Journal articles on the topic 'Restaint of trade'

Cuando a un centroamericano se le menciona el nombre de Guatemala, una de las primeras cosas que le vienen a la mente es su carácter indígena. Este dato no ha de sorprender, pues de cada cinco indígenas de la región, cuatro son guatemaltecos. Y mientras en los demás países, su proporción oscila entre el 1% y el 15%, los indígenas representan aproximadamente la mitad de la población de Guatemala. Ello convierte a este país en el más indígena no sólo del istmo centroamericano, sino de toda América, junto con Bolivia. El 99% de estos indígenas son mayas, mientras que el 1% restante lo integran xincas y garífunas.

This paper explores the relationship between free trade and the rate of economic growth. It is argued that freeing trade has both a level effect and a growth effect. Most empirical studies ignore the growth effect and, therefore, considerably understate the beneficial effects of freeing trade. Progress towards free trade in the GATT/WTO era is far from complete. Regionalism has had a limited effect on freeing trade globally. The completion of the Doha Development Round is needed to restart trade as the engine of growth.

The COVID-19 pandemic has started to subside across the world. However, many developing countries including Malaysia are finding it challenging to restart their economies due to the large damage to all sectors of the economy. The governments in these developing countries are contemplating different methods to revive their economies and resume normal economic activities. In this regard, Islamic personal financing (IPF) instruments may play a crucial role in rejuvenating economic activities. The main purpose of this study is to investigate the potential of IPF to restart economic activities in Malaysia after the COVID-19 pandemic. First, this study analyzes the impact of the pandemic on different economic indicators such as economic growth, gross domestic product (GDP), trade, employment, and investments. Second, this research proposed three IPF tools namely Service Ijarah, Murabahah/Service Ijarah Line-of-Credit with Wakalah, and Murabahah/Service Ijarah Credit Card to restart the economy by fulfilling the financing needs of individuals, businesses, and industries. This study contributes to offering a policy roadmap for governments considering different options to restart their economies in a sustainable way after the Covid-19 pandemic.

This study focuses on tracing the early economic impacts of COVID-19. The pandemic has unleashed a global shock impacting all economies in several ways. The lockdowns have brought economic activity to a standstill, with the closure of businesses and halting of travel, trade and commerce. Even as the impact on sensitive sectors as trade, tourism and remittances are already becoming visible, it is imperative to understand how these are impacting economies in Asia. This article studies these impacts on Thailand and Sri Lanka, both of which being wired to the globalised world, are witnessing adverse impacts on earnings through exports and tourism as well as a huge decline in inward remittances. Even as countries beef up their health infrastructure, they also seek to restart international travel and trade. Hence, the role of the state is critical to pull the economies out of the de-globalisation trends that are expected to gain pace in and beyond 2020.

Using a sample of earnings restatements, we provide evidence that an empirical measure of the comparability in two firms’ earnings (“earnings comparability”) captures the extent to which a firm’s accounting choices and estimates are similar to those of its restating peer firm. We then document that investors appear to underreact to the implications of this earnings comparability signal. Additional analyses reveal that large traders and short sellers react in a timely manner, and their trades trigger an immediate negative price reaction to earnings comparability. Small traders appear to behave inattentively, and their herding-driven delayed trades contribute to a negative drift in prices.

Introduction Both venous thromboembolism (VTE) and intracranial hemorrhage (ICH) are common potentially life-threatening complications of primary and metastatic brain tumors. Despite emerging evidence regarding the safety of anticoagulation in patients with brain tumors, there is little evidence on appropriate management of VTE following an ICH. Potential management options after an ICH in patients with brain tumors include resumption of full or modified dose anticoagulation or cessation of anticoagulant therapy with or without placement of an inferior vena cava (IVC) filter. We evaluated rates of recurrent VTE and ICH following an initial ICH occurring on anticoagulant therapy. Methods A retrospective cohort study was performed using a hospital-based online medical record database (CQ2) which links ICD-9 and ICD-10 codes with prescription medication records. Cases were identified based on coding for primary brain tumors or brain metastases, after which charts were manually reviewed for a diagnosis of ICH. A blinded review of radiographic imaging was performed, and the initial ICH was categorized as either trace, measurable, or major. Measurable intracranial hemorrhages were those defined as greater than 1 mL in volume and major intracranial hemorrhages were defined as greater than 10 mL in volume, symptomatic, or requiring surgical intervention. The electronic medical record was reviewed to ascertain longitudinal anticoagulation status after the initial ICH. The primary endpoints of the study were recurrent ICH and venous thromboembolism (VTE) within 12 months from the initial ICH. Gray's test was used to compare the cumulative incidence of recurrent ICH and VTE between the groups, with death as a competing risk. Results A total of 79 patients with primary brain tumors or brain metastases and confirmed ICH were included in the study. Fifty-four patients (68.4%) restarted anticoagulation after ICH and 25 patients discontinued anticoagulation entirely. The cohorts were well-matched for tumor diagnosis, age, and comorbidities that portend an increased risk of ICH such as hypertension, chronic kidney disease, and concomitant aspirin use (Table 1). The cumulative incidence of recurrent ICH (95% CI) at one year was 6.1% (1.5 - 15.3) in the restart cohort compared to 4.2% (0.3 - 18.3) in patients who did not restart anticoagulation. Median time from anticoagulation restart to recurrent ICH was 36 days. A total of 16 of 31 patients with major ICH restarted anticoagulation and among these patients two developed subsequent ICH (cumulative incidence 14.5%, 95% CI 2.1 - 38.3). Among the 15 patients with a major ICH who did not restart anticoagulation, the cumulative incidence was 6.7% (0.3 - 27.5). Eleven of 15 patients with measurable ICH restarted anticoagulation and among these patients one subsequently developed ICH (cumulative incidence 0.1%, 95% CI 0.0 - 0.3). No recurrent ICH events were observed in 33 patients with trace initial hemorrhages regardless of restart status. All recurrent ICH events met criteria for classification as a major hemorrhage on the basis of clinical symptoms, and 30-day mortality after recurrent ICH was 100%. The cumulative incidence of recurrent VTE was significantly lower in the restart cohort compared to cohort of patients who did not restart anticoagulation (8.1 vs. 35.3, P=0.003, Figure 1). There were a total of five VTE events in the restart cohort, three deep vein thrombi (DVT) and two pulmonary emboli (PE). Two of the DVT were associated with an IVC filter. There were a total of nine VTE events in patients who did not restart anticoagulation, seven DVT and two PE. Five of the DVT were associated with an IVC filter. The two PE were both submassive events requiring ICU admission. Conclusions Recurrent VTE events are less frequent and less severe in patients who restart anticoagulation following ICH in patients with brain tumors on anticoagulation. Restarting anticoagulation after smaller ICH (trace or measurable) appears safe. However, approximately 1 in 7 patients with major initial ICH who restarted anticoagulation subsequently developed recurrent major ICH that was associated with a very high mortality rate. This raises serious questions as to the safety of restarting therapeutic anticoagulation following major hemorrhage in the setting of brain tumors. Disclosures Neuberg: Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership; Celgene: Research Funding. Zwicker:Quercegen: Research Funding; Daiichi: Consultancy; Seattle Genetics: Consultancy; Parexel: Consultancy; Incyte: Research Funding; Bayer: Consultancy; Portola: Consultancy.

