the internal horizon of Underworld’s historical fiction. Jeff has previously been using his computer to search for something in the video footage of the “Texas Highway Killer,” a serial murderer who randomly shoots people on Texan highways. Jeff tries to resolve the image so that the pixels will yield more, exposing their past and future. “He was looking for lost information. He enhanced and super-slowed, trying to find some pixel in the data swarm that might provide a clue to the identity of the shooter” (118). Searching for something more, something buried, Jeff, like WTC Families, is attempting to redeem the artifactual and the overlooked by reconfiguring them as identity. DeLillo recognises this molecular episteme through the “dot theory of reality”: “Once you get inside a dot, you gain access to hidden information, you slide inside the smallest event. This is what technology does. It peels back the shadows and redeems the dazed and rambling past. It makes reality come true” (177). Like the gleaming supermarket products Nick and Marion see as garbage, the unredeemed opens onto complex temporal and rhetorical orders. Getting inside garbage is like getting “inside a dot.” This approach is not possible for the unplanned waste of 9/11. Having already lost its case, WTC Families will almost certainly lose its appeal because its categories and its means are unworkable and inapplicable: they cannot particularise.PremonitionsIn his 9/11 essay “In the Ruins of the Future,” published in Harper’s a few months after the attacks, DeLillo says “We are all breathing the fumes of lower Manhattan where traces of the dead are everywhere, in the soft breeze off the river, on rooftops and windows, in our hair and on our clothes” (39). DeLillo‘s portrait of molecular waste adumbrates the need to create “counternarratives.” Until the events of 11 September 2001 the American narrative was that of the Cold War, and thus also the narrative of Underworld; one for which DeLillo claims the Bush administration was feeling nostalgic. “This is over now,” he says. “The narrative ends in the rubble and it is left to us to create the counternarrative” (34).DeLillo was already at work on a narrative of his own at the time of the terrorist attacks. As Joseph Conte notes, when the World Trade Center was attacked, “DeLillo, had nearly finished drafting his thirteenth novel, Cosmopolis [… and] shared in the collective seizure of the American mind” (179). And while it was released in 2003, DeLillo sets the novel in 2000 on “a day in April.” If the millennium, the year 2000, has been as Boxall claims the horizon of DeLillo’s writing, the tagging of this “day in April” at the beginning of the novel signals Cosmopolis as a limit-work (4). 9/11 functions as a felt absence in the novel, a binding thing floating in the air, like the shirt that DeLillo will use to begin and end Falling Man; a story that will ‘go beyond’ the millennial limit, a story that is, effectively, the counternarrative of which DeLillo speaks in his 9/11 essay. Given the timing of the terrorist attacks in New York, and DeLillo’s development of his novel, it is extraordinary to consider just how Cosmopolis reflects on its author’s position as a man who should have “seen it coming.” The billionaire protagonist Eric Packer traverses Manhattan by car, his journey a bifurcation between sophistication and banality. Along the way he has an onanistic sexual encounter whilst having his prostate examined, hacks into and deletes his wife’s old money European fortune, loses his own self-made wealth by irrationally betting against the rise of the yen, kills a man, and shoots himself in the hand in front of his assassin. Eric actively moves toward his own death. Throughout Eric’s journey the socially binding integrity of the present and the future is teased apart. He continually sees images of future events before they occur – putting his hand on his chin, a bomb explosion, and finally, his own murder – via video screens in his car and wristwatch. These are, as Conte rightly notes, repeated instances of hysteron proteron (186). His corpse does not herald obsolescence but begins the true life of waste: virtual information. Or, as Eric’s “Chief of Theory” asks, “Why die when you can live on a disk?” (106). There are shades here of Jeff’s pixelated excursion into the video footage of the Texas Highway Killer: “Once you get inside a dot, you gain access to hidden information.” Life at this level is not only virtual, it is particularised, a point (or a collection of points) Eric comes to grasp during the protracted scene in which he watches himself die: “The stuff he sneezes when he sneezes, this is him” (207). In Falling Man, the work in which DeLillo engages directly with the 9/11 attack, the particularised body recurs in various forms. First there is the (now iconic) falling man: the otherwise unknown victim of the terrorist attack who leapt from the WTC and whose descent was captured in a photograph by Richard Drew. This figure was named (particularised) by Tom Junod (who provides the epigram for this essay) as “The Falling Man.” In DeLillo’s novel another Falling Man, a performance artist, re-enacts the moment by jumping off buildings, reiterating the photograph (back) into a bodily performance. In these various incarnations the falling man is serially particularised: photographed, named, then emulated. The falling man is a single individual, and multiple copies. He lives on long after death and so does his trauma. He represents the poetic expression of collective grief. Particularised bodies also infect the terror narrative of Falling Man at a molecular level. Falling Man’s terrorist, Hammad, achieves a similar life-after-death by becoming “organic shrapnel.” The surviving victims of the suicide bomb attack, months later, begin to display signs of the suicide bombers in lumps and sores emerging from their bodies, too-small bits of the attacker forever incorporated. Hammad is thus paired with the victims of the crash in a kind of disseminative and absorptive (rhetorical) structure. “The world changes first in the mind of the man who wants to change it. The time is coming, our truth, our shame, and each man becomes the other, and the other still another, and then there is no separation” (80). RevisionsThe traces of American culture that were already contained in the landfill in Underworld have now become the resting place of the dust and the bodies of the trauma of 9/11. Rereading DeLillo’s magnum opus one cannot help but be struck by the new resonance of Fresh Kills.The landfill showed him smack-on how the waste stream ended, where all the appetites and hankerings, the sodden second thoughts came runneling out, the things you wanted ardently and then did not…. He knew the stench must ride the wind into every dining room for miles around. When people heard a noise at night, did they think the heap was coming down around them, sliding toward their homes, an omnivorous movie terror filling their doorways and windows?The wind carried the stink across the kill…. The biggest secrets are the ones spread before us. (184-5)The landfill looms large on the landscape, a huge pile of evidence for the mass trauma of what remains, those that remain, and what may come—waste in all its virtuality. The “omnivorous movie terror filling their doorways and windows” is a picture of dust-blanketed Downtown NYC that everybody, everywhere, continually saw. The mediatory second sight of sifting the landfill, of combing the second site of the victims for its “sodden second thoughts,” is at once something “you wanted ardently and then did not.” The particles are wanted as a distillate, produced by the frameline of an intentional, processual practice that ‘edits’ 9/11 and its aftermath into a less unacceptable sequence that might allow the familiar mourning ritual of burying a corpse. WTC Families Inc. is seeking to throw the frame of human identity around the unincorporated particles of waste in the Fresh Kills landfill, an unbearably man-made, million-ton mountain. This operation is an attempt to immure the victims and their families from the attacks and its afterlife as waste or recycled material, refusing the ever-present virtual life of waste that always accompanied them. Of course, even if WTC Families is granted its wish to sift Fresh Kills, how can it differentiate its remains from those of the 9/11 attackers? The latter have a molecular, virtual afterlife in the present and the living, lumpy reminders that surface as foreign bodies.Resisting the city’s drive to rebuild and move on, WTC Families for Proper Burial Inc. is absorbed with the classification of waste rather than its deployment. In spite of the group’s failed court action, the Fresh Kills site will still be dug over: a civil works project by the NYC Department of Parks & Recreation will reclaim the landfill and rename it “Freshkills Park,” a re-creational area to be twice the size of Central Park—As DeLillo foresaw, “The biggest secrets are the ones spread before us.”ReferencesBoxall, Peter. Don DeLillo: The Possibility of Fiction. London: Routledge, 2006.Conte, Joseph M. “Writing amid the Ruins: 9/11 and Cosmopolis”. The Cambridge Companion to Don DeLillo. Ed. John N. Duvall. Cambridge: Cambridge University Press, 2008. 179-192.Cowart, David. Don DeLillo: The Physics of Language. Athens: University of Georgia Press, 2003.DeLillo, Don. Players. London: Vintage, 1991.———. Mao II. London: Vintage, 1992.———. Underworld. London: Picador, 1997.———. “In the Ruins of the Future”. Harper’s. Dec. 2001: 33-40.———. Cosmopolis. London: Picador, 2003.———. Falling Man. New York: Scribner, 2007.Hartocollis, Anemona. “Landfill Has 9/11 Remains, Medical Examiner Wrote”. 24 Mar. 2007. The New York Times. 7 Mar. 2009 ‹http://www.nytimes.com/2007/03/24%20/nyregion/24remains.html›. Hirsch, Adam. “DeLillo Confronts September 11”. 2 May 2007. The New York Sun. 10 May 2007 ‹http://www.nysun.com/arts/delillo-confronts-september-11/53594/›.Hughes, C. J. “9/11 Families Press Judges on Sifting at Landfill”. 16 Dec. 2009. The New York Times. 17 Dec. 2009 ‹http://www.nytimes.com/2009/12/17/nyregion/17sift.html›.Junod, Tom. “The Man Who Invented 9/11”. 7 May 2007. Rev. of Falling Man by Don DeLillo. Esquire. 28 May 2007 ‹http://www.esquire.com/fiction/book-review/delillo›.O’Rourke, Meghan. “DeLillo Seemed Almost Eerily Primed to Write a Novel about 9/11”. 23 May 2007. Slate.com. 28 May 2007 ‹http://www.slate.com/id/2166831/%20entry/2166848/›.

IntroductionThey shall grow not old, as we that are left grow old; Age shall not weary them, nor the years condemn. At the going down of the sun and in the morning We will remember them.Recited at many Anzac and Remembrance Day services, ‘The Ode’, an excerpt from a poem by Laurence Binyon, speaks of a timelessness within the inexorable march of time. When we memorialise those for whom time no longer matters, time stands still. Whether those who died in service of their country have finally “beaten time” or been forced to acknowledge that “their time on earth was up”, depends on your preference for clichés. Time and death are natural bedfellows. War memorials, be they physical or digital, declare a commitment to “remember them”. This article will compare and contrast the purpose of, and community response to, virtual and physical war memorials. It will examine whether virtual war memorials are a sign of the times – a natural response to the internet era. If, as Marshall McLuhan says, the medium is the message, what experiences do we gain and lose through online war memorials?Physical War MemorialsDuring and immediately after the First World War, physical war memorials were built in almost every city, town and village of the Allied countries involved in the war. They served many purposes. One of the roles of physical war memorials was to keep the impact of war at the centre of a town’s consciousness. In a regional centre like Bathurst, in New South Wales, the town appears to be built around the memorial – the court, council chambers, library, churches and pubs gather around the war memorials.Similarly, in small towns such as Bega, Picton and Kiama, war memorial arches form a gateway to the town centre. It is an architectural signal that you are entering a community that has known pain, death and immense loss. Time has passed, but the names of the men and women who served remain etched in stone: “lest we forget”.The names are listed in a democratic fashion: usually in alphabetical order without their rank. However, including all those who offered their service to “God, King and Country” (not just those who died) also had a more sinister and divisive effect. It reminded communities of those “eligibles” in their midst whom some regarded as “shirkers”, even if they were conscientious objectors or needed to stay and continue vital industries, like farming (Inglis & Phillips 186).Ken Inglis (97) estimated that every second Australian family was in mourning after the Great War. Jay Winter (Sites 2) goes further arguing that “almost every family” in the British Commonwealth was grieving, either for a relative; or for a friend, work colleague, neighbour or lover. Nations were traumatised. Physical war memorials provided a focal point for that universal grief. They signalled, through their prominence in the landscape or dominance of a hilltop, that it was acceptable to grieve. Mourners were encouraged to gather around the memorial in a public place, particularly on Anzac Day and Remembrance Day each year. Grief was seen, observed, respected.Such was the industrial carnage of the Western Front, that about one third of Australia and New Zealand’s fatal casualties were not brought home. Families lost a family member, body and soul, in the Great War. For those people who subscribed to a Victorian view of death, who needed a body to grieve over, the war memorial took on the role of a gravesite and became a place where people would place a sprig of wattle, poke a poppy into the crevice beside a name, or simply touch the letters etched or embossed in the stone (Winter, Experience 206). As Ken Inglis states: “the statue on its pedestal does stand for each dead man whose body, identified or missing, intact or dispersed, had not been returned” to his home town (11).Physical war memorials were also a place where women could forge new identities over time. Women accepted, or claimed their status as war widows, grieving mothers or bereft fiancés, while at the same time coming to terms with their loss. As Joy Damousi writes: “mourning of wartime loss involved a process of sustaining both a continuity with, and a detachment from, a lost soldier” (1). Thus, physical war memorials were transitional, liminal spaces.Jay Winter (Sites 85) believes that physical war memorials were places to both honour and mourn the dead, wounded, missing and shell-shocked. These dual functions of both esteeming and grieving those who served was reinforced at ceremonies, such as Anzac or Remembrance Day.As Joy Damousi (156) and Ken Inglis (457, 463) point out, war memorials in Australia are rarely sites of protest, either for war widows or veterans campaigning for a better pension, or peace activists who opposed militarism. When they are used in this way, it makes headlines in the news (Legge). They are seldom used to highlight the tragedy, inhumanity or futility of war. The exception to this, were the protests against the Vietnam War.The physical war memorials which mushroomed in Australian country towns and cities after the First World War captured and claimed those cataclysmic four years for the families and communities who were devastated by the war. They provided a place to both honour and mourn those who served, not just once, but for as long as the memorial remained. They were also a place of pilgrimage, particularly for families who did not have a grave to visit and a focal point for the annual rituals of remembrance.However, over the past 100 years, some unmaintained physical war memorials are beginning to look like untended graves. They have become obstacles