Статті в журналах з теми "Muddy plug"

Several specimens of biogenic structures somewhat resembling plug-shaped ichnofossils have been collected in two muddy deposits, Sicilian (Early Pleistocene) in age (Bossio et al., 1987), outcropping near Lecce, southern Apulia, Italy. One sequence is exposed in an unused quarry located at the eastern side of the Cutrofiano–Supersano road, 31 km post; the other one is in an active quarry, southwest of Lecce, near the village of San Pietro in Lama (Figure 1). The diagnostic features of the traces differ from those of the five ichnogenera recognized by Pemberton et al. (1988) for plug-shaped ichnofossils. The minor ichnogenera related to plug-shaped trace fossils, as indicated by those authors, are also different from the present structure. A new ichnogenus is proposed to cover this form.

In this paper, we investigate the dynamics of muddy-seabed motions induced by a surface solitary wave. The muddy seabed is characterized as Bingham-plastic mud. We focus our attention on the situations where the horizontal scale of the wave-induced mud flow is much larger than the vertical scale. The thickness of the mud layer is also assumed to be much smaller than the water depth above. With these simplifications, the dynamic pressure in the mud column remains a constant and the vertical displacement of the water–mud interface is negligible. The horizontal gradient of the wave-induced dynamic pressure along the water–seabed interface drives the motions in the mud bed. For a Bingham-plastic muddy seafloor, the mud moves either like a solid (plug flow) or like a viscous fluid (shear flow) depending on whether the magnitude of shear stress is in excess of the yield stress. Velocities inside these two different flow regimes and the location(s) of the yield surface(s) vary in time as functions of water–mud interfacial pressure gradient and the properties of the Bingham-plastic mud. A semi-analytical approach is developed in this paper to analyse the motions inside the mud bed under a surface solitary wave loading. Three possible scenarios are discussed to illustrate the complexity of the seafloor responses. The formula for the damping rate caused by the energy dissipation inside the muddy seabed is also derived. Using realistic values of the physical parameters, the present results for damping rate agree qualitatively with the available field observations.

Liu & Chan (J. Fluid Mech. vol. 579, 2007, p. 467, hereinafter referred to as LC) derived analytical solutions for the interactions between shallow water waves and a viscous fluid seabed. In this paper we present a set of new experimental data on the solitary-wave-induced flows in a viscous muddy seabed so as to validate LC's theory and the approximations employed. In the experiments a clear silicone fluid was used as the viscous mud and particle image velocimetry was employed to measure the velocity field inside the viscous mud. The shear stress along the bottom of the mud bed and the displacement of the water--mud interface were also deduced from data. Experimental results showed excellent agreement with the theoretical solutions. Additional analyses were performed to show that the ratio of the muddy seabed thickness to the corresponding bottom boundary-layer thickness, $\dbar$, plays an important role in characterizing mud flow regimes. When $\dbar\,{\leq}\,1$, the vertical profile of the horizontal velocity in the mud bed can be parameterized as a parabola. On the other hand, when $\dbar\,{\gg}\,1$, the velocity profile appears as a plug flow above a thin viscous layer. When $ \dbar\,{\sim}\,O(1)$, the flow patterns are more complex than the other two regimes and flow reversal can occur inside the viscous mud bed.

PurposeThis paper seeks to describe the process used to develop the multimedia design and planning pyramid (MUDPY) ontology, and the role played by the MUDPY ontology as a planning, design and development tool in multimedia projects.Design/methodology/approachThe MUDPY model was implemented for the semantic web by developing an ontology for it. This ontology facilitates defining the concepts existing in that domain, their attributes and the relationships between them.FindingsThe MUDPY ontology can guide developers through the various phases of a multimedia project in a systematic fashion by allowing them to create a project proposal, specify the functional requirements, decide on the navigational structure and create a storyboard, and thus create high‐quality projects.Research limitations/implicationsThe current system is a prototype. This MUDPY ontology can be extended by adding more classes in order to increase its functionality; for example, one can develop special plug‐in widgets to generate project reports required during multimedia project planning and design.Practical implicationsBy using the MUDPY ontology, developers can follow a systematic process for project development, and better manage the complexity of multimedia projects.Originality/valueThe paper introduces the MUDPY model and its ontology, and shows a multimedia author the pathway to manage a multitude of concepts and assets required in a multimedia project.

We used a three-dimensional coupled hydrodynamic–ecological model to investigate how lake currents can affect walleye ( Sander vitreus ) recruitment in western Lake Erie. Four years were selected based on a fall recruitment index: two high recruitment years (i.e., 1996 and 1999) and two low recruitment years (i.e., 1995 and 1998). During the low recruitment years, the model predicted that (i) walleye spawning grounds experienced destructive bottom currents capable of dislodging eggs from suitable habitats (reefs) to unsuitable habitats (i.e., muddy bottom), and (ii) the majority of newly hatched larvae were transported away from the known suitable nursery grounds at the start of their first feeding. Conversely, during two high recruitment years, predicted bottom currents at the spawning grounds were relatively weak, and the predicted movement of newly hatched larvae was toward suitable nursery grounds. Thus, low disturbance-based egg mortality and a temporal and spatial match between walleye first feeding larvae and their food resources were predicted for the two high recruitment years, and high egg mortality plus a mismatch of larvae with their food resources was predicted for the two low recruitment years. In general, mild westerly or southwesterly winds during the spawning–nursery period should favour walleye recruitment in the lake.

Depuis les années 1990, le populisme est de retour sur le vieux continent et ailleurs dans le monde. Un de ses foyers se situe en Europe centrale et orientale : c’est ici qu’il atteint aujourd’hui ses formes les plus virulentes, remettant en cause les institutions démocratiques et les libertés individuelles. Depuis quelques années, cette évolution attire l’attention des politistes et plus largement des chercheurs en sciences sociales (Zalewski 2016 ; Potel 2019).Le populisme est souvent considéré comme un concept fourre-tout, un terme valise dont la définition et donc l’usage sont problématiques. Certains le définissent comme une idéologie qui divise la société entre deux camps antagonistes, le « peuple » pur et les « élites » corrompues, et qui place l’intérêt du premier avant toute chose (Mudde & Kaltwasser 2018). Pour d’autres, le populisme est le syndrome d’une crise systémique et d’une volonté d’en sortir (Laclau 2008). Pour d’autres encore, il relève plutôt d’un style politique fondé sur une invocation systématique du « peuple » et empruntant divers éléments aux idéologies de droite comme à celles de gauche (Taguieff 2002, Kaltwasser et al. 2017). En Europe, il fait souvent référence aux mouvements anti-immigration et xénophobes, alors qu’en Amérique latine il renvoie plutôt au clientélisme et à la mauvaise gestion économique des pays.

Kinorhyncha is a phylum of exclusively marine, meiofaunal invertebrates (Sørensen & Pardos 2008). Currently, the knowledge about the worldwide distribution of most of its species is considerably patchy, as several taxa have been reported from a single or few localities, usually within a limited geographic area (Sørensen & Pardos 2008; Yamasaki et al. 2018a). This even becomes more evident for deep-sea kinorhynchs, as noticed by Sørensen et al. (2018). Given the particular value of new records from the deep-sea to increase our understanding in the distribution of meiofaunal organisms plus the observed relationship of morphological variation through the bathymetric gradient, we aim to report the first record of Echinoderes unispinosus Yamasaki, Neuhaus & George, 2018 in the southern edge of the Gulf of Mexico (GoM), and contribute with new information about the morphological intraspecific variation of this species. In Mexico, studies of kinorhynch biodiversity are limited to the northern Gulf of California (50–1570m depth) (Álvarez-Castillo et al. 2015, 2018; Cepeda et al. 2019) and the Yucatán Peninsula (Sánchez & Martínez 2019). The GoM is a semi-closed basin located in a transition zone with both subtropical and tropical weather. Deep-sea muddy sediment samples of the present study were collected during the expedition XIXIMI-5 (10–24 June 2016) and processed according to Cisterna-Céliz et al. (2019). Kinorhynch specimens were mounted, measured and photographed according to Cepeda et al. (2019). Two adult males were identified as E. unispinosus, one from station B11 (2298 m depth) and another from station B15 (3708m depth). Kinorhynch specimens were deposited at the Aquatic Invertebrates Collection of the Facultad de Ciencias, Universidad Nacional Autónoma de México (UNAM), Mexico, under accession numbers: KGM.001 and KGM.002.

Abstract. Resuspension of 137Cs from the contaminated ground surface to the atmosphere is essential for understanding the environmental behaviors of 137Cs and estimating external and inhalation exposure of residents. Kajino et al. (2016) assessed the 137Cs resuspension flux from bare soil and forest ecosystems in eastern Japan in 2013 using a numerical simulation constrained by surface air concentration measurements. However, the simulation was found to underestimate the observed deposition amounts by 2 orders of magnitude. The reason for this underestimation is that the simulation assumed that resuspended 137Cs is carried by submicron aerosols, which have low deposition rates. Based on the observational indications that soil dust and bioaerosols are the major carriers of resuspended 137Cs, a new simulation is performed with higher deposition rates constrained by both surface concentrations and deposition amounts. In the new estimation, the total areal annual resuspension of 137Cs in 2013 is 25.7 TBq, which is equivalent to 0.96 % of the initial deposition (2.68 PBq). Due to the rapid deposition rates, the annual redeposition amount is also large at 10.6 TBq, approximately 40 % of the resuspended 137Cs. The resuspension rate through the atmosphere (0.96 % yr−1) seems slow, but it (2.6 × 10−5 d−1) may not be negligibly small compared to the actual decreasing trend of the ambient gamma dose rate obtained in Fukushima Prefecture after the radioactive decay of 137Cs plus 134Cs in 2013 is subtracted (1.0–7.9 × 10−4 d−1): resuspension can account for 1 %–10 % of the decreasing rate due to decontamination and natural decay through land surface processes. The current simulation underestimated the 137Cs deposition in Fukushima city in winter by more than an order of magnitude, indicating the presence of additional resuspension sources. The site of Fukushima city is surrounded by major roads. Heavy traffic on wet and muddy roads after snow removal operations could generate superlarge (approximately 100 µm in diameter) road dust or road salt particles, which are not included in the model but might contribute to the observed 137Cs at the site.