Purpose This paper is submitted for a special issue of Asian Education and Development Studies on the topic of Greater China Development. The purpose of this paper is to explore the challenges and opportunities of developing a free trade zone (FTZ)/free port in China’s Hainan island. Design/methodology/approach Hainan is to be Mainland China’s newest and largest FTZ. However, the experience of the existing Mainland FTZs is not encouraging, their limited, piecemeal reforms attracting little interest from foreign investors. To make a difference and provide a new engine of growth for the Mainland economy, the approach for Hainan needs to be much bolder. Hainan should aim to develop as a free port, a services centre and a financial centre. Findings Regarding the financial sector development, the opportunity should be taken to experiment with special drawing rights. Hong Kong can provide the exemplar and expertise to jump-start Hainan’s development. To provide critical mass, mutual access should be opened between Hainan and the nine Mainland municipalities of the Greater Bay Area. An inner border will be needed to distinguish the experimental area from the rest of the Mainland, and an outer border to preserve its integrity vis-à-vis the international environment. Originality/value If Hainan can be developed into the China Offshore Centre, it would have the potential to restart the Mainland’s stalled reform process, and to relieve international trade and financial tensions.

This paper describes and evaluates a scalable and efficient resilience scheme based on the concept of containment domains. Containment domains are a programming construct that enable applications to express resilience needs and to interact with the system to tune and specialize error detection, state preservation and restoration, and recovery schemes. Containment domains have weak transactional semantics and are nested to take advantage of the machine and application hierarchies and to enable hierarchical state preservation, restoration and recovery. We evaluate the scalability and efficiency of containment domains using generalized trace-driven simulation and analytical analysis and show that containment domains are superior to both checkpoint restart and redundant execution approaches.

The immense potential of the blockchain technology in diverse and critical applications (e.g., financial services, cryptocurrencies, supply chains, smart contracts, and automotive industry) has led to a new challenge: the dependability modeling and analysis of the blockchain-based systems. In this paper, we model the Bitcoin, a peer-to-peer cryptocurrency system built on the blockchain technology that allows individuals to trade freely without involving banks or other intermediate agents. We analyze the dependability of the Bitcoin system subject to the Eclipse attack. A continuous-time Markov chain-based method is suggested to model the system behavior under the Eclipse attack and further quantify the dependability of the Bitcoin system. The effects of several model parameters (related to the miner’s habits in system protection, restart, and mining frequency) on the system dependability are demonstrated through numerical examples. Findings from this work may provide effective guidelines in designing a resilient and robust Bitcoin system.

Continuation of the article. Devoted to the causes, manifestations, circumstances, results and global consequences of US-China trade war in 2018–2021. Based on the analysis of management decisions, expert assessments, statistics and opinion polls, the author makes judgments and assumptions about the continuity of US policy, provoking and aggravating conflict relations between the two countries, as well as contributing to their penetration into all spheres of politics, economy, culture and even sports. At the same time, consistent and adequate measures on the part of the People’s Republic of China, which have a predominantly defensive orientation, are taken into account. At the same time, the anti-Chinese trade, investment, and technology policy, which was already carried out under Donald Trump in the name of ensuring the national security of the United States, and under Joe Biden actually turned into a hybrid cold war, is interpreted in the context of causal relationships characterizing the crisis of the neoliberal model of capitalism and the intentions of the world elite to restart the Bretton Woods system by switching to “green” energy. The most important resource of the transformation that has begun is the ideology of justifying any sanctions and other strong-willed decisions of the “democratic” Western states led by the United States against the “authoritarian” losers of the energy transition. Consequently, the “trade war” of the USA and China, objectively acting as an instrument of disorganization of the global world and a powerful limiter of globalization based on “market fundamentalism”, becomes the demiurge of the new globalization projected on the platform of “ideological fundamentalism”. In the situation of a multipolar world and the intensified rivalry of nuclear powers, restarting the world economy through a global war seems impossible. On the contrary, the mechanism of collecting a “green” contribution in favor of potential beneficiaries of the new globalization has not yet been tested. Within this perspective, the US-China trade war becomes not only an existential concern of the US and its allies, but also a problem of China’s survival. Obviously, this circumstance explains the emerging rapprochement between the PRC and the Russian Federation in the direction of pooling resources and forming a military-political alliance.