rather than sentinels in the landscape. Laurence Aberhart’s haunting photographs show that memorials in places like Dorrigo in rural New South Wales “go largely unnoticed year-round, encroached on by street signage and suburbia” (Lakin 49). Have physical war memorials largely fulfilled their purpose and are they becoming obsolete? Perhaps they have been supplanted by the gathering space of the 21st century: the Internet.Digital War MemorialsThe centenary of the Great War heralded a mushrooming of virtual war memorials. Online First World War memorials focus on collecting and amassing information that commemorates individuals. They are able to include far more information than will fit on a physical war memorial. They encourage users to search the digitised records that are available on the site and create profiles of people who served. While they deal in records from the past, they are very much about the present: the user experience and their connection to their ancestors who served.The Imperial War Museum’s website Lives of the First World War asks users to “help us build the permanent digital memorial to all who contributed during the First World War”. This request deserves scrutiny. Firstly, “permanent” – is this possible in the digital age? When the head of Google, Vint Cerf, disclosed in 2015 that software programming wizards were still grappling with how to create digital formats that can be accessed in 10, 100 or a 1000 years’ time; and recommended that we print out our precious digital data and store it in hard copy or risk losing it forever; then it appears that online permanency is a mirage.Secondly, “all who contributed” – the website administrators informed me that “all” currently includes people who served with Canada and Britain but the intention is to include other Commonwealth nations. It seems that the former British Empire “owns” the First World War – non-allied, non-Commonwealth nations that contributed to the First World War will not be included. One hundred years on, have we really made peace with Germany and Turkey? The armistice has not yet spread to the digital war memorial. The Lives of the First world War website missed an opportunity to be leaders in online trans-national memorialisation.Discovering Anzacs, a website built by the National Archives of Australia and Archives New Zealand, is a little more subdued and honest, as visitors are invited to “enhance a profile dedicated to the wartime journey of someone who served”.Physical and online war memorials can work in tandem. In 2015, the Supreme Court of Victoria created a website that provides background information on the military service of the 159 members of the legal profession who are named on their Memorial board. This is an excellent example of a digital medium expanding on and reinvigorating a physical memorial.It is noteworthy that all of these online memorial websites commemorate those who served in the First World War, and sometimes the Boer or South African War. There is no space for remembering those who served or died in more recent wars like Afghanistan or Iraq. James Brown and others discuss how the cult of Anzac is overshadowing the service and sacrifices of the men and women who have been to more recent wars. The proximity of their service mitigates against its recognition – it is too close for comfortable, detached remembrance.Complementary But Not ExclusiveA comparison of their functions indicates that online memorials which focus on the First World War complement, but will never replace the role of physical war memorials. As discussed, physical war memorials were sites for grieving, pilgrimage and collectively honouring the men and women who served and died. Online websites which allow users to upload scanned documents and photographs; transcribe diary entries or letters; post tribute poems, songs or video clips; and provide links to other relevant records online are neither places of pilgrimage nor sites for grieving. They are about remembrance, not memory (Scates, “Finding” 221).Ken Inglis describes physical war memorials as “bearers of collective memory” (7). In a sense, online war memorials are keepers of individual, user-enhanced archival records. It can be argued that online memorials to the First World War tap into the desire for hero-worship, the boom in family history research and what Scates calls the “cult of remembrance” (“Finding” 218). They provide a way for individuals, often two or three generations removed, to discover, understand and document the wartime experiences of individuals in their family. By allowing descendants to situate their family story within the larger, historically significant narrative of the First World War, online memorials encourage people to feel that the suffering and untimely death of their forbear wasn’t in vain – that it contributed to something worthwhile and worth remembering. At a collective level, this contributes to the ANZAC myth and former Australian Prime Minister John Howard’s attempt to use it as a foundational myth for Australia’s nationhood.Kylie Veale (9) argues that cyberspace has encouraged improvements on traditional memorial practices because online memorials can be created in a more timely fashion, they are more affordable and they are accessible and enable the sharing of grief and bereavement on a global scale. As evidence of this, an enterprising group in the USA has developed an android app which provides a template for creating an online memorial. They compete with Memorialsonline.com. Veale’s arguments remind us that the Internet is a hyper-democratic space where interactions and sites that are collaborative or contemplative exist alongside trolling and prejudice. Veale also contends that memorial websites facilitate digital immortality, which helps keep the memory of the deceased alive. However, given the impermanence of much of the content on the Internet, this final attribute is a bold claim.It is interesting to compare the way individual soldiers are remembered prior to and after the arrival of the Internet. Now that it is possible to create a tribute website, or Facebook page in memory of someone who served, do families do this instead of creating large physical scrapbooks or photo albums? Or do they do both? Garry Roberts created a ‘mourning diary’ as a record of his journey of agonising grief for his eldest son who died in 1918. His diary consists of 27 scrapbooks, weighing 10 kilograms in total. Pat Jalland (318) suggests this helped Roberts to create some sort of order out of his emotional turmoil. Similarly, building websites or digital tribute pages can help friends and relatives through the grieving process. They can also contribute the service person’s story to official websites such as those managed by the Australian Defence Forces. Do grieving family members look up a website or tribute page they’ve created in the same way that they might open up a scrapbook and remind themselves of their loved one? Kylie Veale’s research into online memorials created for anyone who has died, not necessarily those killed by war, suggests online memorials are used in this way (5).Do grieving relatives take comfort from the number of likes, tags or comments on a memorial or tribute website, in the same way that they might feel supported by the number of people who attend a memorial service or send a condolence card? Do they archive the comments? Garry Roberts kept copies of the letters of sympathy and condolence that he received from friends and relatives after his son’s tragic death and added them to his 27 scrapbooks.Both onsite and online memorials can suffer from lack of maintenance and relevance. Memorial websites can become moribund like untended headstones in a graveyard. Once they have passed their use as a focal point of grief, a place to post tributes; they can languish, un-updated and un-commented on.Memorials and PilgrimageOne thing that online memorials will never be, however, are sites of pilgrimage or ritual. One does not need to set out on a journey to visit an online memorial. It is as far away as your portable electronic device. Online memorials cannot provide the closure or sense of identity and community that comes from visiting a memorial or gravesite.This was evident in December 2014 when people felt the need to visit the Lindt Café in Sydney’s Martin Place after the terrorist siege and lay flowers and tributes. While there were also Facebook tribute pages set up for these victims of violence, mourners still felt the need to visit the sites. A permanent memorial to the victims of the siege has now opened in Martin Place.Do people gather around a memorial website for the annual rituals which take place on Anzac or Remembrance Day, or the anniversaries of significant battles? In 2013, the Australian War Memorial (AWM) saw a spike in people logging onto the Memorial’s Remembrance Day web page just prior to 11am. They left the site immediately after the minute’s silence. The AWM web team think they were looking for a live broadcast of the Remembrance Day service in Canberra. When that wasn’t available online, they chose to stay on the site until after the minute’s silence. Perhaps this helped them to focus on the reason for Remembrance Day. Perhaps, as Internet speeds get faster, it will be possible to conduct your own virtual ceremony in real time with friends and family in cyberspace.However, I cannot imagine a time when visiting dignitaries from other countries will post virtual wreaths to virtual war memorials. Ken Inglis argues that the tomb of the Unknown Soldier in the AWM has become the ritual centre of the Australian nation, “receiving obligatory wreaths from every visiting head of state” (459).Physical and Online Memorials to the War in AfghanistanThere are only eight physical war memorials to the Afghanistan conflict in Australia, even though this is the longest war Australia has been involved in to date (2001-2015). Does the lack of physical memorials to the war in Afghanistan mean that our communities no longer need them, and that people are memorialising online instead?One grieving father in far north Queensland certainly felt that an online memorial would never suffice. Gordon Chuck’s son, Private Benjamin Chuck, was killed in a Black Hawk helicopter crash in Afghanistan in 2010 when he was only 27 years old. Spurred by his son’s premature death, Gordon Chuck rallied family, community and government support, in the tiny hinterland town of Yungaburra, west of Cairns in Queensland, to establish an Avenue of Honour. He knocked on the doors of local businesses, the Returned Servicemen’s League (RSL), the Australian Defence Forces and every level of government to raise $300,000. His intention was to create a timeless memorial of world standard and national significance. On 21 June 2013, the third anniversary of his son’s death, the Chief of the Defence Force and the Prime Minister formally opened the Avenue of Honour in front of “thousands” of people (Nancarrow).Diggers from Afghanistan who have visited the Yungaburra Avenue of Honour speak of the closure and sense of healing it gave them (Nancarrow). The Avenue, built on the shores of Lake Tinaroo, features parallel rows of Illawarra flame trees, whose red blossoms are in full bloom around Remembrance Day and symbolise the blood and fire of war and the cycle of life. It commemorates all the Australian soldiers who have died in the Afghanistan war.The Avenue of Honour, and the memorial in Martin Place clearly demonstrate that physical war memorials are not redundant. They are needed and cherished as sites of grief, hope and commemoration. The rituals conducted there gather gravitas from the solemnity that falls when a sea of people is silent and they provide healing through the comfort of reverent strangers.ConclusionEven though we live in an era when most of us are online every day of our lives, it is unlikely that virtual war memorials will ever supplant their physical forebears. When it comes to commemorating the First World War or contemporary conflicts and those who fought or died in them, physical and virtual war memorials can be complementary but they fulfil fundamentally different roles. Because of their medium as virtual memorials, they will never fulfil the human need for a place of remembrance in the real world.ReferencesBinyon, Laurence. “For the Fallen.” The Times. 21 Sep. 1914. 7 Oct. 2019 <https://www.army.gov.au/our-history/traditions/for-the-fallen>.Brown, James. Anzac’s Long Shadow. Sydney: Black Inc., 2014.Damousi, Joy. The Labour of Loss. Great Britain: Cambridge UP, 1999.Hunter, Kathryn. “States of Mind: Remembering the Australian-New Zealand Relationship.” Journal of the Australian War Memorial 36 (2002). 7 Oct. 2019 <https://www.awm.gov.au/articles/journal/j36/nzmemorial>.Inglis, Ken. Sacred Places: War Memorials in the Australian Landscape. Melbourne: Melbourne UP, 1998.Inglis, Ken, and Jock Phillips. “War Memorials in Australia and New Zealand: A Comparative Survey.” Australian Historical Studies 24.96 (1991): 179-191.Jalland, Pat. Australian Ways of Death: A Social and Cultural History 1840-1918. London: Oxford University Press, 2002.Knapton, Sarah. “Print Out Digital Photos or Risk Losing Them, Google Boss Warns.” Telegraph 13 Feb. 2015. 7 Oct. 2019 <http://www.telegraph.co.uk/news/science/science-news/11410506/Print-out-digital-photos-or-risk-losing-them-Google-boss-warns.html>.Lakin, Shaune. “Laurence Aberhart ANZAC.” Artlink 35.1 (2015): 48-51.Legge, James. “Vandals Deface Two London War Memorials with ‘Islam’ Graffiti”. Independent 27 May 2013. 7 Oct. 2019 <https://www.independent.co.uk/news/uk/crime/vandals-deface-two-london-war-memorials-with-islam-graffiti-8633386.html>.Luckins, Tanya. The Gates of Memory. Fremantle, WA: Curtin University Books, 2004.McLuhan, Marshall. Understating Media: The Extensions of Man. New York: Mentor, 1964.McPhedran, Ian. “Families of Dead Soldiers Angered after Defence Chief David Hurley Donates Memorial Plinth to Avenue of Honour.” Cairns Post 7 June 2014. 7 Oct. 2019 <http://www.cairnspost.com.au/news/cairns/families-of-dead-soldiers-angered-after-defence-chief-david-hurley-donates-memorial-plinth-to-avenue-of-honour/story-fnjpusyw-1226946540125>.McPhedran, Ian. “Backflip over Donation of Memorial Stone from Afghanistan to Avenue of Honour at Yungaburra.” Cairns Post 11 June 2014. 7 Oct. 2019 <http://www.cairnspost.com.au/news/cairns/backflip-over-donation-of-memorial-stone-from-afghanistan-to-avenue-of-honour-at-yungaburra/story-fnkxmm0j-1226950508126>.Ministry for Culture and Heritage. “Interpreting First World War Memorials.” Updated 4 Sep. 2014. <http://www.nzhistory.net.nz/war/interpreting-first-world-war-memorials>.Nancarrow, Kirsty. “Thousands Attend Opening of Avenue of Honour, a Memorial to Diggers Killed in Afghanistan”. ABC News 7 Nov. 2014. 2 Oct. 2014 <http://www.abc.net.au/news/2013-06-22/avenue-of-honour-remembers-fallen-diggers/4773592>.Scates, Bruce. “Finding the Missing of Fromelles: When Soldiers Return.” Anzac Legacies: Australians and the Aftermath of War. Eds. Martin Crotty and Marina Larsson. Melbourne: Australian Scholarly Publishing, 2010. 212-231.Scates, Bruce. “Soldiers’ Journeys: Returning to the Battlefields of the Great War.” Journal of the Australian War Memorial 40 (2007): n.p.Scott, Ernest. Australia during the War: The Official History of Australia in the War of 1914–1918. Vol. XI. Sydney: Angus and Robertson, 1941.Stanley, Peter. “Ten Kilos of First World War Grief at the Melbourne Museum.” The Conversation 27 Aug. 2014. 10 Oct. 2019 <https://theconversation.com/ten-kilos-of-first-world-war-grief-at-the-melbourne-museum-30362>.Veale, Kylie. “Online Memorialisation: The Web as a Collective Memorial Landscape for Remembering the Dead.” Fibreculture Journal 3 (2004). 7 Oct. 2019 <http://three.fibreculturejournal.org/fcj-014-online-memorialisation-the-web-as-a-collective-memorial-landscape-for-remembering-the-dead/>.Winter, Jay. Sites of Memory, Sites of Mourning. Cambrigde: Cambridge UP, 1995.———. The Experience of World War I. London: Macmillan, 1988.