The recovery rate of a population of feral pigs (Sus scrofa) in the west Kimberley in north-western Australia was determined 12 months after a 1080 (sodium fluoroacetate)-baiting program. An estimated 56 pigs were present in the 15 000-ha study area in August 2005 compared with the prebaiting levels of 250–275 pigs in 2004 (11 pigs were known to be alive on site after the 2004 baiting). This represents a population recovery of 20–23% of the 2004 prebaiting levels. Although most pigs were in good body condition, environmental conditions were quite different between the two years. In 2005, some waterholes were dry or comprised mainly muddy water with little associated shelter for feral pigs. Consequently, and in contrast to 2004, no pigs were seen, and no bait take could be attributed to feral pigs, at the four resurveyed waterholes. Most pig sightings, and activity, were close to the Fitzroy River. Fermented wheat, with blood and bone, was used to determine areas of pig activity, and also used as prefeed before 1080-baiting commenced in 2005. Using the same bait stations as for 2004, plus additional stations established in new areas of pig activity, 1080-treated wheat and malted barley again proved highly effective in reducing pig numbers. The daily sighting index before and after 1080-baiting indicated that pig numbers had been reduced by ~90% within four days. Estimated pre- and postpoisoning density, with and without an edge effect, was 0.12–1.7 pigs km–2 and 0.05–0.67 pigs km–2. Pig tracks decreased to zero on the six track plots within two days of baiting, but the number of macropod tracks remained constant over the four-day baiting period. Thirty-eight poisoned pigs were found after 1080-baiting, and these were generally in clustered groups within 200 m of an active bait station. Poisoned juvenile pigs were again found closer to the active bait stations than were adult or subadult pigs (P < 0.05).

Abstract Background: Oncogenic KRAS is present in almost all cases of pancreatic ductal adenocarcinoma (PDAC). However, targeting KRAS or its canonical signaling cascades, especially the mitogen-activated protein kinase (MAPK) pathway, remains clinically unsuccessful. Targeting ERK kinases has recently emerged as a promising therapeutic strategy and combinatorial strategies should be developed. Aim: Identify adaptive mechanisms to ERK inhibition that can be co-targeted to achieve effective tumor inhibition in multiple patient-derived xenograft (PDX) models. Methods: Reverse-phase protein array (RPPA) was used in early-passage patient-derived cell lines (PDCLs) to identify potential resistance mechanisms. These were confirmed using RNA interference and overexpression in PDAC cell lines and PDCLs. The promising combinations were tested in 30 early-passaged PDAC PDXs. Results: RPPA showed dramatic downregulation of DUSP4 and DUSP6 phosphatases following MEK and ERK inhibition, which coincided with upregulation of phospho-HER2 and -HER3. Knockdown of DUSP6, but not DUSP4, was sufficient in phosphorylation of HER2. Conversely, overexpression of DUSP6 curbed HER2 and ERK activation. Downregulation of DUSP4 and DUSP6 induced by ulixertinib, an ERK inhibitor now in clinical development, was reversed by bortezomib, suggesting DUSP4 and DUSP6 are proteosomally degraded. Combined ulixertinib plus PI3K inhibitor copanlisib, or pan-HER inhibitor afatinib slowed but did not arrest PDX tumor growth in vivo, and addition of gemcitabine was required to achieve tumor regression or durable growth arrest. Alternatively, ulixertinib or MEK inhibitor (trametinib) in combination with trastuzumab deruxtecan (DS-8201a), an anti-HER2 conjugated topoisomerase I inhibitor, were extremely effective, leading to complete and durable tumor regression for all tested PDX models. We showed that upregulation of HER2 expression following MEK or ERK inhibitor treatment provides a conduit for enhanced internalization of DS-8201a. Conclusions: Our study provided novel mechanistic insight on how PDAC cells evade MAPK inhibition via enhancing HER2 signaling. We demonstrated that the combination of MEK or ERK inhibitor plus DS-8201a is extremely effective, leading to complete tumor regression in multiple PDAC PDX models. This combination should be advanced as a clinical trial for PDAC patients. Keys: DS-8201a, DUSP6, HER2, KRAS, ulixertinib, pancreatic ductal adenocarcinoma Citation Format: Ashenafi Shiferaw Bulle, Kuljeet Seehar, Sapana Bansod, Yali Chen, Chen Hung-Po, Paarth B. Dodhiawala, Lin Li, Vikas Somani, Jacqueline Mudd, Ryan C. Fields, Deborah Knoerzer, Andrea Wang-Gillam, Lim Kian-Huat. Pancreatic cancer enhances HER2 signaling through DUSP6 to circumvent therapeutic MAPK inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5333.

Summary Several areas of the geosciences have benefitted from the application of the new mathematics of "fuzzy logic."1,2 The oil industry now routinely uses new interpretation techniques, based on fuzzy logic, to predict permeability and litho-facies in uncored wells. Litho-facies and permeability prediction have presented a challenge to formation evaluation due to the lack of tools that measure them directly. The method described can be used as a simple tool for confirming known correlations or as a powerful predictor in uncored wells. Fuzzy logic is simply an application of recognized statistical techniques. Whereas conventional techniques deal with absolutes, the new methods carry the inherent error term through the calculation rather than ignoring or minimizing it. This retains the information associated with the error and gives surprisingly better results. One clear application is to litho-facies determination. Litho-facies typing is used in well correlation and is important for building a three-dimensional model of an oil or gas field. The technique makes no assumptions and retains the possibility that a particular litho-facies type can give any well log reading although some are more likely than others. This error or fuzziness has been measured and used to improve the litho-facies prediction in several North Sea fields. In one study, descriptions from 10 cored wells were used to derive litho-facies descriptions in 30 uncored wells. This technique gave near-perfect differentiation between aeolian, fluvial, and sabkha rock types. In addition, it went some way towards differentiating between sandy, mixed, and muddy sabkhas. Using the fuzzy logic technique gives much better predictions than more complicated methods such as neural networks or cluster analysis. A second application is permeability calculation. Knowledge of permeability is important in determining the well completion strategy and the resulting productivity. The problem with permeability prediction is derived from the fact that permeability is related more to the aperture of pore throats rather than pore size, which logging tools find difficult to measure. Determining permeability from well logs is further complicated by the problem of scale, well logs having a vertical resolution of, typically, 2 ft compared to the 2 in. of core plugs. The new techniques quantify these errors and use them, together with the measurement, to improve the prediction. This new approach has been used in several fields to obtain better estimates of permeability compared to conventional techniques. In addition, the method uses basic log data sets such as gamma ray and porosity rather than depending on new logging technology. Introduction Fuzzy logic is an extension of conventional Boolean logic (zeros and ones) developed to handle the concept of "partial truth"— truth values between "completely true" and "completely false." Dr. Lotfi Zadeh of UC/Berkeley introduced it in the 1960's as a means to model uncertainty.3 Science is heavily influenced by Aristotle's laws of logic initiated by the ancient Greeks and developed by many scientists and philosophers since.4 Aristotle's laws are based on "X or not-X;" a thing either is, or is not. This has been used as a basis for almost everything that we do. We use it when we classify things and when we judge things. Managers want to know whether it is this or that, and even movies have clear goodies and baddies. Conventional logic is an extension of our subjective desire to categorize things. Life is simplified if we think in terms of black and white. This way of looking at things as true or false was reinforced with the introduction of computers that only use bits 1 or 0. When the early computers arrived with their machine-driven binary system, Boolean logic was adopted as the natural reasoning mechanism for them. Conventional logic forces the continuous world to be described with a coarse approximation; and in so doing, much of the fine detail is lost. We miss a lot in the simplification. By only accepting the two possibilities, the infinite number of possibilities in between them is lost. Reality does not work in black and white, but in shades of gray. Not only does truth exist on a sliding scale, but also because of the uncertainty in measurements and interpretations, a gray scale can be a more useful explanation than two endpoints. For instance, we can look at a map of the earth and see mountains and valleys, but it is difficult to define where mountains start and the valleys end. This is the mathematics of fuzzy logic. Once the reality of the gray scale has been accepted, a system is required to cope with the multitude of possibilities. Probability theory helps quantify the grayness of fuzziness. It may not be possible to understand the reason behind random events, but fuzzy logic can help bring meaning to the bigger picture. Take, for instance, a piece of reservoir rock. Aeolian rock generally has good porosity and fluvial rock poorer porosity. If we find a piece of rock with a porosity of 2 porosity units (pu) is it aeolian or fluvial? We could say it is definitely fluvial and get on with more important matters. But let us say it is probably fluvial but there is a slim probability that it could be aeolian. Aeolian rocks are generally clean and fluvial rocks shalier. The same piece of rock contains 30% clay minerals. Is it aeolian or fluvial? We could say it is equally likely to be aeolian or fluvial based on this measurement. This is how fuzzy logic works. It does not accept it is either this or that. It assigns a grayness, or probability, to the quality of the prediction on each parameter of the rock, whether it is porosity, shaliness, or color. There is also the possibility that there is a measurement error and the porosity is 20 pu not 2 pu. Fuzzy logic combines these probabilities and predicts that based on porosity, shaliness, and other characteristics, the rock is most likely to be aeolian. Fuzzy logic says that there is also the possibility it could be fluvial. In essence, fuzzy logic maintains that any interpretation is possible but some are more probable than others. One advantage of fuzzy logic is that we never need to make a concrete decision. What is more, fuzzy logic can be described by established statistical algorithms; and computers, which themselves work in ones and zeros, can do this effortlessly for us.