This paper is devoted to the causes, manifestations, circumstances, results and global consequences of US-China trade war in 2018–2021. Based on the analysis of management decisions, expert assessments, statistics and opinion polls, the author makes judgments and assumptions about the continuity of US policy, provoking and aggravating conflict relations between the two countries, as well as contributing to their penetration into all spheres of politics, economy, culture and even sports. At the same time, consistent and adequate measures on the part of the People’s Republic of China, which have a predominantly defensive orientation, are taken into account. At the same time, the anti-Chinese trade, investment, and technology policy, which was already carried out under Donald Trump in the name of ensuring the national security of the United States, and under Joe Biden actually turned into a hybrid cold war, is interpreted in the context of causal relationships characterizing the crisis of the neoliberal model of capitalism and the intentions of the world elite to restart the Bretton Woods system by switching to “green” energy. The most important resource of the transformation that has begun is the ideology of justifying any sanctions and other strong-willed decisions of the “democratic” Western states led by the United States against the “authoritarian” losers of the energy transition. Consequently, the “trade war” of the USA and China, objectively acting as an instrument of disorganization of the global world and a powerful limiter of globalization based on “market fundamentalism”, becomes the demiurge of the new globalization projected on the platform of “ideological fundamentalism”. In the situation of a multipolar world and the intensified rivalry of nuclear powers, restarting the world economy through a global war seems impossible. On the contrary, the mechanism of collecting a “green” contribution in favor of potential beneficiaries of the new globalization has not yet been tested. Within this perspective, the US-China trade war becomes not only an existential concern of the US and its allies, but also a problem of China’s survival. Obviously, this circumstance explains the emerging rapprochement between the PRC and the Russian Federation in the direction of pooling resources and forming a military-political alliance.

Progress in numerical weather and climate prediction accuracy greatly depends on the growth of the available computing power. As the number of cores in top computing facilities pushes into the millions, increased average frequency of hardware and software failures forces users to review their algorithms and systems in order to protect simulations from breakdown. This report surveys hardware, application-level and algorithm-level resilience approaches of particular relevance to time-critical numerical weather and climate prediction systems. A selection of applicable existing strategies is analysed, featuring interpolation-restart and compressed checkpointing for the numerical schemes, in-memory checkpointing, user-level failure mitigation and backup-based methods for the systems. Numerical examples showcase the performance of the techniques in addressing faults, with particular emphasis on iterative solvers for linear systems, a staple of atmospheric fluid flow solvers. The potential impact of these strategies is discussed in relation to current development of numerical weather prediction algorithms and systems towards the exascale. Trade-offs between performance, efficiency and effectiveness of resiliency strategies are analysed and some recommendations outlined for future developments.

Floating-point computation is ubiquitous in high-performance scientific computing, but rounding error can compromise the results of extended calculations, especially at large scales. In this paper, we present new techniques that use binary instrumentation and modification to do fine-grained floating-point precision analysis, simulating any level of precision less than or equal to the precision of the original program. These techniques have an average of 40–70% lower overhead and provide more fine-grained insights into a program’s sensitivity than previous mixed-precision analyses. We also present a novel histogram-based visualization of a program’s floating-point precision sensitivity, as well as an incremental search technique that allows developers to incrementally trade off analysis time for detail, including the ability to restart analyses from where they left off. We present results from several case studies and experiments that show the efficacy of these techniques. Using our tool and its novel visualization, application developers can more quickly determine for specific data sets whether their application could be run using fewer double precision variables, saving both time and memory space.

SUMMARY Based on a recent SEC proposal, publicly traded companies will be required to adopt a clawback in accordance with the Dodd-Frank Act. In response, firms have been voluntarily adopting clawbacks at an increasing rate. Prior research finds one benefit of voluntarily adopting a clawback is a decrease in restatements. A recent study by Pyzoha (2015) uses an experiment to further investigate restatements in a clawback environment by studying executives' restatement decisions based on auditor quality and executive compensation structure. Results show there may be an unintended consequence of clawbacks that partially offsets the aforementioned benefit. The study finds executives are less likely to agree with restating financial statements when their pay consists of a higher percentage of incentives and there is a lower quality auditor. Importantly, the study shows this tendency is reduced with a higher quality auditor. This article summarizes the study's motivation, research method, results, and practical implications.

Com esse artigo – aliando os métodos qualitativo e quantitativo de pesquisa – analisamos a relação comercial bilateral sino-angolana – China-Angola – hodierna com enfoque na questão do petróleo. Como parte de um panorama econômico globalizado, buscamos identificar as assimetrias nessa relação à luz do esquema “Prebichiano” de Centro-Periferia” – elaborado pelo economista Raúl Prebisch no século passado –. A China, um país emergente – em desenvolvimento – (ou já de Centro para alguns pensadores), tem de fato uma economia pujante com uma capilaridade ainda complexa de dimensionar. Enquanto Angola é um país que ainda pode ser conceituado – sob vários aspectos – “subdesenvolvido” (ou seja, um país periférico). Esse artigo pode também ser concebido como mais um passo para entender o que a China almeja econômica, é claro, – mas também politicamente do restante do Continente Africano, do mundo e do Brasil –. Ensejando possibilidades de pesquisar especificamente as relações da China com outros países africanos lusófonos, tais como: Moçambique (fornecedor de madeira para os chineses) e Cabo Verde (fornecedor de pescados para os chineses). Por fim, procuramos extrair das relações comerciais bilaterais sino-angolanas, breves lições para o comércio bilateral sino-brasileiro – China-Brasil – já que a China é hoje o nosso maior parceiro econômico. With this article - combining the qualitative and quantitative research methods - we analyze the Sino-Angolan - China-Angola - bilateral trade relationship today focusing on the oil issue. As part of a globalized economic landscape, we seek to identify asymmetries in this relationship in light of the “Prebichian” Center-Periphery scheme” - elaborated by economist Raúl Prebisch in the last century -. China, an emerging developing country (or already a Center for some thinkers), has indeed a thriving economy with a capillarity that is still complex to scale. While Angola is a country that can still be conceptualized - in many ways - “underdeveloped” (ie a peripheral country). This article can also be conceived as a further step in understanding what China wants economically, of course - but also politically from the rest of the African continent, the world and Brazil -. As a possibility to investigate specifically China's relations with other Lusophone African countries, such as: Mozambique (Chinese wood supplier) and Cape Verde (Chinese fish supplier). Finally, we seek to draw from Sino-Angolan bilateral trade relations, brief lessons for Sino-Brazilian bilateral trade - China-Brazil - as China is today our largest economic partner.