Over the past quarter-century 'the self' has been transformed from a relatively esoteric concept of principal interest to philosophers and psychologists to a mainstay of popular culture and critical reflection. This paper addresses some of the themes linking this transition and suggests that the driving impetus behind it is the commodification of ideas as a strategy of coping with change (as well as the packaging and consumption of goods and services which bridge the gap between the less-than-perfect present and the shining future just around the corner). I start with a vivid recollection of some weeks in my undergraduate years worrying about the issue 'Is self-deception possible?' The problem to be solved for a tutorial presentation was, 'If the self is deceived by the self, which part of the self is doing the deceiving?' This conundrum could be handily addressed by reference to the various models of the divided self: the mind/brain model; or the conscious/subconscious model; the id/ego/superego model; the Parent/Adult/Child model (for all those Transactional Analysis aficionados) and, had I been dealing with the same query today, the Adult/Inner Child model. In addition to these theoretical constructions, there was evidence from physiological psychology of the 'split brain' phenomenon, where some unfortunate patients had had the crossover pathways between the two hemispheres of the brain surgically cut, usually as a strategy for dealing with epilepsy. Here it seemed to be literally possible for the right hand to not know what the left hand was doing (but only under strict laboratory conditions where certain information was only available to one hand or the other, or one eye or the other). Essentially, psychological theory had gone to considerable trouble to identify the self as a potential battleground for warring elements: internal 'others' with which the self is composed; in addition to the external influences impacting upon the self. All of these approaches offered a metaphor for conflict, which tied in with the subjective impression of 'the self' wanting things a number of ways; in particular wanting to have the cake, wanting to have a different cake and also wanting to eat all possible varieties of cake. The trouble was, this approach didn't really answer the question 'Is self-deception possible?' because I knew when I felt conflicted, and thus was not deceived. To be truly deceived, I rationalised, I wouldn't ever be aware that self-deception had been in operation. In which case, had it ever really happened? Where internal warring was evident, the idea of 'deception' failed to convince me, and was replaced instead by one of opposing impulses. Thus I decided that self-deception is impossible, and that instead we use it as a more-or-less conscious excuse for behaviour that is out of character. (My tutor was concerned that I had elided the concepts of 'I' and 'myself', in this presentation, but that is another story.) Two decades later, in the mid-nineties, I suddenly woke up to the fact that popular psychology had spawned a library of self-help literature of Alexandrian proportions. In fact, the volume of books, articles, magazines and related TV/radio shows (such as Oprah) -- not to mention the mega-millionaire motivationalists such as Wayne Dyer and Tony Robbins, whose website promises 'resources for creating an extraordinary quality of life' and whose influence is now evident in other areas of popular culture (eg, Farrelly and Farrelly's embarrassingly awful Shallow Hal). Robbins' claim: 'Within you is a powerful driving force that, once unleashed, can make your boldest visions, dreams, and desires real. You are about to discover the finest resources and tools available for awakening that force within you -- and transforming your life, instantly and forever', somewhat overstates my own experience of trying to put his theories into practice, but I've only bought the books and thus may be deceiving myself that I've truly committed what it takes to achieve transformation... (For those of you lacking 'disposable time' -- too busy to read the books -- the principles are often available on easy-to-consume cassette-tapes, videos, CDs and interactive websites.) A visit to any popular bookshop (although these sections are generally lacking in the academic ones) indicates that self-help is right up there with business/motivational books, and with new age/spiritual guidance. The popular culture of business practice might arguablely have started with Blanchard and Johnson's The One Minute Manager, but it is increasingly evident in such global best sellers as Covey's The 7 Habits of Highly EffectivePeople, Gardner and Gardner's The Motley Fool Investment Guide and Kiyosaki's Rich Dad, Poor Dad (and associated spin-offs). This interest in business, however, is more than an interest in practice and process: it's an interest in versions of the self. Thus the Motley Fool reader is advised to 'go against' their instincts, because that way they do something different from the average. Rich Dad, Poor Dad is a fable of different ways to view life, success and happiness (one of which is presented as more likely to result in a humungous bank balance). If it only takes a minute to be a manager -- why wouldn't you spend that minute? And all of us would like to be more effective in some area of our lives… The business books that make it into the best seller lists offer help to transform the self into someone … rather more suited to the times than we were before we started to read that particular guru's take on the future perfect. The impetus for the growth in the popular culture of the evolving self seems to me to be (at least partly) explained by our sense of accelerating change. The constant in both the business and the self-help literature is a valuing of the capacity of managing and adapting to change. It is no accident that there has been this burgeoning of self-development material at the same time that we are encouraged: to prepare ourselves for new careers every seven years; to reclassify ourselves as lifelong learners; to assess ourselves as a collection of 'skills', 'attributes' and 'competencies', able to apply to others for 'recognition of prior learning'; and, to accept a governmental diktat that we are all in the business of 'mutual obligation'. Under these circumstances, and in this environment, a willing engagement with the self-help literature indicates a positive desire to manage the transition of the self to some acceptance of a changed future. It implies the resolution of the five stages of grief (Kubler-Ross). Having worked through denial and isolation; anger; bargaining; and depression the active self-developer reaches 'acceptance' and manages the stress of change by helping the self adjust to an anticipated future. Even the sense of having a strategy to cope with new demands can be part of a solution to perceived powerlessness: helpless leads to hopeless (and depressed). Self-help is a strategy to cope with change and move on. The pressures may be new, and the books may be growing in number and in applicability, but the marketing principles fuelling this consumer demand are well established. For example, an Australianised Consumer Behaviour textbook identifies (Schiffman et al, 137) 'four specific kinds of self-image: Actual self-image (ie how consumers in fact see themselves) Ideal self-image (ie how consumers would like to see themselves) Social self-image (ie how consumers feel others see them) Ideal social self-image (ie how consumers would like others to see them) before going on to add, "a fifth type of self-image, expected self-image (ie how consumers expect to see themselves at some specified future time)" (137, bold in original). Marketers use the gap between the perceived self-image and the ideal self-image as an opportunity for product development, and for creating strategies to promote existing goods and services. In essence, consumer societies continuously package and represent images of our future selves as ways of selling us products that help us become more beautiful, clever and effective. They might also 'reverse the visible signs of aging'. (The realage.com website is a wonderful place where an older self becomes younger as the days pass and the life-extending strategies are adopted, minimising an individual's 'real' -- as opposed to chronological -- age.) Although Schiffman et al (137) argue that the expected self-image is somewhere between the actual self-image and the ideal self-image, most well-founded (credible) expectations of the future-self involve a planned programme of change -- such as enrolment in a course of study or diligent application to the contents and suggestions of an appropriate self-help book… Thus the expected self-image might differ qualitatively from the ideal self-image in that the former may have some basis in an achievable future while the latter might be impossibly unlikely. An individual's social identity and their consumption practices are already well linked. For example, Hearn, Mandeville and Anthony (104) estimate that 'consumption now accounts for about 60 per cent of GDP … mass communication, advertising and the consumer economy form a nexus that is centrally implicated in the operation of Western societies.' They go on to argue that the 'central assertion of postmodern views of consumption is that social identity can be interpreted as a function of consumption' (106). Green suggests that it is 'the voluntary nature of consumption -- together with the impossibility of not consuming -- [that] prevents [consumption] from being categorised unambiguously as work'. The implication is that the self-help literature represents a complex communication. Purchase of a self-help book identifies one version of an ideal self-image for that person, and also allies them with those aspects of popular culture including and touching upon that book and that self-help philosophy. (Even more is communicated if the book is purchased for someone else, or received as a gift from someone else!) The presence of the book on a person's shelves can also indicate a strategy to manipulate perceptions of the individual's social self-image and might express to others an element of the individual's ideal social self-image (moderated, perhaps, by throw-away statements such as: 'Of course, theory is one thing, practice another', or 'I think Carmen may have been dropping a heavy hint with this present'). At the same time, the individual may have a clear impression of the expected self-image likely to result from consumption of the book's contents, and thus the act of consumption is likely to represent the adoption of a particularly individual vision for the future self. The popularity of the self-help genre and its generalisation into lifestyle programmes and publications -- the Martha Stewart effect -- is an indication that the 'present self' is generally categorised as a work in progress. Paradoxically, the self may be most evident and fixed in the act of becoming, since the self in the present undergoes continual change (apart from its constant requirement for 'help'). References Blanchard, Kenneth and Spencer Johnson. The One Minute Manager. New York: Berkley Books, 1983. Covey, Stephen. The 7 Habits of Highly Effective People: Restoring the Character Ethic. Melbourne: Business Library, 1989. Dyer, Wayne. http://www.drwaynedyer.com [accessed 25 Aug. 2002] Gardner, David and Tom Gardner. The Motley Fool Investment Guide: How the Fool Beats Wall Street's Wise Men and How You Can Too. New York: Fireside Books, 1997. Green, Lelia. 'The Work of Consumption -- Why Aren't We Paid?' M/C: A Journal of Media and Culture. 4.5 (2001) http://www.media-culture.org.au [accessed 25 Aug. 2002] Hearn, Greg, Tom Mandeville, and David Anthony. The Communication Superhighway: Social and Economic Change in the Digital Age. Sydney: Allen & Unwin, 1997. 104-31. Kiyosaki, Richard with Sharon Lechter. Rich Dad, Poor Dad: What the Rich Teach Thei rKids about Money that the Poor and the Middle Class Do Not! Paradise Valley, Arizona: TechPress Inc, 1997. Kubler-Ross, Elizabeth. On Death and Dying. London: Tavistock Publications, 1970. realage.com. http://www.realage.com [accessed 25 Aug. 2002] Robbins, Anthony. http://www.tonyrobbins.com [accessed 25 Aug. 2002] - - - . Unlimited Power: The New Science of Personal Achievement. London: Simon & Schuster, 1988. - - - . Awaken the Giant Within. New York: Summit Books, 1991. - - - . Giant Steps. New York: Fireside Books, 1994. - - - . Notes from a Friend. New York, Fireside Books, 1995. Schiffman, Leon, David Bednall, Elizabeth Cowley, Aaron O'Cass, Judith Watson and Leslie Kanuk. Consumer Behaviour. 2nd ed. French's Forest: Pearson Education Australia, 2001. Shallow Hal. Dir. Bobby and Peter Farrelly. 20th Century Fox, 2001. Links http://www.media-culture.org.au http://www.realage.com http://www.tonyrobbins.com http://www.drwaynedyer.com Citation reference for this article Substitute your date of access for Dn Month Year etc... MLA Style Green, Lelia. "Who is Being Helped When We Help Our Self?" M/C: A Journal of Media and Culture 5.5 (2002). [your date of access] < http://www.media-culture.org.au/mc/0210/Green2.html &gt. Chicago Style Green, Lelia, "Who is Being Helped When We Help Our Self?" M/C: A Journal of Media and Culture 5, no. 5 (2002), < http://www.media-culture.org.au/mc/0210/Green2.html &gt ([your date of access]). APA Style Green, Lelia. (2002) Who is Being Helped When We Help Our Self?. M/C: A Journal of Media and Culture 5(5). < http://www.media-culture.org.au/mc/0210/Green2.html &gt ([your date of access]).