Abstract Background: CHOP plus rituximab (R-CHOP) is the standard of care for previously untreated DLBCL. R-CHOP comprises CHOP and one-dose rituximab in each 21-day cycle; however, the schedule of rituximab administration has not been fully optimized. Dose-dense rituximab was expected to increase its peak concentration to enhance the synergistic effect with chemotherapy at early phase of treatment. To compare weekly administration of rituximab combined with CHOP (RW-CHOP) with standard R-CHOP in patients with previously untreated DLBCL, we conducted a multicenter, randomized phase II/III study (JCOG0601, UMIN000000929). Methods: Previously untreated patients with CD20+ DLBCL were eligible. Other major inclusion criteria were as follows: aged 20-79 years; ECOG performance status 0-2, at least 1 measurable lesion and preserved organ functions. At the beginning of the study, patients with advanced stage disease and the low or low-intermediate risk group by the International Prognostic Index (IPI) were eligible. These criteria were amended in September 2010 to allow enrollment of the patients with any IPI risk and any clinical stage because of slow accrual. Patients were randomly assigned to standard R-CHOP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 [max 2 mg], all IV on day 1, and prednisone 100 mg/day PO [40mg/m2 for aged >65] on days 1-5, every 3 weeks) or RW-CHOP (standard CHOP with eight doses of weekly rituximab [375mg/m2 IV on days1, 8, 15, 22, 29, 36, 43 and 50]). Six cycles of CHOP were given in stage I non-bulky patients, 8 cycles were given in stage I bulky and II-IV patients, and rituximab was given 8 times regardless of cycles of CHOP. Randomization was stratified by institution, presence or absence of bulky mass and patient age. The primary endpoint of phase III part was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and adverse events (AE). Assuming 3-year PFS in the R-CHOP arm to be 77% and expecting a 7% increase in 3-year PFS of the RW-CHOP arm, required sample size was 211 per arm with a one-sided alpha of 5%, power of 80%, an accrual period of 7 years, and a follow-up period of 3 years. Results: Between December 2007 and December 2014, a total of 422 patients were randomized to study treatments but primary analysis was performed in 421 patients: 213 to the R-CHOP arm and 208 to the RW-CHOP arm, because of one consent withdrawal. Baseline characteristics of 421 eligible patients were as follows (R-CHOP vs. RW-CHOP): median age, 61 vs. 62 years; male sex, 54.5% vs. 55.8%; Ann Arbor stage I/II/III/IV, 14.6/32.9/26.8/25.8% vs. 16.3/42.8/20.2/20.7%; and IPI score ≤2, 77.0% vs. 87.5%. With a median follow-up of 63.4 months (range: 3.2-119.2) among all patients, there was no significant difference in PFS between the arms (hazard ratio [HR], 0.95; 90.6% confidence interval [CI], 0.68 to 1.31; one-sided log-rank P = 0.39). The 3-year PFS and OS were 79.2% and 88.7% with the R-CHOP arm and 80.3% and 90.4% with the RW-CHOP arm, respectively. The complete response rate and overall response rate were 77.0% and 93.0% in the R-CHOP arm and 82.2% and 91.8% in the RW-CHOP arm, respectively. Major AEs were hematological toxicities and infections. Grade (G) 3/4 neutropenia and G 3/4 thrombocytopenia were observed in 97.7% and 8.0% in the R-CHOP arm and 97.1% and 5.3% in the RW-CHOP arm, respectively. G3 febrile neutropenia was occurred in 33.8% in the R-CHOP arm and in 22.1% in the RW-CHOP arm. The frequency of severe AE was 2.3% in the R-CHOP arm and 3.8% in the RW-CHOP arm. Safety profile was comparable. No unexpected AEs were experienced. Conclusion: In combination of standard CHOP and rituximab, dose-dense weekly rituximab at early phase of treatment did not improve the PFS in patients with untreated DLBCL. Figure. Figure. Disclosures Ohmachi: Celgene: Honoraria; Takeda Pharmaceutical Co., Ltd,: Honoraria; Pfizer: Honoraria; Chugai Pharma: Honoraria; Kyowa Hakko Kirin: Honoraria; Eisai: Honoraria; Janssen: Honoraria; Meiji Pharma: Honoraria. Kinoshita:Takeda: Honoraria; Takeda: Research Funding; Ono: Research Funding; MSD: Research Funding; Solasia: Research Funding; Janssen: Honoraria; Ono: Honoraria; Zenyaku: Research Funding; Eisai: Research Funding; Gilead: Research Funding. Tobinai:Kyowa Hakko Kirin: Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; HUYA Bioscience International: Consultancy, Honoraria; SERVIER: Research Funding; Abbvie: Research Funding. Fukuhara:Sumitomo Dainippon: Research Funding; Solasia: Research Funding; Symbio: Research Funding; Sanofi: Research Funding; Pfizer: Research Funding; Otsuka Pharmaceutical: Research Funding; Ono: Honoraria, Research Funding; Novartis pharma: Research Funding; Nippon-shinyaku: Research Funding; MSD: Research Funding; Mundipharma: Honoraria, Research Funding; Mitsubishi Tanabe: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Japan Blood Products Organization: Research Funding; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Eisai: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Daiichi-Sankyo: Research Funding; Chugai: Research Funding; Celgene: Research Funding; Baxalta: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Bayer Yakuhin: Research Funding; Alexionpharma: Research Funding; AbbVie: Research Funding; Astellas: Research Funding; Nihon Ultmarc: Research Funding; Taiho: Research Funding; Teijin Pharma: Research Funding; Zenyaku Kogyo: Honoraria, Research Funding; Takeda: Honoraria. Uchida:Takeda Pharmaceutical: Honoraria; Chugai Pharmaceutical: Honoraria; Kyowa Hakko Kirin: Honoraria; Meiji Seika Pharma: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Teijin: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria; Janssen Pharma: Honoraria; Otsuka Pharmaceutical: Honoraria; Eisai: Honoraria. Yamamoto:Solasia Pharma: Research Funding; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria, Research Funding; ARIAD Pharmaceuticals: Research Funding; Bayer: Research Funding; Celgene: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; AbbVie: Research Funding; Boehringer Ingelheim: Consultancy; Chugai: Consultancy, Honoraria, Research Funding; Meiji Seika Pharma: Consultancy; MSD: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku: Research Funding; Kyowa Hakko Kirin: Honoraria; Otsuka: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon: Honoraria; Mundipharma: Consultancy, Honoraria; HUYA: Honoraria; SymBio: Research Funding; Gilead Sciences: Research Funding. Miyazaki:Kyowa Hakko Kirin,: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharma,: Honoraria, Research Funding; Sumitomo Group: Research Funding; Nippon Shinyaku: Research Funding; Takeda: Research Funding; Astellas Pharma: Research Funding; Shionogi Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eisai: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Teijin Pharma: Research Funding; Ono Pharmaceutical: Research Funding; Toyama Chemical Co: Research Funding; Mochida Pharmaceutical Co. Ltd.: Research Funding; Novo Nordisk: Research Funding. Tsukamoto:Kyowa-Kirin: Research Funding; Pfizer: Research Funding; Chugai: Research Funding; Eisai: Research Funding. Iida:Teijin Pharma: Research Funding; Toyama Chemical: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Research Funding; Chugai: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Astellas: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Gilead: Research Funding; MSD: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Sanofi: Consultancy. Yoshida:Taiho Pharma: Honoraria; Takeda Pharma: Honoraria; Celegene: Honoraria; Chugai Pharma: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding. Masaki:Ono: Research Funding; Kyowa Hakko Kirin: Research Funding; Phizer: Research Funding; Astellas: Research Funding; Eisai: Research Funding. Yakushijin:Mundipharma Co.,: Research Funding; Chugai Co.,: Research Funding; Kyowa-kirin Co.,: Research Funding; Merch Sharp & Dohme Corp.,,: Research Funding; Daiichi-Sankyo Inc.,: Research Funding; Eisai Co.: Research Funding. Suehiro:Kyowa Hakko Kirin: Research Funding; Ono Pharmaceutical: Research Funding; Chugai Pharmaceutical: Research Funding; Takeda Pharmaceutical: Research Funding. Nosaka:Bristol-Myers Squibb: Honoraria; Ono Pharmaceutical Co.LTD.: Honoraria; Eisai Co. Ltd.,: Honoraria; Kyowa Kirin Pharmaceutical Development, Inc.,: Honoraria; Chugai Pharmaceutical Co.LTD.,: Honoraria; Celgene Co. LTD.,: Honoraria. Dobashi:Celgene Co.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co. Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Sysmex Co.: Research Funding. Kuroda:Chugai Pharma: Honoraria, Research Funding. Takamatsu:Taisho Toyama Pharmaceutical: Research Funding; TAIHO Pharmaceutical: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Kyowa Hakko Kirin: Research Funding; Chugai Pharma: Research Funding; Takeda Pharmaceutical: Research Funding; Celgene: Honoraria. Maruyama:Ono Pharmaceutical: Honoraria, Research Funding; Fujifilm: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Asahi Kasei Pharma: Honoraria; AstraZeneca: Research Funding; Solasia Pharma: Research Funding; Pfizer: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Dai-Nippon-Sumitomo: Honoraria; Dai-ichi-Sankyo: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Biomedis International: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Novartis: Research Funding; Otsuka: Research Funding; Amgen Astellas BioPharma: Research Funding; Zenyaku Kogyo: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Mundipharma International: Honoraria, Research Funding. Ando:Eisai: Research Funding; Meiji Seika Pharma: Research Funding; Takeda Pharmaceutical: Research Funding; Kyowa Hakko Kirin: Research Funding; Japan Blood Products Organization: Research Funding. Ishizawa:Eisai: Honoraria; Janssen: Honoraria; Chugai: Honoraria; Celgene: Honoraria; Otsuka: Research Funding; Sanofi: Research Funding; Phizer: Research Funding. Ogura:Celltrion: Consultancy, Research Funding; Mundi Pharma: Consultancy; SymBio: Research Funding; Takeda: Honoraria; Cellgene: Honoraria; MeijiSeika Pharma: Consultancy. Hotta:SymBio: Consultancy; CellSeed Inc.: Membership on an entity's Board of Directors or advisory committees. Tsukasaki:Celgene: Honoraria; Eisai: Research Funding; Chugai Pharma: Honoraria, Research Funding; HUYA: Consultancy, Research Funding; Ono Pharma: Consultancy; Daiich-Sankyo: Consultancy; Mundy Pharma: Honoraria; Kyowa-hakko/Kirin: Honoraria; Seattle Genetics: Research Funding. Nagai:HUYA Bioscience International: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Gilead Sciences Inc.: Honoraria, Research Funding; Bayer Yakuhin Ltd.: Research Funding; Sanofi K. K.: Honoraria; Zenyaku Kogyo Co., Ltd.: Honoraria, Research Funding; Solasia Pharma K.K.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Roche Ltd.: Honoraria; Esai Co., Ltd.: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; SymBio Pharmaceuticals Limited: Research Funding; Janssen Pharmaceutical K.K.: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Research Funding; Mundipharma K.K.: Honoraria, Research Funding; AstraZeneca plc.: Research Funding; Abbvie G. K.: Research Funding.