The block chain technology has immense potential in many different applications, including but not limited to cryptocurrencies, financial services, smart contracts, supply chains, healthcare services, and energy trading. Due to the critical nature of these applications, it is pivotal to model and evaluate dependability of the block chain-based systems, contributing to their reliable and robust operation. This paper models and analyzes the dependability of Bitcoin nodes subject to Eclipse attacks and state-dependent mitigation activities. Built upon the block chain technology, the Bitcoin is a peer-to-peer cryptocurrency system enabling an individual user to trade freely without the involvement of banks or any other types of intermediate agents. However, a node in the Bitcoin is vulnerable to the Eclipse attack, which aims to monopolize the information flow of the victim node. A semi-Markov process (SMP) based approach is proposed to model the Eclipse attack behavior and possible mitigation activities that may prevent the attack from being successful during the attack process. The SMP model is then evaluated to determine the steady-state dependability of the Bitcoin node. Numerical examples are provided to demonstrate the influence of the time to restart the Bitcoin software and time to detect and delete the malicious message on the Bitcoin node dependability.

Time-domain seismic simulation can form the basis of reverse time depth migration and full-waveform inversion. These applications need to temporally crosscorrelate a forward simulation state with an adjoint simulation state and therefore need to be able to access each time step of a forward simulation in time-reverse order. This requires saving all forward states for all times (which can require more memory than is typically available on a computer system for many problems of interest), or the ability to checkpoint information and rapidly recompute forward simulation states as needed. Prior work has suggested how to do the latter by optimally choosing which forward simulation time steps to checkpoint, thereby enabling the most efficient reuse of memory buffers and minimizing recomputation. The optimal trade-off between memory usage and recomputation can be further improved under the assumption that the information needed to do temporal crosscorrelation is smaller than the information required to restart a simulation from a given time step. This assumption is true for many geophysical problems of interest. The modification can yield a reduction in the memory requirement and recomputation time. The tested examples applied to isotropic elastic reverse time migration and anisotropic viscoelastic full-waveform inversion.

Introduction: Emicizumab is a subcutaneously administered, humanized bispecific monoclonal antibody, approved for routine prophylaxis in persons with hemophilia A (PwHA) with or without factor VIII inhibitors. Little is known about patterns of emicizumab use in clinical practice. We aimed to evaluate real-world persistence with and adherence to emicizumab treatment for PwHA on prophylaxis. Methods: This retrospective study used de-duplicated commercial insurance claims data from IBM® MarketScan® Commercial Research and IQVIA PharMetrics® Plus databases from 16 November 2017 to 31 December 2019. Individuals included met the following criteria: 1) evidence of emicizumab use (at least two prescription fills) and 2) continuous enrollment for at least three months pre-emicizumab initiation. Individuals were followed until the end of study period or continuous enrollment. Persistence was defined as the proportion of individuals continuing treatment with emicizumab during the study period. Time to discontinuation and proportion of individuals who restarted emicizumab prophylaxis were reported for patients who discontinued emicizumab. Discontinuation was defined as 60 days without a prescription fill. Adherence was measured over the post-index persistence period using the proportion of days covered (PDC), and the proportion of individuals adherent at ≥80% PDC threshold was reported. Results: We identified 328 unique individuals who met the inclusion criteria. All patients were male (100%); the average age was 23 years (standard deviation [SD] ±16; range=1-64); and the average follow-up post-index was eight months (245±147 days). The vast majority of individuals (92%) were persistent with emicizumab prophylaxis during the study period. Among those who discontinued emicizumab (n=25), the average time to discontinuation was approximately three months (84±124 days); 40% restarted emicizumab prophylaxis after discontinuation, with an average time to restart of approximately four months (126±56 days). During the period for which individuals were persistent to treatment, adherence to emicizumab was high (81%); with 70% individuals meeting the ≥80% PDC threshold. Among those with at least one-year post-index enrollment (n=48), adherence during the first year was also high (85%), with 77% individuals adherent at the ≥80% PDC threshold. Conclusions: In this study, the vast majority of individuals treated with emicizumab had high rates of adherence and persistence to treatment. This is one of the first studies to report real-world persistence with and adherence to emicizumab prophylaxis in PwHA. Future evaluations should examine the association of persistence and adherence with health outcomes in this population. Disclosures Mahajerin: Spark Therapeutics, Alexion, Genentech, Inc.: Speakers Bureau. Khairnar:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Meyer:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Abbass:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Wang:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Acumen, LLC: Ended employment in the past 24 months. Lee:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Tzeng:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Raimundo:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company.

How can we accurately and efficiently decompose a tensor stream? Tensor decomposition is a crucial task in a wide range of applications and plays a significant role in latent feature extraction and estimation of unobserved entries of data. The problem of efficiently decomposing tensor streams has been of great interest because many real-world data dynamically change over time. However, existing methods for dynamic tensor decomposition sacrifice the accuracy too much, which limits their usages in practice. Moreover, the accuracy loss becomes even more serious when the tensor stream has an inconsistent temporal pattern since the current methods cannot adapt quickly to a sudden change in data. In this paper, we propose DAO-CP, an accurate and efficient online CP decomposition method which adapts to data changes. DAO-CP tracks local error norms of the tensor streams, detecting a change point of the error norms. It then chooses the best strategy depending on the degree of changes to balance the trade-off between speed and accuracy. Specifically, DAO-CP decides whether to (1) reuse the previous factor matrices for the fast running time or (2) discard them and restart the decomposition to increase the accuracy. Experimental results show that DAO-CP achieves the state-of-the-art accuracy without noticeable loss of speed compared to existing methods.