Introduction It is very common for children’s films to adapt, rework, or otherwise re-imagine existing cultural material. Such re-imaginings are potential candidates for fidelity criticism: a mode of analysis whereby an adaptation is judged according to its degree of faithfulness to the source text. Indeed, it is interesting that while fidelity criticism is now considered outdated and problematic by adaptation theorists (see Stam; Leitch; and Whelehan) the issue of fidelity has tended to linger in the discussions that form around material adapted for children. In particular, it is often assumed that the re-imagining of cultural material for children will involve a process of “dumbing down” that strips the original text of its complexity so that it is more easily consumed by young audiences (see Semenza; Kellogg; Hastings; and Napolitano). This is especially the case when children’s films draw from texts—or genres—that are specifically associated with an adult readership. This paper explores such an interplay between children’s and adult’s culture with reference to the re-imagining of the horror genre in children’s animated film. Recent years have seen an inrush of animated films that play with horror tropes, conventions, and characters. These include Frankenweenie (2012), ParaNorman (2012), Hotel Transylvania (2012), Igor (2008), Monsters Inc. (2001), Monster House (2006), and Monsters vs Aliens (2009). Often diminishingly referred to as “kiddie horror” or “goth lite”, this re-imagining of the horror genre is connected to broader shifts in children’s culture, literature, and media. Anna Jackson, Karen Coats, and Roderick McGillis, for instance, have written about the mainstreaming of the Gothic in children’s literature after centuries of “suppression” (2); a glance at the titles in a children’s book store, they tell us, may suggest that “fear or the pretence of fear has become a dominant mode of enjoyment in literature for young people” (1). At the same time, as Lisa Hopkins has pointed out, media products with dark, supernatural, or Gothic elements are increasingly being marketed to children, either directly or through product tie-ins such as toys or branded food items (116-17). The re-imagining of horror for children demands our attention for a number of reasons. First, it raises questions about the commercialisation and repackaging of material that has traditionally been considered “high culture”, particularly when the films in question are seen to pilfer from sites of the literary Gothic such as Mary Shelley’s Frankenstein (1818) or Bram Stoker’s Dracula (1897). The classic horror films of the 1930s such as James Whale’s Frankenstein (1931) also have their own canonical status within the genre, and are objects of reverence for horror fans and film scholars alike. Moreover, aficionados of the genre have been known to object vehemently to any perceived simplification or dumbing down of horror conventions in order to address a non-horror audience. As Lisa Bode has demonstrated, such objections were articulated in many reviews of the film Twilight, in which the repackaging and simplifying of vampire mythology was seen to pander to a female, teenage or “tween” audience (710-11). Second, the re-imagining of horror for children raises questions about whether the genre is an appropriate source of pleasure and entertainment for young audiences. Horror has traditionally been understood as problematic and damaging even for adult viewers: Mark Jancovich, for instance, writes of the long-standing assumption that horror “is moronic, sick and worrying; that any person who derives pleasure from the genre is moronic, sick and potentially dangerous” and that both the genre and its fans are “deviant” (18). Consequently, discussions about the relationship between children and horror have tended to emphasise regulation, restriction, censorship, effect, and “the dangers of imitative violence” (Buckingham 95). As Paul Wells observes, there is a “consistent concern […] that horror films are harmful to children, but clearly these films are not made for children, and the responsibility for who views them lies with adult authority figures who determine how and when horror films are seen” (24). Previous academic work on the child as horror viewer has tended to focus on children as consumers of horror material designed for adults. Joanne Cantor’s extensive work in this area has indicated that fright reactions to horror media are commonly reported and can be long-lived (Cantor; and Cantor and Oliver). Elsewhere, the work of Sarah Smith (45-76) and David Buckingham (95-138) has indicated that children, like adults, can gain certain pleasures from the genre; it has also indicated that children can be quite media savvy when viewing horror, and can operate effectively as self-censors. However, little work has yet been conducted on whether (and how) the horror genre might be transformed for child viewers. With this in mind, I explore here the re-imagining of horror in two children’s animated films: Frankenweenie and ParaNorman. I will consider the way horror tropes, narratives, conventions, and characters have been reshaped in each film with a child’s perspective in mind. This, I argue, does not make them simplified texts or unsuitable objects of pleasure for adults; instead, the films demonstrate that the act of re-imagining horror for children calls into question long-held assumptions about pleasure, taste, and the boundaries between “adult” and “child”. Frankenweenie and ParaNorman: Rewriting the Myth of Childhood Innocence Frankenweenie is a stop-motion animation written by John August and directed by Tim Burton, based on a live-action short film made by Burton in 1984. As its name suggests, Frankenweenie re-imagines Shelley’s Frankenstein by transforming the relationship between creator and monster into that between child and pet. Burton’s Victor Frankenstein is a young boy living in a small American town, a creative loner who enjoys making monster movies. When his beloved dog Sparky is killed in a car accident, young Victor—like his predecessor in Shelley’s novel—is driven by the awfulness of this encounter with death to discover the “mysteries of creation” (Shelley 38): he digs up Sparky’s body, drags the corpse back to the family home, and reanimates him in the attic. This coming-to-life sequence is both a re-imagining of the famous animation scene in Whale’s film Frankenstein and a tender expression of the love between a boy and his dog. The re-imagined creation scene therefore becomes a site of negotiation between adult and child audiences: adult viewers familiar with Whale’s adaptation and its sense of electric spectacle are invited to rethink this scene from a child’s perspective, while child viewers are given access to a key moment from the horror canon. While this blurring of the lines between child and adult is a common theme in Burton’s work—many of his films exist in a liminal space where a certain childlike sensibility mingles with a more adult-centric dark humour—Frankenweenie is unique in that it actively re-imagines as “childlike” a film and/or work of literature that was previously populated by adult characters and associated with adult audiences. ParaNorman is the second major film from the animation studio Laika Entertainment. Following in the footsteps of the earlier Laika film Coraline (2009)—and paving the way for the studio’s 2014 release, Boxtrolls—ParaNorman features stop-motion animation, twisted storylines, and the exploration of dark themes and spaces by child characters. The film tells the story of Norman, an eleven year old boy who can see and communicate with the dead. This gift marks him as an outcast in the small town of Blithe Hollow, which has built its identity on the historic trial and hanging of an “evil” child witch. Norman must grapple with the town’s troubled past and calm the spirit of the vengeful witch; along the way, he and an odd assortment of children battle zombies and townsfolk alike, the latter appearing more monstrous than the former as the film progresses. Although ParaNorman does not position itself as an adaptation of a specific horror text, as does Frankenweenie, it shares with Burton’s film a playful intertextuality whereby references are constantly made to iconic films in the horror genre (including Halloween [1978], Friday the 13th [1980], and Day of the Dead [1985]). Both films were released in 2012 to critical acclaim. Interestingly, though, film critics seemed to disagree over who these texts were actually “for.” Some reviewers described the films as children’s texts, and warned that adults would likely find them “tame and compromised” (Scott), “toothless” (McCarthy) or “sentimental” (Bradshaw). These comments carry connotations of simplification: the suggestion is that the conventions and tropes of the horror genre have been weakened (or even contaminated) by the association with child audiences, and that consequently adults cannot (or should not) take pleasure in the films. Other reviewers of ParaNorman and Frankenweenie suggested that adults were more likely to enjoy the films than children (O’Connell; Berardinelli; and Wolgamott). Often, this suggestion came together with a warning about scary or dark content: the films were deemed to be too frightening for young children, and this exclusion of the child audience allowed the reviewer to acknowledge his or her own enjoyment of and investment in the film (and the potential enjoyment of other adult viewers). Lou Lumenick, for instance, peppers his review of ParaNorman with language that indicates his own pleasure (“probably the year’s most visually dazzling movie so far”; the climax is “too good to spoil”; the humour is “deliciously twisted”), while warning that children as old as eight should not be taken to see the film. Similarly, Christy Lemire warns that certain elements of Frankenweenie are scary and that “this is not really a movie for little kids”; she goes on to add that this scariness “is precisely what makes ‘Frankenweenie’ such a consistent wonder to watch for the rest of us” (emphasis added). In both these cases a line is drawn between child and adult viewers, and arguably it is the film’s straying into the illicit area of horror from the confines of a children’s text that renders it an object of pleasure for the adult viewer. The thrill of being scared is also interpreted here as a specifically adult pleasure. This need on the part of critics to establish boundaries between child and adult viewerships is interesting given that the films themselves strive to incorporate children (as characters and as viewers) into the horror space. In particular, both films work hard to dismantle the myths of childhood innocence—and associated ideas about pleasure and taste—that have previously seen children excluded from the culture of the horror film. Both the young protagonists, for instance, are depicted as media-literate consumers or makers of horror material. Victor is initially seen exhibiting one of his home-made monster movies to his bemused parents, and we first encounter Norman watching a zombie film with his (dead) grandmother; clearly a consummate horror viewer, Norman decodes the film for Grandma, explaining that the zombie is eating the woman’s head because, “that’s what they do.” In this way, the myth of childhood innocence is rewritten: the child’s mature engagement with the horror genre gives him agency, which is linked to his active position in the narrative (both Norman and Victor literally save their towns from destruction); the parents, meanwhile, are reduced to babbling stereotypes who worry that their sons will “turn out weird” (Frankenweenie) or wonder why they “can’t be like other kids” (ParaNorman). The films also rewrite the myth of childhood innocence by depicting Victor and Norman as children with dark, difficult lives. Importantly, each boy has encountered death and, for each, his parents have failed to effectively guide him through the experience. In Frankenweenie Victor is grief-stricken when Sparky dies, yet his parents can offer little more than platitudes to quell the pain of loss. “When you lose someone you love they never really leave you,” Victor’s mother intones, “they just move into a special place in your heart,” to which Victor replies “I don’t want him in my heart—I want him here with me!” The death of Norman’s grandmother is similarly dismissed by his mother in ParaNorman. “I know you and Grandma were very close,” she says, “but we all have to move on. Grandma’s in a better place now.” Norman objects: “No she’s not, she’s in the living room!” In both scenes, the literal-minded but intelligent child seems to understand death, loss, and grief while the parents are unable to speak about these “mature” concepts in a meaningful way. The films are also reminders that a child’s first experience of death can come very young, and often occurs via the loss of an elderly relative or a beloved pet. Death, Play, and the Monster In both films, therefore, the audience is invited to think about death. Consequently, there is a sense in each film that while the violent and sexual content of most horror texts has been stripped away, the dark centre of the horror genre remains. As Paul Wells reminds us, horror “is predominantly concerned with the fear of death, the multiple ways in which it can occur, and the untimely nature of its occurrence” (10). Certainly, the horror texts which Frankenweenie and ParaNorman re-imagine are specifically concerned with death and mortality. The various adaptations of Frankenstein that are referenced in Frankenweenie and the zombie films to which ParaNorman pays homage all deploy “the monster” as a figure who defies easy categorisation as living or dead. The othering of this figure in the traditional horror narrative allows him/her/it to both subvert and confirm cultural ideas about life, death, and human status: for monsters, as Elaine Graham notes, have long been deployed in popular culture as figures who “mark the fault-lines” and also “signal the fragility” of boundary structures, including the boundary between human and not human, and that between life and death (12). Frankenweenie’s Sparky, as an iteration of the Frankenstein monster, clearly fits this description: he is neither living nor dead, and his monstrosity emerges not from any act of violence or from physical deformity (he remains, throughout the film, a cute and lovable dog, albeit with bolts fixed to his neck) but from his boundary-crossing status. However, while most versions of the Frankenstein monster are deliberately positioned to confront ideas about the human/machine boundary and to perform notions of the posthuman, such concerns are sidelined in Frankenweenie. Instead, the emphasis is on concerns that are likely to resonate with children: Sparky is a reminder of the human preoccupation with death, loss, and the question of why (or whether, or when) we should abide by the laws of nature. Arguably, this indicates a re-imagining of the Frankenstein tale not only for child audiences but from a child’s perspective. In ParaNorman, similarly, the zombie–often read as an articulation of adult anxieties about war, apocalypse, terrorism, and the deterioration of social order (Platts 551-55)—is re-used and re-imagined in a childlike way. From a child’s perspective, the zombie may represent the horrific truth of mortality and/or the troublesome desire to live forever that emerges once this truth has been confronted. More specifically, the notion of dealing meaningfully with the past and of honouring rather than silencing the dead is a strong thematic undercurrent in ParaNorman, and in this sense the zombies are important figures who dramatise the connections between past and present. While this past/present connection is explored on many levels in ParaNorman—including the level of a town grappling with its dark history—it is Norman and his grandmother who take centre stage: the boundary-crossing figure of the zombie is re-realised here in terms of a negotiation with a presence that is now absent (the elderly relative who has died but is still remembered). Indeed, the zombies in this film are an implicit rebuke to Norman’s mother and her command that Norman “move on” after his grandmother’s death. The dead are still present, this film playfully reminds us, and therefore “moving on” is an overly simplistic and somewhat disrespectful response (especially when imposed on children by adult authority figures.) If the horror narrative is built around the notion that “normality is threatened by the Monster”, as Robin Wood has famously suggested, ParaNorman and Frankenweenie re-imagine this narrative of subversion from a child’s perspective (31). Both films open up a space within which the child is permitted to negotiate with the destabilising figure of the monster; the normality that is “threatened” here is the adult notion of the finality of death and, relatedly, the assumption that death is not a suitable subject for children to think or talk about. Breaking down such understandings, Frankenweenie and ParaNorman strive not so much to play with death (a phrase that implies a certain callousness, a problematic disregard for human life) but to explore death through the darkness of play. This is beautifully imaged in a scene from ParaNorman in which Norman and his friend Neil play with the ghost of Neil’s recently deceased dog. “We’re going to play with a dead dog in the garden,” Neil enthusiastically announces to his brother, “and we’re not even going to have to dig him up first!” Somewhat similarly, film critic Richard Corliss notes in his review of Frankenweenie that the film’s “message to the young” is that “children should play with dead things.” Through this intersection between “death” and “play”, both films propose a particularly child-like (although not necessarily child-ish) way of negotiating horror’s dark territory. Conclusion Animated film has always been an ambiguous space in terms of age, pleasure, and viewership. As film critic Margaret Pomeranz has observed, “there is this perception that if it’s an animated film then you can take the little littlies” (Pomeranz and Stratton). Animation itself is often a signifier of safety, fun, nostalgia, and childishness; it is a means of addressing families and young audiences. Yet at the same time, the fantastic and transformative aspects of animation can be powerful tools for telling stories that are dark, surprising, or somehow subversive. It is therefore interesting that the trend towards re-imagining horror for children that this paper has identified is unfolding within the animated space. It is beyond the scope of this paper to fully consider what animation as a medium brings to this re-imagining process. However, it is worth noting that the distinctive stop-motion style used in both films works to position them as alternatives to Disney products (for although Frankenweenie was released under the Disney banner, it is visually distinct from most of Disney’s animated ventures). The majority of Disney films are adaptations or re-imaginings of some sort, yet these re-imaginings look to fairytales or children’s literature for their source material. In contrast, as this paper has demonstrated, Frankenweenie and ParaNorman open up a space for boundary play: they give children access to tropes, narratives, and characters that are specifically associated with adult viewers, and they invite adults to see these tropes, narratives, and characters from a child’s perspective. Ultimately, it is difficult to determine the success of this re-imagining process: what, indeed, does a successful re-imagining of horror for children look like, and who might be permitted to take pleasure from it? Arguably, ParaNorman and Frankenweenie have succeeded in reshaping the genre without simplifying it, deploying tropes and characters from classic horror texts in a meaningful way within the complex space of children’s animated film. References Berardinelli, James. “Frankenweenie (Review).” Reelviews, 4 Oct. 2012. 