Introduction The phase 3 ECHELON-2 study (NCT01777152) demonstrated that frontline treatment with brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) is superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for patients (pts) with systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL) (Horowitz S, et al. Lancet 2019). With a median follow-up of 36.2 months for progression-free survival (PFS), the hazard ratio (HR) (0.71 [95% confidence interval {CI}: 0.54, 0.93], P=0.01) favored A+CHP over CHOP. The median PFS was 48.2 months (95% CI: 35.2, not evaluable) versus 20.8 months (95% CI: 12.7, 47.6) for A+CHP and CHOP, respectively. With a median follow-up of 42.1 months for overall survival (OS), the HR (0.66 [95% CI: 0.46, 0.95], P=0.02) also favored A+CHP over CHOP. Median OS was not reached for either arm. With these results, A+CHP was the first treatment regimen to show an OS benefit over CHOP in this pt population. Herein, we report results with a median follow-up of 44.3 months for PFS and 55.5 months for OS. Methods ECHELON-2 is a phase 3, randomized, double-blind, double-dummy, placebo-controlled, active-comparator, multicenter study. Eligible adult pts with previously untreated CD30-positive PTCL (targeting 75% ± 5% with sALCL) were randomized to A+CHP or CHOP for six or eight cycles. Randomization was stratified by histological subtype and international prognostic index score. The primary endpoint of PFS was assessed per blinded independent central review in the primary analysis and per investigator in this updated analysis. Key secondary endpoints were OS, PFS in sALCL, complete remission (CR) rate, and objective response rate (ORR). Subsequent therapies, including BV or BV-containing regimens, were permitted. Results A total of 452 pts were enrolled and randomized 1:1 with 226 pts in each arm. The study included pts with advanced disease (Stage III [27%] and Stage IV [53%]; IPI ≥2 [78%]); given target enrollment, most pts (316 [70%]) had sALCL (218 [48%] anaplastic lymphoma kinase [ALK]-negative and 98 pts [22%] ALK-positive). With additional follow-up, the HRs for PFS per investigator (0.70 [95% CI: 0.53, 0.91], P=0.0075) (Figure 1) and OS (0.74 [95% CI: 0.54, 1.02], P=0.0688) continue to favor A+CHP over CHOP. The median PFS was 63.5 months (95% CI: 42.0, not evaluable) versus 23.8 months (95% CI: 13.6, 55.9) for A+CHP and CHOP, respectively. The estimated 5-year PFS was 50.9% (95% CI: 42.1, 59.1) for the A+CHP arm versus 42.7% (95% CI: 35.3, 49.8) for the CHOP arm. Median OS was not reached for either arm. The estimated 5-year OS was 68.7% (95% CI: 61.3, 75.0) for the A+CHP arm versus 60.3% (95% CI: 52.8, 67.0) for the CHOP arm. The PFS analyses for key prespecified subgroups were generally consistent with the overall study results (Figure 2). In the subset of pts with sALCL, the HR for PFS (0.55 [95% CI: 0.39, 0.78]) also favors A+CHP over CHOP, with an estimated 5-year PFS of 59.8% (95% CI: 48.0, 69.7) for the A+CHP arm versus 48.1% (95% CI: 39.1, 56.6) for the CHOP arm. A total of 23 pts (10%) in the A+CHP arm (16 pts with sALCL, 4 pts with PTCL not otherwise specified, and 3 pts with angioimmunoblastic T-cell lymphoma) and 51 pts (23%) in the CHOP arm received subsequent systemic therapy with BV. In the A+CHP arm, the median time to retreatment was 12.3 months (range, 3, 51); 15 pts (ORR: 65%) had CR (9 pts) or partial remission (6 pts) after retreatment with BV monotherapy (21 pts) or BV-containing regimen (2 pts). With additional follow-up in pts with treatment-emergent peripheral neuropathy (PN) (117 pts A+CHP and 124 pts CHOP), 68% of pts in the A+CHP arm had either resolution or improvement of these events compared with 77% of pts in the CHOP arm. Of the pts with ongoing PN events at last follow-up, 73% in A+CHP arm and 74% in the CHOP arm had grade 1 events, 25% and 23% of pts, respectively, had grade 2 events, and 2% of pts in each arm had grade 3 events. Conclusions At 5 years, frontline treatment with A+CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP, including ongoing remission in ~60% of pts with sALCL, with a manageable safety profile, including continued resolution or improvement of PN. Additional 5-year results, including data from prespecified subgroups, will be presented. Disclosures Horwitz: C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; Affirmed: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; ASTEX: Consultancy; Vividion Therapeutics: Consultancy; Beigene: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding. Pro:Verastem Oncology: Research Funding. Illidge:Takeda: Current Employment, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Iyer:Legend Biotech: Consultancy; Rhizen: Research Funding; Spectrum: Research Funding; CRISPR: Research Funding; Curio Biosciences: Honoraria; Trillium: Research Funding; Target Oncology: Honoraria; Afffimed: Research Funding; Daiichi Sankyo: Consultancy; Merck: Research Funding; Seattle Genetics, Inc.: Research Funding. Advani:Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy; Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding. Bartlett:BTG: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy; Forty Seven: Research Funding; Autolus: Research Funding; Acerta: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Affimed Therapeutics: Research Funding; BMS/Celgene: Research Funding; Roche/Genentech: Consultancy, Research Funding. Christensen:Odense University Hospital: Current Employment; Seattle Genetics, Inc.: Research Funding. Morschhauser:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy. Domingo-Domenech:Takeda: Consultancy, Other: Travel, accomodations and expenses , Research Funding; Bristol-Myers Squibb: Other: Travel, Research Funding; Roche: Other: Travel, accomodations and expenses ; Janssen: Other: Travel, accomodations and expenses ; Seattle Genetics, Inc.: Research Funding. Rossi:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Kim:Donga: Research Funding; Joihnson & Johnson: Research Funding; Kyowa Kirin: Research Funding; Mundipharma: Research Funding; Pfizer: Research Funding; Roche: Research Funding; Takeda: Research Funding; Celltrion: Research Funding. Feldman:Celgene: Honoraria, Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Rhizen: Research Funding; Janssen: Speakers Bureau; Pharmacyclics: Honoraria, Other, Speakers Bureau; AstraZeneca: Consultancy; Bayer: Consultancy, Honoraria; Abbvie: Honoraria; Takeda: Honoraria, Other: Travel expenses; Pfizer: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Trillium: Research Funding; Portola: Research Funding; Corvus: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Eisai: Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Viracta: Research Funding. Menne:Daiichi Sankyo: Honoraria; Kyowa Kirin: Other: Travel expenses; Pfizer: Honoraria, Other; Roche: Honoraria; Bayer: Other: Travel expenses; Kite/Gilead: Honoraria, Other: Travel expenses; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel expenses; Takeda: Honoraria; Atara: Honoraria; AstraZeneca: Research Funding; Amgen: Honoraria, Other: Travel expenses; Janssen: Honoraria, Research Funding. Belada:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene: Research Funding. Illés:Celgene, Janssen, Novartis,Roche, Takeda: Consultancy; Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria; Takeda, Seattle Genetics: Research Funding. Tobinai:Daiichi Sankyo: Consultancy, Honoraria; Kyowa Kirin: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria; Ono Pharma: Consultancy, Honoraria; Solasia: Honoraria; SymBio: Consultancy; Takeda: Consultancy, Honoraria; HUYA Bioscience: Consultancy, Honoraria; Eisai: Honoraria; Yakult: Consultancy, Honoraria; Zenyaku Kogyo: Consultancy, Honoraria; Chugai Pharma: Consultancy, Honoraria. Tsukasaki:Ono Pharma: Consultancy; Mundy Pharma: Honoraria; HUYA: Consultancy, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharma: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Eizai: Research Funding; Seattle Genetics: Research Funding. Yeh:AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees. Shustov:Seattle Genetics: Research Funding. Hüttmann:Lead Discovery Center GmbH: Consultancy; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Other: Travel expenses; Seattle Genetics: Research Funding; University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment. Savage:Verastem: Honoraria; Takeda: Honoraria; Servier: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria. Zinzani:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, 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; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Miao:Takeda: Current equity holder in publicly-traded company. Bunn:Seattle Genetics: Research Funding; Takeda: Current Employment. Fenton:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Fanale:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Puhlmann:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Truemper:Janssen: Consultancy; Mundipharma: Research Funding; Nordic Nanovector: Consultancy; Roche: Research Funding; Seattle Genetics: Research Funding; Takeda Europe: Consultancy, Research Funding.