In this article, we study the contagion effects of accounting restatements issued by foreign firms traded in the United States. Specifically, we predict and find that accounting restatements that negatively affect the share prices of the restating foreign firms raise investor concerns that nonrestating foreign firms from the same home countries have similar accounting issues, and therefore induce a negative stock market reaction to nonrestating home country peer firms. We refer to this as a restatement-induced home country contagion effect. On average, nonrestating home country peer firms experience a negative stock market return of approximately −0.69% over a 3-day window around the restatement announcement. Moreover, we hypothesize and show that the strength of the home market rule of law (ROL) affects investor assessment of the likelihood that peer firms have similar accounting issues, and therefore affects the magnitude of the contagion. Specifically, nonrestating home country peer firms from countries with weak ROL experience an average stock price decline of approximately −1.32%, whereas peer firms from strong ROL countries experience an average negative return of only −0.26% over the 3-day window around the restatement. These results suggest that restatements filed by weak ROL firms are perceived to be more “contagious” than those filed by strong ROL firms.

Abstract Background: Brexucabtagene autoleucel (brexu-cel) is the first CD19 chimeric antigen receptor T-cell (CAR T) therapy approved for use in patients (pts) with relapsed mantle cell lymphoma (MCL). The ZUMA-2 trial demonstrated that brexu-cel induces durable remissions in these pts with an ORR of 85% (59% CR), estimated 12-month PFS rate of 61%, and similar toxicity profile to other CAR T therapies (Wang et al, NEJM 2020). We conducted a multicenter, retrospective study of pts treated with commercial brexu-cel to evaluate its safety and efficacy in the non-trial setting. Methods: We reviewed records of pts with relapsed MCL across 12 US academic medical centers. Pts who underwent leukapheresis between July 2020 and June 2021 with the intent to proceed to commercial brexu-cel were included. Baseline demographic and clinical characteristics were summarized using descriptive statistics. Survival curves were generated using the Kaplan-Meier method, and univariate models were fit to identify predictors of post-CAR T outcomes. Results: Fifty-five pts underwent leukapheresis. There were 3 manufacturing failures. Baseline characteristics of the 52 pts who received brexu-cel are summarized in Table 1. Median age was 66 yrs (range: 47-79 yrs) and 82% were male. Twenty of 29 (69%) pts with known baseline MIPI were intermediate or high risk. Seven pts had a history of CNS involvement. The median number of prior therapies was 3 (range: 2-8), including prior autologous stem cell transplant (ASCT) in 21 (40%) and prior allogeneic transplant in 2 pts (1 with prior ASCT and 1 without). Fifty percent had relapsed within 24 months of their initial therapy. All pts had previously received a Bruton's tyrosine kinase inhibitor (BTKi), including 29 (56%) with disease progression on a BTKi. Forty (77%) pts received bridging therapy (17 BTKi, 10 BTKi + venetoclax, 6 chemo, 3 venetoclax, 2 XRT only, 1 steroids only, 1 lenalidomide + rituximab). The ORR was 88% (CR 69%) among patients who received brexu-cel. Two pts had PD on initial restaging and 3 died prior to first response assessment (without evidence of relapse). Seven pts have not completed restaging due to limited follow-up (< 3 months) and were not included in the response assessment. Five pts have progressed, including 2 with CR and 1 with PR on initial restaging. With a median follow-up of 4.2 months, the estimated 6-month PFS and OS rates were 82.7% and 89.0%, respectively. All 7 pts with prior CNS involvement were alive without relapse at last follow-up. The incidence of cytokine release syndrome (CRS) was 84% (10% grade ≥ 3) with a median time to max grade of 5 days (range: 0-10 days). There were no cases of grade 5 CRS. The incidence of neurotoxicity (NT) was 57% (31% grade ≥ 3) with a median time to onset of 7 days (range: 4-15 days). NT occurred in 4/7 pts with prior CNS involvement (3 grade 3, 1 grade 4). Grade 5 NT occurred in 1 pt who developed cerebral edema and died 8 days after infusion. Thirty-five pts received tocilizumab, 33 received steroids, 7 received anakinra, and 1 received siltuximab for management of CRS and/or NT. Post-CAR T infections occurred in 8 pts, including two grade 5 infectious AEs (covid19 on day +80 and septic shock on day +40 after infusion). Rates of grade ≥ 3 neutropenia and thrombocytopenia were 38% and 37%, respectively. Among pts with at least 100 days of follow-up and lab data available, 5/34 (15%) had persistent grade ≥ 3 neutropenia and 4/34 (12%) had persistent grade ≥ 3 thrombocytopenia at day +100. Five pts have died, with causes of death being disease progression (2), septic shock (1), NT (1), and covid19 (1). Univariate analysis did not reveal any significant associations between survival and baseline/pre-CAR T MIPI, tumor pathologic or cytogenetic features, prior therapies, receipt of steroids/tocilizumab, or pre-CAR T tumor bulk. Conclusions: This analysis of relapsed MCL pts treated with commercial brexu-cel reveals nearly identical response and toxicity rates compared to those reported on ZUMA-2. Longer follow-up is required to confirm durability of response, but these results corroborate the efficacy of brexu-cel in a population of older adults with high-risk disease features. While all 7 pts with prior CNS involvement are alive and in remission, strategies to mitigate the risk of NT in this setting need to be evaluated. Further studies to define the optimal timing of CAR T, bridging strategies, and salvage therapies for post-CAR T relapse in MCL are warranted. Figure 1 Figure 1. Disclosures Gerson: TG Therapeutics: Consultancy; Kite: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy. Sawalha: TG Therapeutics: Consultancy, Research Funding; Celgene/BMS: Research Funding; BeiGene: Research Funding; Epizyme: Consultancy. Bond: Kite/Gilead: Honoraria. Karmali: Janssen/Pharmacyclics: Consultancy; BeiGene: Consultancy, Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Takeda: Research Funding; Genentech: Consultancy; AstraZeneca: Speakers Bureau; Roche: Consultancy; Karyopharm: Consultancy; Epizyme: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Consultancy, Research Funding; EUSA: Consultancy. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Chow: ADC Therapeutics: Current holder of individual stocks in a privately-held company, Research Funding; AstraZeneca: Research Funding. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Ghosh: Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharma: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genmab: Consultancy, Honoraria; Epizyme: Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Adaptive Biotech: Consultancy, Honoraria; AbbVie: Honoraria, Speakers Bureau. Moyo: Seattle Genetics: Consultancy. Fenske: TG Therapeutics: Consultancy, Speakers Bureau; Servier Pharmaceuticals: Consultancy; Seattle Genetics: Speakers Bureau; Sanofi: Speakers Bureau; Pharmacyclics: Consultancy; MorphoSys: Consultancy; Kite (Gilead): Speakers Bureau; KaryoPharm: Consultancy; CSL Therapeutics: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Biogen: Consultancy; Beigene: Consultancy; AstraZeneca: Speakers Bureau; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy. Grover: Genentech: Research Funding; Novartis: Consultancy; ADC: Other: Advisory Board; Kite: Other: Advisory Board; Tessa: Consultancy. Maddocks: Seattle Genetics: Divested equity in a private or publicly-traded company in the past 24 months; BMS: Divested equity in a private or publicly-traded company in the past 24 months; Pharmacyclics: Divested equity in a private or publicly-traded company in the past 24 months; Novatis: Divested equity in a private or publicly-traded company in the past 24 months; Janssen: Divested equity in a private or publicly-traded company in the past 24 months; Morphosys: Divested equity in a private or publicly-traded company in the past 24 months; ADC Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Karyopharm: Divested equity in a private or publicly-traded company in the past 24 months; Beigene: Divested equity in a private or publicly-traded company in the past 24 months; Merck: Divested equity in a private or publicly-traded company in the past 24 months; KITE: Divested equity in a private or publicly-traded company in the past 24 months; Celgene: Divested equity in a private or publicly-traded company in the past 24 months. Jacobson: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Lonza: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau. Cohen: Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy; Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding.