6 Aug. 2014 ‹http://www.reelviews.net/php_review_template.php?identifier=2530›. Bode, Lisa. “Transitional Tastes: Teen Girls and Genre in the Critical Reception of Twilight.” Continuum: Journal of Media & Cultural Studies 24.5 (2010): 707-19. Bradshaw, Peter. “Frankenweenie: First Look Review.” The Guardian, 11 Oct. 2012. 6 Aug. 2014 ‹http://www.theguardian.com/film/2012/oct/10/frankenweenie-review-london-film-festival-tim-burton›. Buckingham, David. Moving Images: Understanding Children’s Emotional Responses to Television. Manchester and New York: Manchester University Press, 1996. Cantor, Joanne. “‘I’ll Never Have a Clown in My House’ – Why Movie Horror Lives On.” Poetics Today 25.2 (2004): 283-304. Cantor, Joanne, and Mary Beth Oliver. “Developmental Differences in Responses to Horror”. The Horror Film. Ed. Stephen Prince. New Brunswick, NJ: Rutgers UP, 2004. 224-41. Corliss, Richard. “‘Frankenweenie’ Movie Review: A Re-Animated Delight”. Time, 4 Oct. 2012. 6 Aug. 2014 ‹http://entertainment.time.com/2012/10/04/tim-burtons-frankenweenie-a-re-animated-delight/›. Frankenweenie. Directed by Tim Burton. Walt Disney Pictures, 2012. Graham, Elaine L. Representations of the Post/Human: Monsters, Aliens and Others in Popular Culture. Manchester: Manchester UP, 2002. Hastings, A. Waller. “Moral Simplification in Disney’s The Little Mermaid.” The Lion and the Unicorn 17.1 (1993): 83-92. Hopkins, Lisa. Screening the Gothic. Austin: U of Texas P, 2005. Jackson, Anna, Karen Coats, and Roderick McGillis. “Introduction.” The Gothic in Children’s Literature: Haunting the Borders. Eds. Anna Jackson, Karen Coats, and Roderick McGillis. New York: Routledge, 2008. 1-14. Jancovich, Mark. “General Introduction.” Horror: The Film Reader. Ed. Mark Jancovich. London: Routledge, 2002. 1-19. Kellogg, Judith L. “The Dynamics of Dumbing: The Case of Merlin.” The Lion and the Unicorn 17.1 (1993): 57-72. Leitch, Thomas. “Twelve Fallacies in Contemporary Adaptation Theory.” Criticism 45.2 (2003): 149-71. Lemire, Christy. “‘Frankenweenie’ Review: Tim Burton Reminds Us Why We Love Him.” The Huffington Post, 2 Oct. 2012. 6 Aug. 2014 ‹http://www.huffingtonpost.com/2012/10/03/frankenweenie-review-tim-burton_n_1935142.html›. Lumenick, Lou. “So Good, It’s Scary (ParaNorman Review)”. New York Post, 17 Aug. 2012. 3 Jun. 2015 ‹http://nypost.com/2012/08/17/so-good-its-scary/›. McCarthy, Todd. “Frankenweenie: Film Review.” The Hollywood Reporter, 20 Sep. 2012. 6 Aug. 2014 ‹http://www.hollywoodreporter.com/movie/frankenweenie/review/372720›. Napolitano, Marc. “Disneyfying Dickens: Oliver & Company and The Muppet Christmas Carol as Dickensian Musicals.” Studies in Popular Culture 32.1 (2009): 79-102. O’Connell, Sean. “Middle School and Zombies? Awwwkward!” Washington Post, 17 Aug. 2012. 3 Jun. 2015 ‹http://www.washingtonpost.com/gog/movies/paranorman,1208210.html›. ParaNorman. Directed by Chris Butler and Sam Fell. Focus Features/Laika Entertainment, 2012. Platts, Todd K. “Locating Zombies in the Sociology of Popular Culture”. Sociology Compass 7 (2013): 547-60. Pomeranz, Margaret, and David Stratton. “Igor (Review).” At the Movies, 14 Dec. 2008. 6 Aug. 2014 ‹http://www.abc.net.au/atthemovies/txt/s2426109.htm›. Scott, A.O. “It’s Aliiiive! And Wagging Its Tail: ‘Frankenweenie’, Tim Burton’s Homage to Horror Classics.” New York Times, 4 Oct. 2012. 6 Aug. 2014 ‹http://www.nytimes.com/2012/10/05/movies/frankenweenie-tim-burtons-homage-to-horror-classics.html›. Semenza, Gregory M. Colón. “Teens, Shakespeare, and the Dumbing Down Cliché: The Case of The Animated Tales.” Shakespeare Bulletin 26.2 (2008): 37-68. Shelley, Mary. Frankenstein, or, The Modern Prometheus. Hertfordshire: Wordsworth Editions, 1993 [1818]. Smith, Sarah J. Children, Cinema and Censorship: From Dracula to the Dead End Kids. London: I.B. Tauris, 2005. Stam, Robert. “Introduction: The Theory and Practice of Adaptation.” Literature and Film: A Guide to the Theory and Practice of Film Adaptation. Eds. Robert Stam and Alessandra Raengo. Oxford: Blackwell, 2005. 1-52. Wells, Paul. The Horror Genre: From Beelzebub to Blair Witch. London: Wallflower, 2000. Whelehan, Imelda. “Adaptations: the Contemporary Dilemmas.” Adaptations: From Text to Screen, Screen to Text. Eds. Deborah Cartmell and Imelda Whelehan. London: Routledge, 1999. 3-19. Wolgamott, L. Kent. “‘Frankenweenie’ A Box-Office Bomb, But Superior Film.” Lincoln Journal Star, 10 Oct. 2012. 18 Aug. 2014 ‹http://journalstar.com/entertainment/movies/l-kent-wolgamott-frankenweenie-a-box-office-bomb-but-superior/article_42409e82-89b9-5794-8082-7b5de3d469e2.html›. Wood, Robin. “The American Nightmare: Horror in the 70s.” Horror: The Film Reader. Ed. Mark Jancovich. London: Routledge, 2002. 25-32.

IntroductionThe 2009 American film Trash Humpers, directed by Harmony Korine, was released at a time when the hipster had become a ubiquitous concept, entering into the common vernacular of numerous cultures throughout the world, and gaining significant press, social media and academic attention (see Žižek; Arsel and Thompson; Greif et al.; Stahl; Ouellette; Reeve; Schiermer; Maly and Varis). Trash Humpers emerged soon after the 2008 Global Financial Crisis triggered Occupy movements in numerous cities, aided by social media platforms, reported on by blogs such as Gawker, and stylized by multi-national youth-subculture brands such as Vice, American Apparel, Urban Outfitters and a plethora of localised variants.Korine’s film, which is made to resemble found VHS footage of old-aged vandals, epitomises the ironic, retro stylizations and “counterculture-meets-kitsch” aesthetics so familiar to hipster culture. As a creative stereotype from 1940s and ‘50s jazz and beatnik subcultures, the hipster re-emerged in the twenty-first century as a negative embodiment of alternative culture in the age of the Internet. As well as plumbing the recent past for things not yet incorporated into contemporary marketing mechanisms, the hipster also signifies the blurring of irony and authenticity. Such “outsiderness as insiderness” postures can be regarded as a continuation of the marginality-from-the-centre logic of cool capitalism that emerged after World War Two. Particularly between 2007 and 2015, the post-postmodern concept of the hipster was a resonant cultural trope in Western and non-Western cultures alike, coinciding with the normalisation of the new digital terrain and the establishment of mobile social media as an integral aspect of many people’s daily lives. While Korine’s 79-minute feature could be thought of as following in the schlocky footsteps of the likes of Rob Zombie’s The Devil’s Rejects (2006), it is decidedly more arthouse, and more attuned to the influence of contemporary alternative media brands and independent film history alike – as if the love child of Jack Smith’s Flaming Creatures (1963) and Vice Video, the latter having been labelled as “devil-may-care hipsterism” (Carr). Upon release, Trash Humpers was described by Gene McHugh as “a mildly hip take on Jackass”; by Mike D’Angelo as “an empty hipster pose”; and by Aaron Hillis as either “the work of an insincere hipster or an eccentric provocateur”. Lacking any semblance of a conventional plot, Trash Humpers essentially revolves around four elderly-looking protagonists – three men and a woman – who document themselves with a low-quality video camera as they go about behaving badly in the suburbs of Nashville, Tennessee, where Korine still lives. They cackle eerily to themselves as they try to stave off boredom, masturbating frantically on rubbish bins, defecating and drinking alcohol in public, fellating foliage, smashing televisions, playing ten-pin bowling, lighting firecrackers and telling gay “hate” jokes to camera with no punchlines. In one purposefully undramatic scene half-way through the film, the humpers are shown in the aftermath of an attack on a man wearing a French maid’s outfit; he lies dead in a pool of blood on their kitchen floor with a hammer at his feet. The humpers are consummate “bad” performers in every sense of the term, and they are joined by a range of other, apparently lower-class, misfits with whom they stage tap dance routines and repetitively sing nursery-rhyme-styled raps such as: “make it, make it, don’t break it; make it, make it, don’t fake it; make it, make it, don’t take it”, which acts as a surrogate theme song for the film. Korine sometimes depicts his main characters on crutches or in a wheelchair, and a baby doll is never too far away from the action, as a silent and Surrealist witness to their weird, sinister and sometimes very funny exploits. The film cuts from scene to scene as if edited on a video recorder, utilising in-house VHS titling sequences, audio glitches and video static to create the sense that one is engaging voyeuristically with a found video document rather than a scripted movie. Mainstream AlternativesAs a viewer of Trash Humpers, one has to try hard to suspend disbelief if one is to see the humpers as genuine geriatric peeping Toms rather than as hipsters in old-man masks trying to be rebellious. However, as Korine’s earlier films such as Gummo (1997) attest, he clearly delights in blurring the line between failure and transcendence, or, in this case, between pretentious art-school bravado and authentic redneck ennui. As noted in a review by Jeannette Catsoulis, writing for the New York Times: “Much of this is just so much juvenile posturing, but every so often the screen freezes into something approximating beauty: a blurry, spaced-out, yellow-green landscape, as alien as an ancient photograph”. Korine has made a career out of generating this wavering uncertainty in his work, polarising audiences with a mix of critical, cinema-verité styles and cynical exploitations. His work has consistently revelled in ethical ambiguities, creating environments where teenagers take Ritalin for kicks, kill cats, wage war with their families and engage in acts of sexual deviancy – all of which are depicted with a photographer’s eye for the uncanny.The elusive and contradictory aspects of Korine’s work – at once ugly and beautiful, abstract and commercial, pessimistic and nostalgic – are evident not just in films such as Gummo, Julien Donkey Boy (1999) and Mister Lonely (2007) but also in his screenplay for Kids (1995), his performance-like appearances on The Tonight Show with David Letterman (1993-2015) and in publications such as A Crackup at the Race Riots (1998) and Pass the Bitch Chicken (2001). As well as these outputs, Korine is also a painter who is represented by Gagosian Gallery – one of the world’s leading art galleries – and he has directed numerous music videos, documentaries and commercials throughout his career. More than just update of the traditional figure of the auteur, Korine, instead, resembles a contemporary media artist whose avant-garde and grotesque treatments of Americana permeate almost everything he does. Korine wrote the screenplay for Kids when he was just 19, and subsequently built his reputation on the paradoxical mainstreaming of alternative culture in the 1990s. This is exemplified by the establishment of music and film genres such “alternative” and “independent”; the popularity of the slacker ethos attributed to Generation X; the increased visibility of alternative press zines; the birth of grunge in fashion and music; and the coining of “cool hunting” – a bottom-up market research phenomenon that aimed to discover new trends in urban subcultures for the purpose of mass marketing. Key to “alternative culture”, and its related categories such as “indie” and “arthouse”, is the idea of evoking artistic authenticity while covertly maintaining a parasitic relationship with the mainstream. As Holly Kruse notes in her account of the indie music scenes of the 1990s, which gained tremendous popularity in the wake of grunge bands such as Nirvana: without dominant, mainstream musics against which to react, independent music cannot be independent. Its existence depends upon dominant music structures and practices against which to define itself. Indie music has therefore been continually engaged in an economic and ideological struggle in which its ‘outsider’ status is re-examined, re-defined, and re-articulated to sets of musical practices. (Kruse 149)Alternative culture follows a similar, highly contentious, logic, appearing as a nebulous, authentic and artistic “other” whose exponents risk being entirely defined by the mainstream markets they profess to oppose. Kids was directed by the artist cum indie-director Larry Clark, who discovered Korine riding his skateboard with a group of friends in New York’s Washington Square in the early 1990s, before commissioning him to write a script. The then subcultural community of skating – which gained prominence in the 1990s amidst the increased visibility of “alternative sports” – provides an important backdrop to the film, which documents a group of disaffected New York teenagers at a time of the Aids crisis in America. Korine has been active in promoting the DIY ethos, creativity and anti-authoritarian branding of skate culture since this time – an industry that, in its attempts to maintain a non-mainstream profile while also being highly branded, has become emblematic of the category of “alternative culture”. Korine has undertaken commercial projects with an array skate-wear brands, but he is particularly associated with Supreme, a so-called “guerrilla fashion” label originating in 1994 that credits Clark and other 1990s indie darlings, and Korine cohorts, Chloë Sevigny and Terry Richardson, as former models and collaborators (Williams). The company is well known for its designer skateboard decks, its collaborations with prominent contemporary visual artists, its hip-hop branding and “inscrutable” web videos. It is also well known for its limited runs of new clothing lines, which help to stoke demand through one-offs – blending street-wear accessibility with the restricted-market and anti-authoritarian sensibility of avant-garde art.Of course, “alternative culture” poses a notorious conundrum for analysis, involving highly subjective demarcations of “mainstream” from “subversive” culture, not to mention “genuine subversion” from mere “corporate alternatives”. As Pierre Bourdieu has argued, the roots of alternative culture lie in the Western tradition of the avant-garde and the “aesthetic gaze” that developed in the nineteenth century (Field 36). In analysing the modernist notion of advanced cultural practice – where art is presented as an alternative to bourgeois academic taste and to the common realm of cultural commodities – Bourdieu proposed a distinction between two types of “fields”, or logics of cultural production. Alternative culture follows what Bourdieu called “the field of restricted production”, which adheres to “art for art’s sake” ideals, where audiences are targeted as if like-minded peers (Field 50). In contrast, the “field of large-scale production” reflects the commercial imperatives of mainstream culture, in which goods are produced for the general public at large. The latter field of large-scale production tends to service pre-established markets, operating in response to public