The study of the interaction processes between polymer-based drilling fluids and clay rocks is essential. Careful selection of drilling fluid composition will allow you to avoid such complications during drilling as the bridge over, clogging of the bottom-hole zone with cuttings, reduction of the mechanical drilling speed, differential wall sticking, a fluid wash of the wellbore walls and core plugs, and drilling fluid losses. Various salts of alkali and alkaline earth metals are often used as clay swelling inhibitors, which can cause changes in the rheological properties of the drilling fluid on their addition at high concentrations. The paper presents the experimental results of determining the swelling value of the clay mineral illite in drilling fluids prepared on the basis of cationic (K-6729) and anionic (EZ-MUDDP) polymers with the addition of inorganic salts – potassium chloride, sodium chloride and sodium silicate. The rheology of the tested samples deteriorates when salts are added to polymer solutions. This fact is explained by the hydration of salts and water molecules binding to the hydration shells of electrolyte ions, as well as the destruction of hydrogen bonds in water's structure with an increase in its molecular mobility. The paper demonstrates that in a sodium silicate solution, the hydration and swelling of illite are significantly inhibited. Thus, the change in the linear dimensions of pressed clay powder tablets with different permeabilities in distilled water, potassium, and sodium chloride solutions amounted to 30%, while in sodium silicate solution it did not exceed 6.3%. However, compared to potassium and sodium chlorides, when sodium silicate as a clay inhibitor, then the rheological characteristics of the drilling fluid decrease less significantly.