Purpose Prior research has examined the impact of corporate governance mechanisms, including external auditing, on accounting restatements likelihood. However, little is known about auditor’s monitoring role in restatement disclosure practices. The purpose of this study is to address this gap by investigating the impact of auditor’s oversight on the timeliness of accounting restatement disclosures as measured by the length of the restatement dark period. Design/methodology/approach The study examines panel data from a sample of restating publicly traded US firms. Negative binomial regression is used to analyze the data because the dependent variable is a count variable and is over-dispersed. Findings The main study’s results indicate that longer auditor tenure and non-audit services provision improve restatement disclosure timeliness. Conversely, companies whose auditors exerted abnormally high levels of audit effort have longer restatement dark periods. Originality/value This study is the first archival research that focuses on auditor’s monitoring role and its impact on the timeliness of restatement disclosures. By doing so, this study contributes to the auditing academic research, professional practice and regulation by providing empirical evidence on an exasperating issue for all participants in the financial markets. In addition, it provides a better understanding of auditor’s monitoring role in the accounting restatement process and offers insights to policymakers, practitioners and investors interested in corporate financial transparency and corporate governance.

Este texto analisa a importância dos arquivos regionais, nomeadamente os escolares, para a preservação da história da educação na região oeste do Paraná. Os acervos escolares constituem-se em espaços privilegiados que servem para albergar documentos que contribuem para a preservação da memória histórica, são, portanto, importantes repositórios de fontes manuscritas, escritas e iconográficas que contribuem decisivamente para o avanço da pesquisa sobre a trajetória histórica das instituições escolares regionais e auxiliam na reconstituição e preservação da História da Educação brasileira. Nas últimas décadas, ampliou-se a discussão sobre a conservação das fontes para o conhecimento do patrimônio cultural e histórico, todavia, os pesquisadores ainda encontram dificuldades, especialmente relacionadas ao acesso e à conservação dos documentos. No caso do oeste paranaense, embora se trate de uma região de colonização recente - década de 1940 -, quando comparada ao restante do estado do Paraná, são poucos os arquivos que acondicionam documentos e fontes históricas para preservação da memória coletiva. Nesse contexto, os acervos das instituições educativas exercem importante papel no processo de catalogação e acondicionamento de fontes documentais para pesquisa sobre a História da Educação regional. Neste texto, listamos os principais arquivos públicos e privados que podem auxiliar o trabalho dos investigadores que optarem pela realização de pesquisas que incidem sobre o campo temático da história das instituições educacionais e da História da Educação regional.