demand. Furthermore, whereas success in the field of restricted production is often indirect, and latent – involving artists who create niche markets without making any concessions to those markets – success in the field of large-scale production is typically more immediate and quantifiable (Field 39). Here we can see that central to the branding of “alternative culture” is the perceived refusal to conform to popular taste and the logic of capitalism more generally is. As Supreme founder James Jebbia stated about his brand in a rare interview: “The less known the better” (Williams). On this, Bourdieu states that, in the field of restricted production, the fundamental principles of all ordinary economies are inversed to create a “loser wins” scenario (Field 39). Profit and cultural esteem become detrimental attributes in this context, potentially tainting the integrity and marginalisation on which alternative products depend. As one ironic hipster t-shirt puts it: “Nothing is any good if other people like it” (Diesel Sweeties).Trash HipstersIn abandoning linear narrative for rough assemblages of vignettes – or “moments” – recorded with an unsteady handheld camera, Trash Humpers positions itself in ironic opposition to mainstream filmmaking, refusing the narrative arcs and unwritten rules of Hollywood film, save for its opening and closing credits. Given Korine’s much publicized appreciation of cinema pioneers, we can understand Trash Humpers as paying homage to independent and DIY film history, including Jack Smith’s Flaming Creatures, William Eggleston’s Stranded in Canton (1973), Andy Warhol’s and Paul Morrissey’s Lonesome Cowboys (1967) and Trash (1970), and John Waters’s Pink Flamingos (1972), all of which jubilantly embraced the “bad” aesthetic of home movies. Posed as fantasized substitutions for mainstream movie-making, such works were also underwritten by the legitimacy of camp as a form of counter-culture critique, blurring parody and documentary to give voice to an array of non-mainstream and counter-cultural identities. The employment of camp in postmodern culture became known not merely as an aesthetic subversion of cultural mores but also as “a gesture of self-legitimation” (Derrida 290), its “failed seriousness” regarded as a critical response to the specific historical problem of being a “culturally over-saturated” subject (Sontag 288).The significant difference between Korine’s film and those of his 1970s-era forbears is precisely the attention he pays to the formal aspects of his medium, revelling in analogue editing glitches to the point of fetishism, in some cases lasting as long as the scenes themselves. Consciously working out-of-step with the media of his day, Trash Humpers in imbued with nostalgia from its very beginning. Whereas Smith, Eggleston, Warhol, Morrissey and Waters blurred fantasy and documentary in ways that raised the social and political identities of their subjects, Korine seems much more interested in “trash” as an aesthetic trope. In following this interest, he rightfully pays homage to the tropes of queer cinema, however, he conveniently leaves behind their underlying commentaries about (hetero-) normative culture. A sequence where the trash humpers visit a whorehouse and amuse themselves by smoking cigars and slapping the ample bottoms of prostitutes in G-strings confirms the heterosexual tenor of the film, which is reiterated throughout by numerous deadpan gay jokes and slurs.Trash Humpers can be understood precisely in terms of Korine’s desire to maintain the aesthetic imperatives of alternative culture, where formal experimentation and the subverting of mainstream genres can provide a certain amount of freedom from explicated meaning, and, in particular, from socio-political commentary. Bourdieu rightly points out how the pleasures of the aesthetic gaze often manifest themselves curiously as form of “deferred pleasure” (353) or “pleasure without enjoyment” (495), which corresponds to Immanuel Kant’s notion of the disinterested nature of aesthetic judgement. Aesthetic dispositions posed in the negative – as in the avant-garde artists who mined primitive and ugly cultural stereotypes – typically use as reference points “facile” or “vulgar” (393) working-class tropes that refer negatively to sensuous pleasure as their major criterion of judgment. For Bourdieu, the pleasures provided by the aesthetic gaze in such instances are not sensual pleasures so much as the pleasures of social distinction – signifying the author’s distance from taste as a form of gratification. Here, it is easy to see how the orgiastic central characters in Trash Humpers might be employed by Korine for a similar end-result. As noted by Jeremiah Kipp in a review of the film: “You don't ‘like’ a movie like Trash Humpers, but I’m very happy such films exist”. Propelled by aesthetic, rather than by social, questions of value, those that “get” the obscure works of alternative culture have a tendency to legitimize them on the basis of the high-degree of formal analysis skills they require. For Bourdieu, this obscures the fact that one’s aesthetic “‘eye’ is a product of history reproduced by education” – a privileged mode of looking, estranged from those unfamiliar with the internal logic of decoding presupposed by the very notion of “aesthetic enjoyment” (2).The rhetorical priority of alternative culture is, in Bourdieu’s terms, the “autonomous” perfection of the form rather than the “heteronomous” attempt to monopolise on it (Field 40). However, such distinctions are, in actuality, more nuanced than Bourdieu sometimes assumed. This is especially true in the context of global digital culture, which makes explicit how the same cultural signs can have vastly different meanings and motivations across different social contexts. This has arguably resulted in the destabilisation of prescriptive analyses of cultural taste, and has contributed to recent “post-critical” advances, in which academics such as Bruno Latour and Rita Felski advocate for cultural analyses and practices that promote relationality and attachment rather than suspicious (critical) dispositions towards marginal and popular subjects alike. Latour’s call for a move away from the “sledge hammer” of critique applies as much to cultural practice as it does to written analysis. Rather than maintaining hierarchical oppositions between authentic versus inauthentic taste, Latour understands culture – and the material world more generally – as having agency alongside, and with, that of the social world.Hipsters with No AlternativeIf, as Karl Spracklen suggests, alternativism is thought of “as a political project of resistance to capitalism, with communicative oppositionality as its defining feature” (254), it is clear that there has been a progressive waning in relevance of the category of “alternative culture” in the age of the Internet, which coincides with the triumph of so-called “neoliberal individualism” (258). To this end, Korine has lost some of his artistic credibility over the course of the 2000s. If viewed negatively, icons of 1990s alternative culture such as Korine can be seen as merely exploiting Dada-like techniques of mimetic exacerbation and symbolic détournement for the purpose of alternative, “arty” branding rather than pertaining to a counter-hegemonic cultural movement (Foster 31). It is within this context of heightened scepticism surrounding alternative culture that the hipster stereotype emerged in cultures throughout the world, as if a contested symbol of the aesthetic gaze in an era of neoliberal identity politics. Whatever the psychological motivations underpinning one’s use of the term, to call someone a hipster is typically to point out that their distinctive alternative or “arty” status appears overstated; their creative decisions considered as if a type of bathos. For detractors of alternative cultural producers such as Korine, he is trying too hard to be different, using the stylised codes of “alternative” to conceal what is essentially his cultural and political immaturity. The hipster – who is rarely ever self-identified – re-emerged in the 2000s to operate as a scapegoat for inauthentic markers of alternative culture, associated with men and women who appear to embrace Realpolitik, sincerity and authentic expressions of identity while remaining tethered to irony, autonomous aesthetics and self-design. Perhaps the real irony of the hipster is the pervasiveness of irony in contemporary culture. R. J Magill Jnr. has argued that “a certain cultural bitterness legitimated through trenchant disbelief” (xi) has come to define the dominant mode of political engagement in many societies since the early 2000s, in response to mass digital information, twenty-four-hour news cycles, and the climate of suspicion produced by information about terrorism threats. He analyses the prominence of political irony in American TV shows including The Daily Show with Jon Stewart, The Simpsons, South Park, The Chappelle Show and The Colbert Report but he also notes its pervasiveness as a twenty-first-century worldview – a distancing that “paradoxically and secretly preserves the ideals of sincerity, honesty and authenticity by momentarily belying its own appearance” (x). Crucially, then, the utterance “hipster” has come to signify instances when irony and aesthetic distance are perceived to have been taken too far, generating the most disdain from those for whom irony, aesthetic discernment and cultural connoisseurship still provide much-needed moments of disconnection from capitalist cultures drowning in commercial hyperbole and grave news hype. Korine himself has acknowledged that Spring Breakers (2013) – his follow-up feature film to Trash Humpers – was created in response to the notion that “alternative culture”, once a legitimate challenge to mainstream taste, had lost its oppositional power with the decentralization of digital culture. He states that he made Spring Breakers at a moment “when there’s no such thing as high or low, it’s all been exploded. There is no underground or above-ground, there’s nothing that’s alternative. We’re at a point of post-everything, so it’s all about finding the spirit inside, and the logic, and making your own connections” (Hawker). In this context, we can understand Trash Humpers as the last of the Korine films to be branded with the authenticity of alternative culture. In Spring Breakers Korine moved from the gritty low-fi sensibility of his previous films and adopted a more digital, light-filled and pastel-coloured palette. Focussing more conventionally on plot than ever before, Spring Breakers follows four college girls who hold up a restaurant in order to fund their spring break vacation. Critic Michael Chaiken noted that the film marks a shift in Korine’s career, from the alternative stylings of the pre-Internet generation to “the cultural heirs [of] the doomed protagonists of Kids: nineties babies, who grew up with the Internet, whose sensibilities have been shaped by the sweeping technological changes that have taken place in the interval between the Clinton and Obama eras” (33).By the end of the 2000s, an entire generation came of age having not experienced a time when the obscure films, music or art of the past took more effort to track down. Having been a key participant in the branding of alternative culture, Korine is in a good position to recall a different, pre-YouTube time – when cultural discernment was still caught up in the authenticity of artistic identity, and when one’s cultural tastes could still operate with a certain amount of freedom from sociological scrutiny. Such ideas seem a long way away from today’s cultural environments, which have been shaped not only by digital media’s promotion of cultural interconnection and mass information, but also by social media’s emphasis on mobilization and ethical awareness. ConclusionI should reiterate here that is not Korine’s lack of seriousness, or irony, alone that marks Trash Humpers as a response to the scepticism surrounding alternative culture symbolised by the figure of the hipster. It is, rather, that Korine’s mock-documentary about juvenile geriatrics works too hard to obscure its implicit social commentary, appearing driven to condemn contemporary capitalism’s exploitations of youthfulness only to divert such “uncool” critical commentaries through unsubtle formal distractions, visual poetics and “bad boy” avant-garde signifiers of authenticity. Before being bludgeoned to death, the unnamed man in the French maid’s outfit recites a poem on a bridge amidst a barrage of fire crackers let off by a nearby humper in a wheelchair. Although easily overlooked, it could, in fact, be a pivotal scene in the film. Spoken with mock high-art pretentions, the final lines of the poem are: So what? Why, I ask, why? Why castigate these creatures whose angelic features are bumping and grinding on trash? Are they not spawned by our greed? Are they not our true seed? Are they not what we’ve bought for our cash? We’ve created this lot, of the ooze and the rot, deliberately and unabashed. Whose orgiastic elation and one mission in creation is to savagely fornicate TRASH!Here, the character’s warning of capitalist overabundance is drowned out by the (aesthetic) shocks of the fire crackers, just as the stereotypical hipster’s ethical ideals are drowned out by their aesthetic excess. The scene also functions as a metaphor for the humpers themselves, whose elderly masks – embodiments of nostalgia – temporarily suspend their real socio-political identities for the sake of role-play. It is in this sense that Trash Humpers is too enamoured with its own artifices – including its anonymous “boys club” mentality – to suggest anything other than the aesthetic distance that has come to mark the failings of the “alternative culture” category. In such instances, alternative taste appears as a rhetorical posture, with Korine asking us to gawk knowingly at the hedonistic and destructive pleasures pursued by the humpers while factoring in, and accepting, our likely disapproval.ReferencesArsel, Zeynep, and Craig J. Thompson. “Demythologizing Consumption Practices: How Consumers Protect Their Field-Dependent Identity Investments from Devaluing Marketplace Myths.” Journal of Consumer Research 37.5 (2011): 791-806.Bourdieu, Pierre. Distinction: A Social Critique of the Judgement of Taste. Trans. Richard Nice. Cambridge: Harvard University Press, 1984.Bourdieu, Pierre. The Field of Cultural Production Essays on Art and Literature. Edited by Randal Johnson. London: Polity Press, 1993.Carr, David. “Its Edge Intact, Vice Is Chasing Hard News.” New York Times 24 Aug. 2014. 12 Nov. 2016 <https://www.nytimes.com/2014/08/25/business/media/its-edge-intact-vice-is-chasing-hard-news-.html>.Catsoulis, Jeannette. “Geriatric Delinquents, Rampaging through Suburbia.” New York Times 6 May 2010. 1` Nov. 2016 <http://www.nytimes.com/2010/05/07/movies/07trash.html>.Chaiken, Michael. “The Dream Life.” Film Comment (Mar./Apr. 2013): 30-33.D’Angelo, Mike. “Trash Humpers.” Not Coming 18 Sep. 2009. 12 Nov. 2016 <http://www.notcoming.com/reviews/trashhumpers>.Derrida, Jacques. Positions. London: Athlone, 1981.Diesel Sweeties. 1 Nov. 2016 <https://store.dieselsweeties.com/products/nothing-is-any-good-if-other-people-like-it-shirt>.Felski, Rita. The Limits of Critique. Chicago: University of Chicago Press, 2015.Greif, Mark. What Was the Hipster? A Sociological Investigation. New York: n+1 Foundation, 2010.Hawker, Philippa. “Telling Tales Out of School.” Sydney Morning Herald 4 May 2013. 12 Nov. 2016 <http://www.smh.com.au/entertainment/movies/telling-tales-out-of-school-20130503-2ixc3.html>.Hillis, Aaron. “Harmony Korine on Trash Humpers.” IFC 6 May 2009. 12 Nov. 2016 <http://www.ifc.com/2010/05/harmony-korine-2>.Jay Magill Jr., R. Chic Ironic Bitterness. Ann Arbor: University of Michigan Press, 2007.Kipp, Jeremiah. “Clean Off the Dirt, Scrape Off the Blood: An Interview with Trash Humpers Director Harmony Korine.” Slant Magazine 18 Mar. 2011. 1 Nov. 2016 <http://www.slantmagazine.com/house/article/clean-off-the-dirt-scrape-off-the-blood-an-interview-with-trash-humpers-director-harmony-korine>.Latour, Bruno. “Why Has Critique Run Out of Steam? From Matters of Fact to Matters of Concern.” Critical Inquiry 30.2 (2004): 225-248.Maly, Ico, and Varis, Piia. “The 21st-Century Hipster: On Micro-Populations in Times of Superdiversity.” European Journal of Cultural Studies 19.6 (2016): 637–653.McHugh, Gene. “Monday May 10th 2010.” Post Internet. New York: Lulu Press, 2010.Ouellette, Marc. “‘I Know It When I See It’: Style, Simulation and the ‘Short-Circuit Sign’.” Semiotic Review 3 (2013): 1–15.Reeve, Michael. “The Hipster as the Postmodern Dandy: Towards an Extensive Study.” 2013. 12 Nov. 2016. <http://www.academia.edu/3589528/The_hipster_as_the_postmodern_dandy_towards_an_extensive_study>.Schiermer, Bjørn. “Late-Modern Hipsters: New Tendencies in Popular Culture.” Acta Sociologica 57.2 (2014): 167–181.Sontag, Susan. “Notes on Camp.” Against Interpretation. New York: Octagon, 1964/1982. 275-92. Stahl, Geoff. “Mile-End Hipsters and the Unmasking of Montreal’s Proletaroid Intelligentsia; Or How a Bohemia Becomes BOHO.” Adam Art Gallery, Apr. 2010. 12 May 2015 <http://www.adamartgallery.org.nz/wp-content/uploads/2010/04/adamartgallery_vuwsalecture_geoffstahl.pdf>.Williams, Alex. “Guerrilla Fashion: The Story of Supreme.” New York Times 21 Nov. 2012. 1 Nov. 2016 <http://www.nytimes.com/2012/11/22/fashion/guerrilla-fashion-the-story-of-supreme.html>.Žižek, Slavoj. “L’Etat d’Hipster.” Rhinocerotique. Trans. Henry Brulard. Sep. 2009. 3-10.