Introduction The recent AOL/Time-Warner merger invites us to re-think the relationships amongst content producers, distributors, and audiences. Worth an estimated $300 billion (US), the largest Internet transaction of all time, the deal is 45 times larger than the AOL/Netscape merger of November 1998 (Ledbetter). Additionally, the Time Warner/EMI merger, which followed hard on the heels of the AOL/Time-Warner deal and is itself worth $28 billion (US), created the largest content rights organisation in the music industry. The joining of the Internet giant (AOL) with what was already the world's largest media corporation (Time-Warner-EMI) has inspired some exuberant reactions. An Infoworld column proclaimed: The AOL/Time-Warner merger signals the demise of traditional media companies and the ascendancy of 'new economy' media companies that will force any industry hesitant to adopt a complete electronic-commerce strategy to rethink and put itself on Internet time. (Saap & Schwarrtz) This comment identifies the distribution channel as the dominant component of the "new economy" media. But this might not really be much of an innovation. Indeed, the assumption of all industry observers is that Time-Warner will provide broadband distribution (through its extensive cable holdings) as well as proprietary content for AOL. It is also expected that Time-Warner will adopt AOL's strategy of seeking sponsorship for development projects as well as for content. However, both of these phenomena -- merger and sponsorship -- are at least as old as radio. It seems that the Internet is merely repeating an old industrial strategy. Nonetheless, one important difference distinguishes the Internet from earlier media: its characterisation of the audience. Internet companies such as AOL and Microsoft tend towards a simple and simplistic media- centred view of the audience as market. I will show, however, that as the Internet assumes more of the traditional mass media functions, it will be forced to adopt a more sophisticated notion of the mass audience. Indeed, the Internet is currently the site in which audience definitions borrowed from broadcasting are encountering and merging with definitions borrowed from marketing. The Internet apparently lends itself to both models. As a result, definitions of what the Internet does or is, and of how we should understand the audience, are suitably confused and opaque. And the behaviour of big Internet players, such as AOL and MSN, perfectly reflects this confusion as they seem to careen between a view of the Internet as the new television and a contrasting view of the Internet as the new shopping mall. Meanwhile, Internet users move in ways that most observers fail to capture. For example, Baran and Davis characterise mass communication as a process involving (1) an organized sender, (2) engaged in the distribution of messages, (3) directed toward a large audience. They argue that broadcasting fits this model whereas a LISTSERV does not because, even though the LISTSERV may have very many subscribers, its content is filtered through a single person or Webmaster. But why is the Webmaster suddenly more determining than a network programmer or magazine editor? The distinction seems to grow out of the Internet's technological characteristics: it is an interactive pipeline, therefore its use necessarily excludes the possibility of "broadcasting" which in turn causes us to reject "traditional" notions of the audience. However, if a media organisation were to establish an AOL discussion group in order to promote Warner TV shows, for example, would not the resulting communication suddenly fall under the definition as set out by Baran and Davis? It was precisely the confusion around such definitions that caused the CRTC (Canada's broadcasting and telecommunications regulator) to hold hearings in 1999 to determine what kind of medium the Internet is. Unlike traditional broadcasting, Internet communication does indeed include the possibility of interactivity and niche communities. In this sense, it is closer to narrowcasting than to broadcasting even while maintaining the possibility of broadcasting. Hence, the nature of the audience using the Internet quickly becomes muddy. While such muddiness might have led us to sharpen our definitions of the audience, it seems instead to have led many to focus on the medium itself. For example, Morris & Ogan define the Internet as a mass medium because it addresses a mass audience mediated through technology (Morris & Ogan 39). They divide producers and audiences on the Internet into four groups: One-to-one asynchronous communication (e-mail); Many-to-many asynchronous communication (Usenet and News Groups); One-to-one, one-to-few, and one-to-many synchronous communication (topic groups, construction of an object, role-playing games, IRC chats, chat rooms); Asynchronous communication (searches, many-to-one, one-to-one, one to- many, source-receiver relations (Morris & Ogan 42-3) Thus, some Internet communication qualifies as mass communication while some does not. However, the focus remains firmly anchored on either the sender or the medium because the receiver --the audience -- is apparently too slippery to define. When definitions do address the content distributed over the Net, they make a distinction between passive reception and interactive participation. As the World Wide Web makes pre-packaged content the norm, the Internet increasingly resembles a traditional mass medium. Timothy Roscoe argues that the main focus of the World Wide Web is not the production of content (and, hence, the fulfilment of the Internet's democratic potential) but rather the presentation of already produced material: "the dominant activity in relation to the Web is not producing your own content but surfing for content" (Rosco 680). He concludes that if the emphasis is on viewing material, the Internet will become a medium similar to television. Within media studies, several models of the audience compete for dominance in the "new media" economy. Denis McQuail recalls how historically, the electronic media furthered the view of the audience as a "public". The audience was an aggregate of common interests. With broadcasting, the electronic audience was delocalised and socially decomposed (McQuail, Mass 212). According to McQuail, it was not a great step to move from understanding the audience as a dispersed "public" to thinking about the audience as itself a market, both for products and as a commodity to be sold to advertisers. McQuail defines this conception of the audience as an "aggregate of potential customers with a known social- economic profile at which a medium or message is directed" (McQuail, Mass 221). Oddly though, in light of the emancipatory claims made for the Internet, this is precisely the dominant view of the audience in the "new media economy". Media Audience as Market How does the marketing model characterise the relationship between audience and producer? According to McQuail, the marketing model links sender and receiver in a cash transaction between producer and consumer rather than in a communicative relationship between equal interlocutors. Such a model ignores the relationships amongst consumers. Indeed, neither the effectiveness of the communication nor the quality of the communicative experience matters. This model, explicitly calculating and implicitly manipulative, is characteristically a "view from the media" (McQuail, Audience 9). Some scholars, when discussing new media, no longer even refer to audiences. They speak of users or consumers (Pavick & Dennis). The logic of the marketing model lies in the changing revenue base for media industries. Advertising-supported media revenues have been dropping since the early 1990s while user-supported media such as cable, satellite, online services, and pay-per-view, have been steadily growing (Pavlik & Dennis 19). In the Internet-based media landscape, the audience is a revenue stream and a source of consumer information. As Bill Gates says, it is all about "eyeballs". In keeping with this view, AOL hopes to attract consumers with its "one-stop shopping and billing". And Internet providers such as MSN do not even consider their subscribers as "audiences". Instead, they work from a consumer model derived from the computer software industry: individuals make purchases without the seller providing content or thematising the likely use of the software. The analogy extends well beyond the transactional moment. The common practice of prototyping products and beta-testing software requires the participation of potential customers in the product development cycle not as a potential audience sharing meanings but as recalcitrant individuals able to uncover bugs. Hence, media companies like MTV now use the Internet as a source of sophisticated demographic research. Recently, MTV Asia established a Website as a marketing tool to collect preferences and audience profiles (Slater 50). The MTV audience is now part of the product development cycle. Another method for getting information involves the "cookie" file that automatically provides a Website with information about the user who logs on to a site (Pavick & Dennis). Simultaneously, though, both Microsoft and AOL have consciously shifted from user-subscription revenues to advertising in an effort to make online services more like television (Gomery; Darlin). For example, AOL has long tried to produce content through its own studios to generate sufficiently heavy traffic on its Internet service in order to garner profitable advertising fees (Young). However, AOL and Microsoft have had little success in providing content (Krantz; Manes). In fact, faced with the AOL/Time-Warner merger, Microsoft declared that it was in the software rather than the content business (Trott). In short, they are caught between a broadcasting model and a consumer model and their behaviour is characteristically erratic. Similarly, media companies such as Time-Warner have failed to establish their own portals. Indeed, Time-Warner even abandoned attempts to create large Websites to compete with other Internet services when it shut down its Pathfinder site (Egan). Instead it refocussed its Websites so as to blur the line between pitching products and covering them (Reid; Lyons). Since one strategy for gaining large audiences is the creation of portals - - large Websites that keep surfers within the confines of a single company's site by providing content -- this is the logic behind the AOL/Time-Warner merger though both companies have clearly been unsuccessful at precisely such attempts. AOL seems to hope that Time- Warner will act as its content specialist, providing the type of compelling material that will make users want to use AOL, whereas Time- Warner seems to hope that AOL will become its privileged pipeline to the hearts and minds of untold millions. Neither has a coherent view of the audience, how it behaves, or should behave. Consequently, their efforts have a distinctly "unmanaged" and slighly inexplicable air to them, as though everyone were simultaneously hopeful and clueless. While one might argue that the stage is set to capitalise on the audience as commodity, there are indications that the success of such an approach is far from guaranteed. First, the AOL/Time-Warner/EMI transaction, merely by existing, has sparked conflicts over proprietary rights. For example, the Recording Industry Association of America, representing Sony, Universal, BMG, Warner and EMI, recently launched a $6.8 billion lawsuit against MP3.com -- an AOL subsidiary -- for alleged copyright violations. Specifically, MP3.com