Worldwide, Corona virus Lock down, including India has improved- Air Quality, Water Quality and Reduction in Green House Gases-Emission as Industries shut, transportation slowed, Flights grounded and Human Activities minimised; there was no Air pollution emission, there was no dumping and /or discharging of Industrial effluents, Solid wastes, Sewage etc. which are sources of pollution. India’s Corona virus –Lock down improves water quality of Rivers-Ganga and Yamuna and others water resources as well. Industrial effluents and Sewage, if not discharged, in Ganga-River, Ganga Water can be purified. People in Delhi, one of the World’s polluted Cities, are now breathing Cleaner Air. Many other Countries around the World have also seen Air Quality improved Amid the Pandemic. The Covid-19 –Lock down. Corona virus measures imposed in different countries have positive impact on Environment. There is a need to end the illegal wildlife trade globally to prevent future pandemic and biodiversity loss. The Covid-19 had positive and negative consequences on biodiversity resources. The Covid-19 pandemic remains a threat to biodiversity conservation. Worldwide- Green House Gases- Emissions reduced: India (Delhi)-70%, USA (North-East)-30%, China -10%, European Countries-58% likewise. However, Environmentalist worried- reduction in Air Pollution & GHG’s-emission is Temporary, as Work will retain to Business, the Level of Air Pollution and GHS’s –level again will come back to the level as found, before Corona virus-Lock down. European Activist call for Green Investment to restart growth after Corona virus Crises; and ensure that rebuilt Economies are stronger. Green Groups in India’s suggested to take note and rethink Policies on Industrial Development for Concern of Environment. During covid-19 lockdown period climate changes have also been highlighted.

O Brasil é reconhecido mundialmente pelo seu excelente desempenho econômico e produtivo nos setores agropecuários. Com o crescimento da demanda mundial por alimentos o país ampliou sua área produtivas através da criação da última fronteira agrícola do mundo (MATOPIBA). A fim de apresentar a importância dessa fronteira agrícola no Brasil, construiu-se e analisou-se uma matriz de Insumo-Produto Inter-Regional contendo fluxos comerciais entre as regiões do MATOPIBA, Resto no Norte (RN), Resto do Nordeste (RNDT) e Restante do Brasil (RB). Tal matriz apresentou desagregação para 14 setores nas quatro regiões. Concluiu-se que, os setores do MATOPIBA, apesar de apresentarem menores multiplicadores de produção em relação ao RB, possui as maiores taxas de transbordamento de investimentos para as demais regiões, apresentando assim, capacidade mais elevada em impulsionar a indústria nacional do que qualquer outra região do modelo. E o choque na demanda final, nos principais setores agrícolas da região do MATOPIBA, apresentou grande perspectiva de crescimento em todo modelo, tonando-se provavelmente, grande alvo para investimentos futuros.Abstract: Brazil is recognized worldwide for its excellent economic and productive performance in the agricultural sectors. With the growth in world demand for food, the country expanded its productive area through the creation of the last agricultural frontier in the world (MATOPIBA). In order to present the importance of this agricultural frontier in Brazil, an Inter-Regional Input-Output matrix was constructed and analyzed containing trade flows between the regions of MATOPIBA, Resto no Norte (RN), Rest of Northeast (RNDT) and Rest of Brazil (RB). It was concluded that the MATOPIBA sectors, despite having lower production multipliers in relation to the RB, have the highest investment spillover rates to the other regions, thus presenting a higher capacity to boost the national industry than any other region of the model. And the shock in the final demand, in the main agricultural sectors of the MATOPIBA region, presented great growth perspective in every model.

Introduction: In the phase 3 ECHELON-1 study (NCT01712490), treatment with brentuximab vedotin, doxorubicin, vinblastine and dacarbazine (A+AVD) significantly improved modified progression-free survival in patients with newly-diagnosed stage III or IV classical Hodgkin lymphoma (cHL) compared with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). The results of ECHELON-1 supported the March 2018 US FDA approval of A+AVD for adults with frontline (FL) stage III or IV cHL. To optimize outcomes for patients with stage III or IV cHL receiving ABVD, the current National Comprehensive Cancer Network guidelines recommend an interim PET/CT imaging (PET2) at the end of cycle 2 to inform escalation or de-escalation of therapy. In the current study we describe the real-world patient characteristics, supportive care use, and PET2 utilization in A+AVD and ABVD patients outside of the clinical trial setting in the US. Methods: Using medical and pharmacy claims data in the US Symphony Health Solutions database, a retrospective cohort analysis of patients with cHL receiving FL A+AVD or ABVD was conducted to compare treatment and utilization characteristics. Patients ≥18 years with one inpatient or two outpatient ICD-9 or 10 cHL diagnosis codes, newly prescribed A+AVD or ABVD (index date) between March 2018 and January 2020, and with ≥6 months continuous activity before and a minimum of 3 months after the index date were included. To adjust for confounding factors, a 1:1 propensity score matching analysis was performed based on age, gender, baseline comorbidities, geographic region and length of follow-up. Results: A total of 4259 patients met inclusion criteria (1002 A+AVD and 3257 ABVD) with a median follow-up duration of 14 and 15 months, respectively. In unmatched cohorts, median age at index date of A+AVD vs ABVD was 48 and 39 years, with 41% and 52% of patients between the ages of 18-39, and 34% vs 20% age ≥60, respectively. Patients on A+AVD had higher comorbidity burden across all conditions included in the Charlson Comorbidity Index, with 41% vs 33% of ABVD patients reporting 1+ comorbidities, with chronic pulmonary disease (18% vs 14%, p=0.006) being the most prevalent (Table 1). Following propensity score matching, A+AVD patients received significantly higher granulocyte-colony stimulating factor (G-CSF), 90% vs 44%, with 80% and 20% as primary prophylaxis (p<0.001) vs ABVD, respectively. In the A+AVD and ABVD cohorts, only 31% and 38% of patients underwent interim PET2 restaging, respectively (Table 2). In ABVD patients, 44% who received an interim PET2 and 33% who did not receive an interim PET2 de-escalated to AVD. The rate of subsequent therapy was similar between A+AVD and ABVD (13% vs 11%; p=0.163); of the patients who received subsequent therapy, 43% of ABVD patients received a brentuximab vedotin-containing regimen and 19% of A+AVD were retreated with a brentuximab vedotin-containing regimen. Conclusions: In this first real-world evaluation, patients with cHL receiving FL A+AVD were older, had higher burden of comorbidities, utilized recommended G-CSF as primary prophylaxis, and had similar rate of subsequent therapy compared to ECHELON-1 patients. Only about one third of patients underwent interim PET2 restaging, and less than half of the patients who started on ABVD were de-escalated to AVD. Confounding by unmeasured characteristics, such as disease stage and PET/CT results, is a limitation of this and any retrospective study based on claims data. However, this hypothesis-generating analysis suggests the need to: 1) control for patient characteristics (e.g., age, comorbidities) in comparative real-world analyses; 2) understand reasons for the lack of PET/CT use; and 3) evaluate the actual use of the interim PET2 to escalate or de-escalate treatment in patients with cHL. The need to optimize treatment outcomes while maximizing short- and long-term treatment efficacy and safety is paramount. Characteristics and management of this real-world population with cHL differed from those in the ECHELON-1 trial, demonstrating the importance of retrospective studies in assessing the impact of new regimens on clinical practice and in identifying areas for further education of practitioners. Disclosures Phillips: Beigene: Consultancy; Karyopharm: Consultancy; AstraZeneca: Consultancy; Incyte: Consultancy, Research Funding; Seattle Genetics: Consultancy; BMS: Consultancy; Bayer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Cardinal Health: Consultancy. Yu-Isenberg:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Liu:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Surinach:Seattle Genetics: Research Funding. Flores:Seattle Genetics: Research Funding. Lisano:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Fanale:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Burke:Verastem: Consultancy; Astra Zeneca: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Roche: Consultancy; Bristol Myers Squibb: Consultancy; Gilead: Consultancy; Seattle Genetics: Speakers Bureau; Celgene: Consultancy; Kura: Consultancy; Epizyme: Consultancy; Adaptive: Consultancy; Morphosys: Consultancy; Adaptive Biotechnologies: Consultancy.