'He did what the cipher could not, he rescued himself.' -- Alfred Bester, The Stars My Destination (23) On many levels, the new Nine Inch Nails album The Fragile is a gritty meditation about different types of End: the eternal relationship cycle of 'fragility, tension, ordeal, fragmentation' (adapted, with apologies to Wilhelm Reich); fin-de-siècle anxiety; post-millennium foreboding; a spectre of the alien discontinuity that heralds an on-rushing future vastly different from the one envisaged by Enlightenment Project architects. In retrospect, it's easy for this perspective to be dismissed as jargon-filled cyber-crit hyperbole. Cyber-crit has always been at its best too when it invents pre-histories and finds hidden connections between different phenomena (like the work of Greil Marcus and early Mark Dery), and not when it is closer to Chinese Water Torture, name-checking the canon's icons (the 'Deleuze/Guattari' tag-team), texts and key terms. "The organization of sound is interpreted historically, politically, socially ... . It subdues music's ambition, reins it in, restores it to its proper place, reconciles it to its naturally belated fate", comments imagineer Kodwo Eshun (4) on how cyber-crit destroys albums and the innocence of the listening experience. This is how official histories are constructed a priori and freeze-dried according to personal tastes and prior memes: sometimes the most interesting experiments are Darwinian dead-ends that fail to make the canon, or don't register on the radar. Anyone approaching The Fragile must also contend with the music industry's harsh realities. For every 10 000 Goth fans who moshed to the primal 'kill-fuck-dance' rhythms of the hit single "Closer" (heeding its siren-call to fulfil basic physiological needs and build niche-space), maybe 20 noted that the same riff returned with a darker edge in the title track to The Downward Spiral, undermining the glorification of Indulgent hedonism. "The problem with such alternative audiences," notes Disinformation Creative Director Richard Metzger, "is that they are trying to be different -- just like everyone else." According to author Don Webb, "some mature Chaos and Black Magicians reject their earlier Nine Inch Nails-inspired Goth beginnings and are extremely critical towards new adopters because they are uncomfortable with the subculture's growing popularity, which threatens to taint their meticulously constructed 'mysterious' worlds. But by doing so, they are also rejecting their symbolic imprinting and some powerful Keys to unlocking their personal history." It is also difficult to separate Nine Inch Nails from the commercialisation and colossal money-making machine that inevitably ensued on the MTV tour circuit: do we blame Michael Trent Reznor because most of his audience are unlikely to be familiar with 'first-wave' industrial bands including Cabaret Voltaire and the experiments of Genesis P. Orridge in Throbbing Gristle? Do we accuse Reznor of being a plagiarist just because he wears some of his influences -- Dr. Dre, Daft Punk, Atari Teenage Riot, Pink Floyd's The Wall (1979), Tom Waits's Bone Machine (1992), David Bowie's Low (1977) -- on his sleeve? And do we accept no-brain rock critic album reviews who quote lines like 'All the pieces didn't fit/Though I really didn't give a shit' ("Where Is Everybody?") or 'And when I suck you off/Not a drop will go to waste' ("Starfuckers Inc") as representative of his true personality? Reznor evidently has his own thoughts on this subject, but we should let the music speak for itself. The album's epic production and technical complexity turned into a post-modern studio Vision Quest, assisted by producer Alan Moulder, eleventh-hour saviour Bob Ezrin (brought in by Reznor to 'block-out' conceptual and sonic continuity), and a group of assault-technicians. The fruit of these collaborations is an album where Reznor is playing with our organism's time-binding sense, modulating strange emotions through deeply embedded tonal angularities. During his five-year absence, Trent Reznor fought diverse forms of repetitious trauma, from endogenous depression caused by endless touring to the death of his beloved grandmother (who raised him throughout childhood). An end signals a new beginning, a spiral is an open-ended and ever-shifting structure, and so Reznor sought to re-discover the Elder Gods within, a shamanic approach to renewal and secular salvation utilised most effectively by music PR luminary and scientist Howard Bloom. Concerned with healing the human animal through Ordeals that hard-wire the physiological baselines of Love, Hate and Fear, Reznor also focusses on what happens when 'meaning-making' collapses and hope for the future cannot easily be found. He accurately captures the confusion that such dissolution of meaning and decline of social institutions brings to the world -- Francis Fukuyama calls this bifurcation 'The Great Disruption'. For a generation who experienced their late childhood and early adolescence in Reagan's America, Reznor and his influences (Marilyn Manson and Filter) capture the Dark Side of recent history, unleashed at Altamont and mutating into the Apocalyptic style of American politics (evident in the 'Star Wars'/SDI fascination). The personal 'psychotic core' that was crystallised by the collapse of the nuclear family unit and supportive social institutions has returned to haunt us with dystopian fantasies that are played out across Internet streaming media and visceral MTV film-clips. That such cathartic releases are useful -- and even necessary (to those whose lives have been formed by socio-economic 'life conditions') is a point that escapes critics like Roger Scruton, some Christian Evangelists and the New Right. The 'escapist' quality of early 1980s 'Rapture' and 'Cosmocide' (Hal Lindsey) prophecies has yielded strange fruit for the Children of Ezekiel, whom Reznor and Marilyn Manson are unofficial spokes-persons for. From a macro perspective, Reznor's post-human evolutionary nexus lies, like J.G. Ballard's tales, in a mythical near-future built upon past memory-shards. It is the kind of worldview that fuses organic and morphogenetic structures with industrial machines run amok, thus The Fragile is an artefact that captures the subjective contents of the different mind produced by different times. Sonic events are in-synch but out of phase. Samples subtly trigger and then scramble kinaesthetic-visceral and kinaesthetic-tactile memories, suggestive of dissociated affective states or body memories that are incapable of being retrieved (van der Kolk 294). Perhaps this is why after a Century of Identity Confusion some fans find it impossible to listen to a 102-minute album in one sitting. No wonder then that the double album is divided into 'left' and 'right' discs (a reference to split-brain research?). The real-time track-by-track interpretation below is necessarily subjective, and is intended to serve as a provisional listener's guide to the aural ur-text of 1999. The Fragile is full of encrypted tones and garbled frequencies that capture a world where the future is always bleeding into a non-recoverable past. Turbulent wave-forms fight for the listener's attention with prolonged static lulls. This does not make for comfortable or even 'nice' listening. The music's mind is a snapshot, a critical indicator, of the deep structures brewing within the Weltanschauung that could erupt at any moment. "Somewhat Damaged" opens the album's 'Left' disc with an oscillating acoustic strum that anchor's the listener's attention. Offset by pulsing beats and mallet percussion, Reznor builds up sound layers that contrast with lyrical epitaphs like 'Everything that swore it wouldn't change is different now'. Icarus iconography is invoked, but perhaps a more fitting mythopoeic symbol of the journey that lies ahead would be Nietzsche's pursuit of his Ariadne through the labyrinth of life, during which the hero is steadily consumed by his numbing psychosis. Reznor fittingly comments: 'Didn't quite/Fell Apart/Where were you?' If we consider that Reznor has been repeating the same cycle with different variations throughout all of his music to date, retro-fitting each new album into a seamless tapestry, then this track signals that he has begun to finally climb out of self-imposed exile in the Underworld. "The Day the World Went Away" has a tremendously eerie opening, with plucked mandolin effects entering at 0:40. The main slashing guitar riff was interpreted by some critics as Reznor's attempt to parody himself. For some reason, the eerie backdrop and fragmented acoustic guitar strums recalls to my mind civil defence nuclear war films. Reznor, like William S. Burroughs, has some powerful obsessions. The track builds up in intensity, with a 'Chorus of the Damned' singing 'na na nah' over apocalyptic end-times imagery. At 4:22 the track ends with an echo that loops and repeats. "The Frail" signals a shift to mournful introspectiveness with piano: a soundtrack to faded 8 mm films and dying memories. The piano builds up slowly with background echo, holds and segues into ... "The Wretched", beginning with a savage downbeat that recalls earlier material from Pretty Hate Machine. 'The Far Aways/Forget It' intones Reznor -- it's becoming clear that despite some claims to the contrary, there is redemption in this album, but it is one borne out of a relentless move forward, a strive-drive. 'You're finally free/You could be' suggest Reznor studied Existentialism during his psychotherapy visits. This song contains perhaps the ultimate post-relationship line: 'It didn't turn out the way you wanted it to, did it?' It's over, just not the way you wanted; you can always leave the partner you're with, but the ones you have already left will always stain your memories. The lines 'Back at the beginning/Sinking/Spinning' recall the claustrophobic trapped world and 'eternal Now' dislocation of Post-Traumatic Stress Disorder victims. At 3:44 a plucked cello riff, filtered, segues into a sludge buzz-saw guitar solo. At 5:18 the cello riff loops and repeats. "We're in This Together Now" uses static as percussion, highlighting the influence of electricity flows instead of traditional rock instrument configurations. At 0:34 vocals enter, at 1:15 Reznor wails 'I'm impossible', showing he is the heir to Roger Waters's self-reflective rock-star angst. 'Until the very end of me, until the very end of you' reverts the traditional marriage vow, whilst 'You're the Queen and I'm the King' quotes David Bowie's "Heroes". Unlike earlier tracks like "Reptile", this track is far more positive about relationships, which have previously resembled toxic-dyads. Reznor signals a delta surge (breaking through barriers at any cost), despite a time-line morphing between present-past-future. At 5:30 synths and piano signal a shift, at 5:49 the outgoing piano riff begins. The film-clip is filled with redemptive water imagery. The soundtrack gradually gets more murky and at 7:05 a subterranean note signals closure. "The Fragile" is even more hopeful and life-affirming (some may even interpret it as devotional), but this love -- representative of the End-Times, alludes to the 'Glamour of Evil' (Nico) in the line 'Fragile/She doesn't see her beauty'. The fusion of synths and atonal guitars beginning at 2:13 summons forth film-clip imagery -- mazes, pageants, bald eagles, found sounds, cloaked figures, ruined statues, enveloping darkness. "Just like You Imagined" opens with Soundscapes worthy of Robert Fripp, doubled by piano and guitar at 0:39. Drums and muffled voices enter at 0:54 -- are we seeing a pattern to Reznor's writing here? Sonic debris guitar enters at 1:08, bringing forth intensities from white noise. This track is full of subtle joys like the 1:23-1:36 solo by David Bowie pianist Mike Garson and guitarist Adrian Belew's outgoing guitar solo at 2:43, shifting back to the underlying soundscapes at 3:07. The sounds are always on the dissipative edge of chaos. "Just like You Imagined" opens with Soundscapes worthy of Robert Fripp, doubled by piano and guitar at 0:39. Drums and muffled voices enter at 0:54 -- are we seeing a pattern to Reznor's writing here? Sonic debris guitar enters at 1:08, bringing forth intensities from white noise. This track is full of subtle joys like the 1:23-1:36 solo by David Bowie pianist Mike Garson and guitarist Adrian Belew's outgoing guitar solo at 2:43, shifting back to the underlying soundscapes at 3:07. The sounds are always on the dissipative edge of chaos. "Pilgrimage" utilises a persistent ostinato and beat, with a driving guitar overlay at 0:18. This is perhaps the most familiar track, using Reznor motifs like the doubling of the riff with acoustic guitars between 1:12-1:20, march cries, and pitch-shift effects on a 3:18 drumbeat/cymbal. Or at least I could claim it was familiar, if it were not that legendary hip-hop producer and 'edge-of-panic' tactilist Dr. Dre helped assemble the final track mix. "No, You Don't" has been interpreted as an attack on Marilyn Manson and Hole's Courntey Love, particularly the 0:47 line 'Got to keep it all on the outside/Because everything is dead on the inside' and the 2:33 final verse 'Just so you know, I did not believe you could sink so low'. The song's structure is familiar: a basic beat at 0:16, guitars building from 0:31 to sneering vocals, a 2:03 counter-riff that merges at 2:19 with vocals and ascending to the final verse and 3:26 final distortion... "La Mer" is the first major surprise, a beautiful and sweeping fusion of piano, keyboard and cello, reminiscent of Symbolist composer Debussy. At 1:07 Denise Milfort whispers, setting the stage for sometime Ministry drummer Bill Reiflin's jazz drumming at 1:22, and a funky 1:32 guitar/bass line. The pulsing synth guitar at 2:04 serves as anchoring percussion for a cinematic electronica mindscape, filtered through new layers of sonic chiaroscuro at 2:51. 