is being sued for selling digitized music over the Internet without paying royalties to the record companies (Anderson). A similar lawsuit has recently been launched over the issue of re- broadcasting television programs over the Internet. The major US networks have joined together against Canadian Internet company iCravetv for the unlawful distribution of content. Both the iCravetv and the MP3.com cases show how dominant media players can marshal their forces to protect proprietary rights in both content and distribution. Since software and media industries have failed to recreate the Internet in the image of traditional broadcasting, the merger of the dominant players in each industry makes sense. However, their simultaneous failure to secure proprietary rights reflects both the competitive nature of the "new media economy" and the weakness of the marketing view of the audience. Media Audience as Public It is often said that communication produces social cohesion. From such cohesion communities emerge on which political or social orders can be constructed. The power of social cohesion and attachment to group symbols can even create a sense of belonging to a "people" or nation (Deutsch). Sociologist Daniel Bell described how the mass media helped create an American culture simply by addressing a large enough audience. He suggested that on the evening of 7 March 1955, when one out of every two Americans could see Mary Martin as Peter Pan on television, a kind of social revolution occurred and a new American public was born. "It was the first time in history that a single individual was seen and heard at the same time by such a broad public" (Bell, quoted in Mattelart 72). One could easily substitute the 1953 World Series or the birth of little Ricky on I Love Lucy. The desire to document such a process recurs with the Internet. Internet communities are based on the assumption that a common experience "creates" group cohesion (Rheingold; Jones). However, as a mass medium, the Internet has yet to find its originary moment, that event to which all could credibly point as the birth of something genuine and meaningful. A recent contender was the appearance of Paul McCartney at the refurbished Cavern Club in Liverpool. On Tuesday, 14 December 1999, McCartney played to a packed club of 300 fans, while another 150,000 watched on an outdoor screen nearby. MSN arranged to broadcast the concert live over the Internet. It advertised an anticipated global audience of 500 million. Unfortunately, there was such heavy Internet traffic that the system was unable to accommodate more than 3 million people. Servers in the United Kingdom were so congested that many could only watch the choppy video stream via an American link. The concert raises a number of questions about "virtual" events. We can draw several conclusions about measuring Internet audiences. While 3 million is a sizeable audience for a 20 minute transmission, by advertising a potential audience of 500 million, MSN showed remarkably poor judgment of its inherent appeal. The Internet is the first medium that allows access to unprocessed material or information about events to be delivered to an audience with neither the time constraints of broadcast media nor the space limitations of the traditional press. This is often cited as one of the characteristics that sets the Internet apart from other media. This feeds the idea of the Internet audience as a participatory, democratic public. For example, it is often claimed that the Internet can foster democratic participation by providing voters with uninterpreted information about candidates and issues (Selnow). However, as James Curran argues, the very process of distributing uninterrupted, unfiltered information, at least in the case of traditional mass media, represents an abdication of a central democratic function -- that of watchdog to power (Curran). In the end, publics are created and maintained through active and continuous participation on the part of communicators and audiences. The Internet holds together potentially conflicting communicative relationships within the same technological medium (Merrill & Ogan). Viewing the audience as co-participant in a communicative relationship makes more sense than simply focussing on the Internet audience as either an aggregate of consumers or a passively constructed symbolic public. Audience as Relationship Many scholars have shifted attention from the producer to the audience as an active participant in the communication process (Ang; McQuail, Audience). Virginia Nightingale goes further to describe the audience as part of a communicative relationship. Nightingale identifies four factors in the relationship between audiences and producers that emphasize their co-dependency. The audience and producer are engaged in a symbiotic relationship in which consumption and use are necessary but not sufficient explanations of audience relations. The notion of the audience invokes, at least potentially, a greater range of activities than simply use or consumption. Further, the audience actively, if not always consciously, enters relationships with content producers and the institutions that govern the creation, distribution and exhibition of content (Nightingale 149-50). Others have demonstrated how this relationship between audiences and producers is no longer the one-sided affair characterised by the marketing model or the model of the audience as public. A global culture is emerging based on critical viewing skills. Kavoori calls this a reflexive mode born of an increasing familiarity with the narrative conventions of news and an awareness of the institutional imperatives of media industries (Kavoori). Given the sophistication of the emergent global audience, a theory that reduces new media audiences to a set of consumer preferences or behaviours will inevitably prove inadequate, just as it has for understanding audience behavior in old media. Similarly, by ignoring those elements of audience behavior that will be easily transported to the Web, we run the risk of idealising the Internet as a medium that will create an illusory, pre-technological public. Conclusion There is an understandable confusion between the two models of the audience that appear in the examples above. The "new economy" will have to come to terms with sophisticated audiences. Contrary to IBM's claim that they want to "get to know all about you", Internet users do not seem particularly interested in becoming a perpetual source of market information. The fragmented, autonomous audience resists attempts to lock it into proprietary relationships. Internet hypesters talk about creating publics and argue that the Internet recreates the intimacy of community as a corrective to the atomisation and alienation characteristic of mass society. This faith in the power of a medium to create social cohesion recalls the view of the television audience as a public constructed by the common experience of watching an important event. However, MSN's McCartney concert indicates that creating a public from spectacle it is not a simple process. In fact, what the Internet media conglomerates seem to want more than anything is to create consumer bases. Audiences exist for pleasure and by the desire to be entertained. As Internet media institutions are established, the cynical view of the audience as a source of consumer behavior and preferences will inevitably give way, to some extent, to a view of the audience as participant in communication. Audiences will be seen, as they have been by other media, as groups whose attention must be courted and rewarded. Who knows, maybe the AOL/Time-Warner merger might, indeed, signal the new medium's coming of age. References Anderson, Lessley. "To Beam or Not to Beam. MP3.com Is Being Sued by the Major Record Labels. Does the Digital Download Site Stand a Chance?" Industry Standard 31 Jan. 2000. <http://www.thestandard.com>. Ang, Ien. Watching Dallas: Soap Opera and the Melodramatic Imagination. London: Methuen, 1985. Baran, Stanley, and Dennis Davis. Mass Communication Theory: Foundations, Ferment, and Future. 2nd ed. Belmont, Calif.: Wadsworth 2000. Curran, James. "Mass Media and Democracy Revisited." Mass Media and Society. Eds. James Curran and Michael Gurevitch. New York: Hodder Headline Group, 1996. Darlin, Damon. "He Wants Your Eyeballs." Forbes 159 (16 June 1997): 114-6. Egan, Jack, "Pathfinder, Rest in Peace: Time-Warner Pulls the Plug on Site." US News and World Report 126.18 (10 May 1999): 50. Gomery, Douglas. "Making the Web Look like Television (American Online and Microsoft)." American Journalism Review 19 (March 1997): 46. Jones, Steve, ed. CyberSociety: Computer-Mediated Communication and Community. Thousand Oaks: Sage, 1995. Kavoori, Amandam P. "Discursive Texts, Reflexive Audiences: Global Trends in Television News Texts and Audience Reception." Journal of Broadcasting and Electronic Media 43.3 (Summer 1999): 386-98. Krantz, Michael. "Is MSN on the Block?" Time 150 (20 Oct. 1997): 82. Ledbetter, James. "AOL-Time-Warner Make It Big." Industry Standard 11 Jan. 2000. <http://www.thestandard.com>. Lyons, Daniel. "Desparate.com (Media Companies Losing Millions on the Web Turn to Electronic Commerce)." Forbes 163.6 (22 March 1999): 50-1. Manes, Stephen. "The New MSN as Prehistoric TV." New York Times 4 Feb. 1997: C6. McQuail, Denis. Audience Analysis. Thousand Oaks, Calif.: Sage, 1997. ---. Mass Communication Theory. 2nd ed. London: Sage, 1987. Mattelart, Armand. Mapping World Communication: War, Progress, Culture. Trans. Susan Emanuel and James A. Cohen. Minneapolis: U of Minnesota P, 1994. Morris, Merrill, and Christine Ogan. "The Internet as Mass Medium." Journal of Communications 46 (Winter 1996): 39-50. Nightingale, Virginia. Studying Audience: The Shock of the Real. London: Routledge, 1996. Pavlik, John V., and Everette E. Dennis. New Media Technology: Cultural and Commercial Perspectives. 2nd ed. Boston: Allyn and Bacon, 1998. Reid, Calvin. "Time-Warner Seeks Electronic Synergy, Profits on the Web (Pathfinder Site)." Publisher's Weekly 242 (4 Dec. 1995): 12. Rheingold, Howard. Virtual Community: Homesteading on the Electronic Frontier. New York: Harper, 1993. Roscoe, Timothy. "The Construction of the World Wide Web Audience." Media, Culture and Society 21.5 (1999): 673-84. Saap, Geneva, and Ephraim Schwarrtz. "AOL-Time-Warner Deal to Impact Commerce, Content, and Access Markets." Infoworld 11 January 2000. <http://infoworld.com/articles/ic/xml/00/01/11/000111icimpact.xml>. Slater, Joanna. "Cool Customers: Music Channels Hope New Web Sites Tap into Teen Spirit." Far Eastern Economic Review 162.9 (4 March 1999): 50. Trott, Bob. "Microsoft Views AOL-Time-Warner as Confirmation of Its Own Strategy." Infoworld 11 Jan. 2000. <http://infoworld.com/articles/pi/xml/00/01/11/000111pimsaoltw.xml>. Yan, Catherine. "A Major Studio Called AOL?" Business Week 1 Dec. 1997: 1773-4. Citation reference for this article MLA style: Daniel M. Downes. "The Medium Vanishes? The Resurrection of the Mass Audience in the New Media Economy." M/C: A Journal of Media and Culture 3.1 (2000). [your date of access] <http://www.uq.edu.au/mc/0003/mass.php>. Chicago style: Daniel M. Downes, "The Medium Vanishes? The Resurrection of the Mass Audience in the New Media Economy," M/C: A Journal of Media and Culture 3, no. 1 (2000), <http://www.uq.edu.au/mc/0003/mass.php> ([your date of access]). APA style: Daniel M. Downes. (2000) The Medium Vanishes? The Resurrection of the Mass Audience in the New Media Economy. M/C: A Journal of Media and Culture 3(1). <http://www.uq.edu.au/mc/0003/mass.php> ([your date of access]).

‘Historiographic Metafiction’ (HM) is a literary term first coined by creative writing academic Linda Hutcheon in 1988, and which refers to the postmodern practice of a fiction author inserting imagined--or illegitimate--characters into narratives that are intended to be received as authentic and historically accurate, that is, ostensibly legitimate. Such adventurous and bold authorial strategies frequently result in “novels which are both intensely self-reflexive and yet paradoxically also lay claim to historical events and personages” (Hutcheon, A Poetics 5). They can be so entertaining and engaging that the overtly intertextual, explicitly inventive work of biographical HM can even change the “hegemonic discourse of history” (Nunning 353) for, as Philippa Gregory, the author of HM novel The Other Boleyn Girl (2001), has said regarding this genre of creative writing: “Fiction is about imagined feelings and thoughts. History depends on the outer life. The novel is always about the inner life. Fiction can sometimes do more than history. It can fill the gaps” (University of Sussex). In a way, this article will be filling one of the gaps regarding HM.Forrest Gump (Robert Zemeckis, 1994) is possibly the best known cinematic example of HM, and this film version of the 1986 novel by Winston Groom particularly excels in seamlessly inserting images of a fictional character into verified history, as represented by well-known television newsreel footage. In Zemeckis’s adaptation, gaps were created in the celluloid artefact and filled digitally with images of the actor, Tom Hanks, playing the eponymous role. Words are often deemed less trustworthy than images, however, and fiction is considered particularly unreliable--although there are some exceptions conceded. In addition to Gregory’s novel; Midnight’s Children (1980) by Salman Rushdie; The Name of the Rose (1983) by Umberto Eco; and The Flashman Papers (1969-2005) by George MacDonald Fraser, are three well-known, loved and lauded examples of literary HM, which even if they fail to convince the reader of their bona fides, nevertheless win a place in many hearts. But despite the genre’s popularity, there is nevertheless a conceptual gap in the literary theory of Hutcheon given her (perfectly understandable) inability in 1988 to predict the future of e-publishing. This article will attempt to address that shortcoming by exploring the potential for authors of HM e-novels to use hyperlinks which immediately direct the reader to fact providing webpages such as those available at the website Wikipedia, like a much speedier (and more independent) version of the footnotes in Fraser’s Flashman novels.Of course, as Roland Barthes declared in 1977, “the text is a tissue of quotations drawn from innumerable centres of culture” (146) and, as per any academic work that attempts to contribute to knowledge, a text’s sources--its “quotations”--must be properly identified and acknowledged via checkable references if credibility is to be securely established. Hence, in explaining the way claims to fact in the HM novel can be confirmed by independently published experts on the Internet, this article will also address the problem Hutcheon identifies, in that for many readers the entirety of the HM novel assumes questionable authenticity, that is, the novel’s “meta-fictional self-reflexivity (and intertextuality) renders their claims to historical veracity somewhat problematic, to say the least” ("Historiographic Metafiction: Parody", 3). This article (and the PhD in creative writing I am presently working on at Murdoch University in Perth, Western Australia) will possibly develop the concept of HM to a new level: one at which the Internet-connected reader of the hyperlinked e-novel is made fully (and even instantly) aware of those literary elements of the narrative that are legitimate and factual as distinct from those that are fictional, that is, illegitimate. Furthermore, utilising examples from my own (yet-to-be published) hyperlinked HM e-novel, this article demonstrates that such hyperlinking can add an ironic sub-text to a fictional character’s thoughts and utterances, through highlighting the reality concerning their mistaken or naïve beliefs, thus creating HM narratives that serve an entertainingly complex yet nevertheless truly educational purpose.As a relatively new and under-researched genre of historical writing, HM differs dramatically from the better known style of standard historical or biographical narrative, which typically tends to emphasise mimesis, the cataloguing of major “players” in historical events and encyclopaedic accuracy of dates, deaths and places. Instead, HM involves the re-contextualisation of real-life figures from the past, incorporating the lives of entirely (or, as in the case of Gregory’s Mary Boleyn, at least partly) fictitious characters into their generally accepted famous and factual activities, and/or the invention of scenarios that gel realistically--but entertainingly--within a landscape of well-known and well-documented events. As Hutcheon herself states: “The formal linking of history and fiction through the common denominators of intertextuality and narrativity is usually offered not as a reduction, as a shrinking of the scope and value of fiction, but rather as an expansion of these” ("Intertextuality", 11). Similarly, Gregory emphasises the need for authors of HM to extend themselves beyond the encyclopaedic archive: “Archives are not history. The trouble with archives is that the material is often random and atypical. To have history, you have to have a narrative” (University of Sussex). Functionally then, HM is an intertextual narrative genre which serves to communicate to a contemporary audience an expanded story or stories of the past which present an ultimately more self-reflective, personal and unpredictable authorship: it is a distinctly auteurial mode of biographical history writing for it places the postmodern author’s imaginative “signature” front and foremost.Hutcheon later clarified that the quest for historical truth in fiction cannot possibly hold up to the persuasive powers of a master novelist, as per the following rationale: “Fact is discourse-defined: an event is not” ("Historiographic Metafiction", 843). This means, in a rather simplistic nutshell, that the new breed of HM novel writer is not constrained by what others may call fact: s/he knows that the alleged “fact” can be renegotiated and redefined by an inventive discourse. An event, on the other hand, is responsible for too many incontrovertible consequences for it to be contested by her/his mere discourse. So-called facts are much easier for the HM writer to play with than world changing events. This notion was further popularised by Ansgar Nunning when he claimed the overtly explicit work of HM can even change the “hegemonic discourse of history” (353). HM authors can radically alter, it seems, the way the reader perceives the facts of history especially when entertaining, engaging and believable characters are deliberately devised and manipulated into the narrative by the writer. Little wonder, then, that Hutcheon bemoans the unfortunate reality that for many readers the entirety of a HM work assumes questionable “veracity” due to its author’s insertion of imaginary and therefore illegitimate personages.But there is an advantage to be found in this, the digital era, and that is the Internet’s hyperlink. In our ubiquitously networked electronic information age, novels written for publication as e-books may, I propose, include clickable links on the names of actual people and events to Wikipedia entries or the like, thus strengthening the reception of the work as being based on real history (the occasional unreliability of Wikipedia notwithstanding). If picked up for hard copy publication this function of the HM e-novel can be replicated with the inclusion of icons in the printed margins that can be scanned by smartphones or similar gadgets. This small but significant element of the production reinforces the e-novel’s potential status as a new form of HM and addresses Hutcheon’s concern that for HM novels, their imaginative but illegitimate invention of characters “renders their claims to historical veracity somewhat problematic, to say the least” ("Historiographic Metafiction: Parody", 3).Some historic scenarios are so little researched or so misunderstood and discoloured by the muddy waters of time and/or rumour that such hyperlinking will be a boon to HM writers. Where an obscure facet of Australian history is being fictionalised, for example, these edifying hyperlinks can provide additional background information, as Glenda Banks and Martin Andrew might have wished for when they wrote regarding Bank’s Victorian goldfields based HM novel A Respectable Married Woman. This 2012 printed work explores the lives of several under-researched and under-represented minorities, such as settler women and Aboriginal Australians, and the author Banks lamented the dearth of public awareness regarding these peoples. Indeed, HM seems tailor-made for exposing the subaltern lives of those repressed individuals who form the human “backdrop” to the lives of more famous personages. Banks and Andrew explain:To echo the writings of Homi K. Bhaba (1990), this sets up a creative site for interrogating the dominant, hegemonic, ‘normalised’ master narratives about the Victorian goldfields and ‘re-membering’ a marginalised group - the women of the goldfields, the indigenous [sic], the Chinese - and their culture (2013).In my own hyperlinked short story (presently under consideration for publishing elsewhere), which is actually a standalone version of the first chapter of a full-length HM e-novel about Aboriginal Australian activists Eddie Mabo and Chicka Dixon and the history of the Aboriginal Tent Embassy in Canberra, entitled The Bullroarers, I have focussed on a similarly under-represented minority, that being light-complexioned, mixed race Aboriginal Australians. My second novel to deal with Indigenous Australian issues (see Starrs, That Blackfella Bloodsucka Dance), it is my first attempt at writing HM. Hopefully avoiding overkill whilst alerting readers to those Wikipedia pages with relevance to the narrative theme of non-Indigenous attitudes towards light-complexioned Indigenous Australians, I have inserted a total of only six hyperlinks in this 2200-word piece, plus the explanatory foreword stating: “Note, except where they are well-known place names or are indicated as factual by the insertion of Internet hyperlinks verifying such, all persons, organisations, businesses and places named in this text are entirely fictitious.”The hyperlinks in my short story all take the reader not to stubs but to well-established Wikipedia pages, and provide for the uninformed audience the following near-unassailable facts (i.e. events):The TV program, A Current Affair, which the racist character of the short story taken from The Bullroarers, Mrs Poulter, relies on for her prejudicial opinions linking Aborigines with the dealing of illegal drugs, is a long-running, prime-time Channel Nine production. Of particular relevance in the Wikipedia entry is the comment: “Like its main rival broadcast on the Seven Network, Today Tonight, A Current Affair is often considered by media critics and the public at large to use sensationalist journalism” (Wikipedia, “A Current Affair”).The Aboriginal Tent Embassy, located on the lawns opposite the Old Parliament House in Canberra, was established in 1972 and ever since has been the focus of Aboriginal Australian land rights activism and political agitation. In 1995 the Australian Register of the National Estate listed it as the only Aboriginal site in Australia that is recognised nationally for representing Aboriginal and Torres Strait Islander people and their political struggles (Wikipedia, “The Aboriginal Tent Embassy”).In 1992, during an Aboriginal land rights case known as Mabo, the High Court of Australia issued a judgment constituting a direct overturning of terra nullius, which is a Latin term meaning “land belonging to no one”, and which had previously formed the legal rationale and justification for the British invasion and colonisation of Aboriginal Australia (Wikipedia, “Terra Nullius”).Aboriginal rights activist and Torres Strait Islander, Eddie Koiki Mabo (1936 to 1992), was instrumental in the High Court decision to overturn the doctrine of terra nullius in 1992. In that same year, Eddie Mabo was posthumously awarded the Australian Human Rights Medal in the Human Rights and Equal Opportunity Commission Awards (Wikipedia, “Eddie Mabo”).The full name of what Mrs Poulter blithely refers to as “the Department of Families and that” is the Australian Government’s Department of Families, Housing, Community Services and Indigenous Affairs (Wikipedia, “The Department of Families, Housing, Community Services and Indigenous Affairs”).The British colonisation of Australia was a bloody, murderous affair: “continuous Aboriginal resistance for well over a century belies the ‘myth’ of peaceful settlement in Australia. Settlers in turn often reacted to Aboriginal resistance with great violence, resulting in numerous indiscriminate massacres by whites of Aboriginal men, women and children” (Wikipedia, “History of Australia (1788 - 1850)”).Basically, what is not evidenced empirically with regard to the subject matter of my text, that is, the egregious attitudes of non-Indigenous Australians towards Indigenous Australians, can be extrapolated thanks to the hyperlinks. This resonates strongly with Linda Tuhiwai Smith’s assertion in 2012 that those under-represented by mainstream, patriarchal epistemologies need to be engaged in acts of “reclaiming, reformulating and reconstituting” (143) so as to be re-presented as authentic identities in these HM artefacts of literary research.Exerting auteurial power as an Aboriginal Australian author myself, I have sought to imprint on my writing a multi-levelled signature pertaining to my people’s under-representation: there is not just the text I have created but another level to be considered by the reader, that being my careful choice of Wikipedia pages to hyperlink certain aspects of the creative writing to. These electronic footnotes serve as politically charged acts of “reclaiming, reformulating and reconstituting” Aboriginal Australian history, to reuse the words of Smith, for when we Aboriginal Australian authors reiterate, when we subjugated savages wrestle the keyboard away from the colonising overseers, our readers witness the Other writing back, critically. As I have stated previously (see Starrs, "Writing"), receivers of our words see the distorted and silencing master discourse subverted and, indeed, inverted. Our audiences are subjectively repositioned to see the British Crown as the monster. The previously presumed rational, enlightened and civil coloniser is instead depicted as the author and perpetrator of a violently racist, criminal discourse, until, eventually, s/he is ultimately eroded and made into the Other: s/he is rendered the villainous, predatory savage by the auteurial signatures in revisionist histories such as The Bullroarers.Whilst the benefit in these hyperlinks as electronic educational footnotes in my short story is fairly obvious, what may not be so obvious is the ironic commentary they can make, when read in conjunction with the rest of The Bullroarers. Although one must reluctantly agree with Wayne C. Booth’s comment in his classic 1974 study A Rhetoric of Irony that, in some regards, “the very spirit and value [of irony] are violated by the effort to be clear about it” (ix), I will nevertheless strive for clarity and understanding by utilizing Booth’s definition of irony “as something that under-mines clarities, opens up vistas of chaos, and either liberates by destroying all dogmas or destroys by revealing the inescapable canker of negation at the heart of every affirmation” (ix). The reader of The Bullroarers is not expecting the main character, Mrs Poulter, to be the subject of erosive criticism that destroys her “dogmas” about Aboriginal Australians--certainly not so early in the narrative when it is unclear if she is or is not the protagonist of the story--and yet that’s exactly what the hyperlinks do. They expose her as hopelessly unreliable, laughably misinformed and yes, unforgivably stupid. They reveal the illegitimacy of her beliefs. Perhaps the most personally excoriating of these revelations is provided by the link to the Wikipedia entry on the Australian Government’s Department of Families, Housing, Community Services and Indigenous Affairs, which is where her own daughter, Roxy, works, but which Mrs Poulter knows, gormlessly, as “the Department of Families and that”. The ignorant woman spouts racist diatribes against Aboriginal Australians without even realising how inextricably linked she and her family, who live at the deliberately named Boomerang Crescent, really are. Therein lies the irony I am trying to create with my use of hyperlinks: an independent, expert adjudication reveals my character, Mrs Poulter, and her opinions, are hiding an “inescapable canker of negation at the heart of every affirmation” (Booth ix), despite the air of easy confidence she projects.Is the novel-reading public ready for these HM hyperlinked e-novels and their potentially ironic sub-texts? Indeed, the question must be asked: can the e-book ever compete with the tactile sensations a finely crafted, perfectly bound hardcover publication provides? Perhaps, if the economics of book buying comes into consideration. E-novels are cheap to publish and cheap to purchase, hence they are becoming hugely popular with the book buying public. Writes Mark Coker, the founder of Smashwords, a successful online publisher and distributor of e-books: “We incorporated in 2007, and we officially launched the business in May 2008. In our first year, we published 140 books from 90 authors. Our catalog reached 6,000 books in 2009, 28,800 in 2010, 92,000 in 2011, 191,000 in 2012 and as of this writing (November 2013) stands at over 250,000 titles” (Coker 2013). Coker divulged more about his company’s success in an interview with Forbes online magazine: “‘It costs essentially the same to pump 10,000 new books a month through our network as it will cost to do 100,000 a month,’ he reasons. Smashwords book retails, on average, for just above $3; 15,000 titles are free” (Colao 2012).In such a burgeoning environment of technological progress in publishing I am tempted to say that yes, the time of the hyperlinked e-novel has come, and to even predict that HM will be a big part of this new wave of postmodern literature. The hyperlinked HM e-novel’s strategy invites the reader to reflect on the legitimacy and illegitimacy of different forms of narrative, possibly concluding, thanks to ironic electronic footnoting, that not all the novel’s characters and their commentary are to be trusted. Perhaps my HM e-novel will, with its untrustworthy Mrs Poulter and its little-known history of the Aboriginal Tent Embassy addressed by gap-filling hyperlinks, establish a legitimising narrative for a people who have traditionally in white Australian society been deemed the Other and illegitimate. Perhaps The Bullroarers will someday alter attitudes of non-Indigenous Australians to the history and political activities of this country’s first peoples, to the point even, that as Nunning warns, we witness a change in the “hegemonic discourse of history” (353). If that happens we must be thankful for our Internet-enabled information age and its concomitant possibilities for hyperlinked e-publications, for technology may be separated from the world of art, but it can nevertheless be effectively used to recreate, enhance and access that world, to the extent texts previously considered illegitimate achieve authenticity and veracity.ReferencesBanks, Glenda. A Respectable Married Woman. Melbourne: Lacuna, 2012.Banks, Glenda, and Martin Andrew. “Populating a Historical Novel: A Case Study of a Practice-led Research Approach to Historiographic Metafiction.” Bukker Tillibul 7 (2013). 19 Sep. 2014 ‹http://bukkertillibul.net/Text.html?VOL=7&INDEX=2›.Barthes, Roland. Image, Music, Text. Trans. Stephen Heath. London: Fontana Press, 1977.Booth, Wayne C. A Rhetoric of Irony. Chicago: U of Chicago P, 1974.Colao, J.J. “Apple’s Biggest (Unknown) Supplier of E-books.” Forbes 7 June 2012. 19 Sep. 2014 ‹http://www.forbes.com/sites/jjcolao/2012/06/07/apples-biggest-unknown-supplier-of-e-books/›.Coker, Mark. “Q & A with Smashwords Founder, Mark Coker.” About Smashwords 2013. 19 Sep. 2014 ‹https://www.smashwords.com/about›.Eco, Umberto. The Name of the Rose. Trans. William Weaver, San Diego: Harcourt, 1983.Forrest Gump. Dir. Robert Zemeckis. Paramount Pictures, 1994.Fraser, George MacDonald. The Flashman Papers. Various publishers, 1969-2005.Groom, Winston. Forrest Gump. NY: Doubleday, 1986.Gregory, Philippa. The Other Boleyn Girl. UK: Scribner, 2001.Hutcheon, Linda. A Poetics of Postmodernism: History, Theory, Fiction, 2nd ed. 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