3:06 phase shifting, 3:22 layer doubling, 3:37 outgoing solo, 3:50-3:54 more swirling vocal fragments, seguing into a fading cello quartet as shadows creep. David Carson's moody film-clip captures the end more ominously, depicting the beauty of drowning. This track contains the line 'Nothing can stop me now', which appears to be Reznor's personal mantra. This track rivals 'Hurt' and 'A Warm Place' from The Downward Spiral and 'Something I Can Never Have' from Pretty Hate Machine as perhaps the most emotionally revealing and delicate material that Reznor has written. "The Great Below" ends the first disc with more multi-layered textures fusing nostalgia and reverie: a twelve-second cello riff is counter-pointed by a plucked overlay, which builds to a 0:43 washed pulse effect, transformed by six second pulses between 1:04-1:19 and a further effects layer at 1:24. E-bow effects underscore lyrics like 'Currents have their say' (2:33) and 'Washes me away' (2:44), which a 3:33 sitar riff answers. These complexities are further transmuted by seemingly random events -- a 4:06 doubling of the sitar riff which 'glitches' and a 4:32 backbeat echo that drifts for four bars. While Reznor's lyrics suggest that he is unable to control subjective time-states (like The Joker in the Batman: Dark Knight series of Kali-yuga comic-books), the track constructions show that the Key to his hold over the listener is very carefully constructed songs whose spaces resemble Pythagorean mathematical formulas. Misdirecting the audience is the secret of many magicians. "The Way Out Is Through" opens the 'Right' disc with an industrial riff that builds at 0:19 to click-track and rhythm, the equivalent of a weaving spiral. Whispering 'All I've undergone/I will keep on' at 1:24, Reznor is backed at 1:38 by synths and drums coalescing into guitars, which take shape at 1:46 and turn into a torrential electrical current. The models are clearly natural morphogenetic structures. The track twists through inner storms and torments from 2:42 to 2:48, mirrored by vocal shards at 2:59 and soundscapes at 3:45, before piano fades in and out at 4:12. The title references peri-natal theories of development (particularly those of Stanislav Grof), which is the source of much of the album's imagery. "Into the Void" is not the Black Sabbath song of the same name, but a catchy track that uses the same unfolding formula (opening static, cello at 0:18, guitars at 0:31, drums and backbeat at 1:02, trademark industrial vocals and synth at 1:02, verse at 1:23), and would not appear out of place in a Survival Research Laboratories exhibition. At 3:42 Reznor plays with the edge of synth soundscapes, merging vocals at 4:02 and ending the track nicely at 4:44 alone. "Where Is Everybody?" emulates earlier structures, but relies from 2:01 on whirring effects and organic rhythms, including a flurry of eight beat pulses between 2:40-2:46 and a 3:33 spiralling guitar solo. The 4:26 guitar solo is pure Adrian Belew, and is suddenly ended by spluttering static and white noise at 5:13. "The Mark Has Been Made" signals another downshift into introspectiveness with 0:32 ghostly synth shimmers, echoed by cello at 1:04 which is the doubled at 1:55 by guitar. At 2:08 industrial riffs suddenly build up, weaving between 3:28 distorted guitars and the return of the repressed original layer at 4:16. The surprise is a mystery 32 second soundscape at the end with Reznor crooning 'I'm getting closer, all the time' like a zombie devil Elvis. "Please" highlights spacious noise at 0:48, and signals a central album motif at 1:04 with the line 'Time starts slowing down/Sink until I drown'. The psychic mood of the album shifts with the discovery of Imagination as a liberating force against oppression. The synth sound again is remarkably organic for an industrial album. "Starfuckers Inc" is the now infamous sneering attack on rock-stardom, perhaps at Marilyn Manson (at 3:08 Reznor quotes Carly Simon's 'You're So Vain'). Jungle beats and pulsing synths open the track, which features the sound-sculpting talent of Pop Will Eat Itself member Clint Mansell. Beginning at 0:26, Reznor's vocals appear to have been sampled, looped and cut up (apologies to Brion Gysin and William S. Burroughs). The lines 'I have arrived and this time you should believe the hype/I listened to everyone now I know everyone was right' is a very savage and funny exposure of Manson's constant references to Friedrich Nietzsche's Herd-mentality: the Herd needs a bogey-man to whip it into submission, and Manson comes dangerous close to fulfilling this potential, thus becoming trapped by a 'Stacked Deck' paradox. The 4:08 lyric line 'Now I belong I'm one of the Chosen Ones/Now I belong I'm one of the Beautiful Ones' highlights the problem of being Elect and becoming intertwined with institutionalised group-think. The album version ditches the closing sample of Gene Simmons screaming "Thankyou and goodnight!" to an enraptured audience on the single from KISS Alive (1975), which was appropriately over-the-top (the alternate quiet version is worth hearing also). "The danger Marilyn Manson faces", notes Don Webb (current High Priest of the Temple of Set), "is that he may end up in twenty years time on the 'Tonight Show' safely singing our favourite songs like a Goth Frank Sinatra, and will have gradually lost his antinomian power. It's much harder to maintain the enigmatic aura of an Evil villain than it is to play the clown with society". Reznor's superior musicianship and sense of irony should keep him from falling into the same trap. "Complication" juggernauts in at 0:57 with screaming vocals and a barrage of white noise at 1:56. It's clear by now that Reznor has read his psychological operations (PSYOP) manuals pertaining to blasting the hell out of his audiences' psyche by any means necessary. Computer blip noise and black light flotation tank memories. Dislocating pauses and time-bends. The aural equivalent of Klein bottles. "Complication" juggernauts in at 0:57 with screaming vocals and a barrage of white noise at 1:56. It's clear by now that Reznor has read his psychological operations (PSYOP) manuals pertaining to blasting the hell out of his audiences' psyche by any means necessary. Computer blip noise and black light flotation tank memories. Dislocating pauses and time-bends. The aural equivalent of Klein bottles. "The Big Come Down" begins with a four-second synth/static intro that is smashed apart by a hard beat at 0:05 and kaleidoscope guitars at 0:16. Critics refer to the song's lyrics in an attempt to project a narcissistic Reznor personality, but don't comment on stylistic tweaks like the AM radio influenced backing vocals at 1:02 and 1:19, or the use of guitars as a percussion layer at 1:51. A further intriguing element is the return of the fly samples at 2:38, an effect heard on previous releases and a possible post-human sub-text. The alien mythos will eventually reign over the banal and empty human. At 3:07 the synths return with static, a further overlay adds more synths at 3:45 as the track spirals to its peak, before dissipating at 3:1 in a mesh of percussion and guitars. "Underneath It All" opens with a riff that signals we have reached the album's climatic turning point, with the recurring theme of fragmenting body-memories returning at 0:23 with the line 'All I can do/I can still feel you', and being echoed by pulsing static at 0:42 as electric percussion. A 'Messiah Complex' appears at 1:34 with the line 'Crucify/After all I've died/After all I've tried/You are still inside', or at least it appears to be that on the surface. This is the kind of line that typical rock critics will quote, but a careful re-reading suggests that Reznor is pointing to the painful nature of remanifesting. Our past shapes us more than we would like to admit particularly our first relationships. "Ripe (With Decay)" is the album's final statement, a complex weaving of passages over a repetitive mesh of guitars, pulsing echoes, back-beats, soundscapes, and a powerful Mike Garson piano solo (2:26). Earlier motifs including fly samples (3:00), mournful funeral violas (3:36) and slowing time effects (4:28) recur throughout the track. Having finally reached the psychotic core, Reznor is not content to let us rest, mixing funk bass riffs (4:46), vocal snatches (5:23) and oscillating guitars (5:39) that drag the listener forever onwards towards the edge of the abyss (5:58). The final sequence begins at 6:22, loses fidelity at 6:28, and ends abruptly at 6:35. At millennium's end there is a common-held perception that the world is in an irreversible state of decay, and that Culture is just a wafer-thin veneer over anarchy. Music like The Fragile suggests that we are still trying to assimilate into popular culture the 'war-on-Self' worldviews unleashed by the nineteenth-century 'Masters of Suspicion' (Charles Darwin, Sigmund Freud, Friedrich Nietzsche). This 'assimilation gap' is evident in industrial music, which in the late 1970s was struggling to capture the mood of the Industrial Revolution and Charles Dickens, so the genre is ripe for further exploration of the scarred psyche. What the self-appointed moral guardians of the Herd fail to appreciate is that as the imprint baseline rises (reflective of socio-political realities), the kind of imagery prevalent throughout The Fragile and in films like Strange Days (1995), The Matrix (1999) and eXistenZ (1999) is going to get even darker. The solution is not censorship or repression in the name of pleasing an all-saving surrogate god-figure. No, these things have to be faced and embraced somehow. Such a process can only occur if there is space within for the Sadeian aesthetic that Nine Inch Nails embodies, and not a denial of Dark Eros. "We need a second Renaissance", notes Don Webb, "a rejuvenation of Culture on a significant scale". In other words, a global culture-shift of quantum (aeon or epoch-changing) proportions. The tools required will probably not come just from the over-wordy criticism of Cyber-culture and Cultural Studies or the logical-negative feeding frenzy of most Music Journalism. They will come from a dynamic synthesis of disciplines striving toward a unity of knowledge -- what socio-biologist Edward O. Wilson has described as 'Consilience'. Liberating tools and ideas will be conveyed to a wider public audience unfamiliar with such principles through predominantly science fiction visual imagery and industrial/electronica music. The Fragile serves as an invaluable model for how such artefacts could transmit their dreams and propagate their messages. For the hyper-alert listener, it will be the first step on a new journey. But sadly for the majority, it will be just another hysterical industrial album promoted as selection of the month. References Bester, Alfred. The Stars My Destination. London: Millennium Books, 1999. Eshun, Kodwo. More Brilliant than the Sun: Adventures in Sonic Fiction. London: Quartet Books, 1998. Van der Kolk, Bessel A. "Trauma and Memory." Traumatic Stress: The Effects of Overwhelming Experience on Mind, Body, and Society. Eds. Bessel A. van der Kolk et al. New York: Guilford Press, 1996. Nine Inch Nails. Downward Spiral. Nothing/Interscope, 1994. ---. The Fragile. Nothing, 1999. ---. Pretty Hate Machine. TVT, 1989. Citation reference for this article MLA style: Alex Burns. "'This Machine Is Obsolete': A Listeners' Guide to Nine Inch Nails' The Fragile." M/C: A Journal of Media and Culture 2.8 (1999). [your date of access] <http://www.uq.edu.au/mc/9912/nine.php>. Chicago style: Alex Burns, "'This Machine Is Obsolete': A Listeners' Guide to Nine Inch Nails' The Fragile," M/C: A Journal of Media and Culture 2, no. 8 (1999), <http://www.uq.edu.au/mc/9912/nine.php> ([your date of access]). APA style: Alex Burns. (1999) 'This machine is obsolete': a listeners' guide to Nine Inch Nails' The fragile. M/C: A Journal of Media and Culture 2(8). <http://www.uq.edu.au/mc/9912/nine.php> ([your date of access]).