Abstract The paper is focused on nonlinear analog circuits, with the special attention paid to circuits comprising bipolar and MOS transistors manufactured in micrometer and submicrometer technology. The problem of fault diagnosis of this class of circuits is discussed, including locating faulty elements and evaluating their parameters. The paper deals with multiple parametric fault diagnosis using the simulation after test approach as well as detection and location of single catastrophic faults, using the simulation before test approach. The discussed methods are based on diagnostic test, leading to a system of nonlinear algebraic type equations, which are not given in explicit analytical form. An important and new aspect of the fault diagnosis is finding multiple solutions of the test equation, i.e. several sets of the parameters values that meet the test. Another new problems in this area are global fault diagnosis of technological parameters in CMOS circuits fabricated in submicrometer technology and testing the circuits having multiple DC operating points. To solve these problems several methods have been recently developed, which employ different concepts and mathematical tools of nonlinear analysis. In this paper they are sketched and illustrated. All the discussed methods are based on the homotopy (continuation) idea. It is shown that various versions of homotopy and combinations of the homotopy with some other mathematical algorithms lead to very powerful tools for fault diagnosis of nonlinear analog circuits. To trace the homotopy path which allows finding multiple solutions, the simplicial method, the restart method, the theory of linear complementarity problem and Lemke’s algorithm are employed. For illustration four numerical examples are given

Abstract Contentions about the origin of early modern empiricism have been floating about at least since the 1980s, where its exclusive “Britishness” was initially question, and the name of Gassendi was provocatively put forward as the putative “founder” of the current to the detriment of Francis Bacon. Recent scholarship has shown that early modern empiricism did not derive from philosophical speculation exclusively but had multiple sources and “foundations.” Yet, from a historical viewpoint, the question whether Bacon’s method had any influence on the origin and development of Gassendi’s version of empiricism still carries significance, for its answer may open up different views on how the relation between British and “continental” empiricisms shall be framed. In this paper, I deal with Gassendi’s reception of Bacon. On the basis of a deep examination of Gassendi’s corpus, I contend that there is no trace of a consistent influence of Bacon on Gassendi’s empiricism before 1650s; although I show that an indirect influence can be found through the mediation of Peiresc, I put forward the hypothesis that it was more the empirical attitude characterizing Peiresc’s intellectual figure, rather than his interest in Baconianism, to be relevant, along with Epicurus’ philosophy, for Gassendi’s early empiricism. I then analyze Gassendi’s treatment of Bacon’s logic in Gassendi’s Syntagma philosophicum. I show that despite Gassendi’s sympathy for Bacon’s project, his own logic lays on fundamentally different assumptions. Despite this, I argue for Gassendi’s reception of Bacon’s theory of the idols in Syntagma philosophicum. On this basis, I conclude by restating the untenability of “national” accounts of the rise of empiricism, and the importance of highlighting instead the sharing of ideas between its actors.

English Abstract:Green Belts are often proposed as an alternative for containing urban sprawl, restoring ecological processes, recovering connectivity, and maintaining the multi-functionality that cities need. This article analyzes a proposed Green Belt for Xalapa, Veracruz, Mexico. It is spatially examined through GIS analysis and designed on the notion of Garden City as a strip to circumvent the city. Existing conditions are also discussed. Two existing conservation initiatives are compared to the proposed Green Belt strategy. Its establishment requires agreements between Xalapa and surrounding municipalities. The proposed strategy brings local government and citizens together to preserve the remaining vegetation and thus promote the well-being of local inhabitants.Spanish Abstract:Los cinturones verdes frecuentemente se han propuesto como una alternativa para contener la expansión urbana desordenada, restaurar los procesos ecológicos y recuperar la conectividad, y mantener la multifuncionalidad que las ciudades necesitan. Este artículo analiza un esquema de Cinturón Verde para Xalapa, Veracruz, México. Es espacialmente examinado, diseñado bajo el concepto de Ciudad Jardín, como una franja que rodea a la ciudad, el análisis se elaboró con un SIG. Las condiciones existentes también se discuten. Se comparan dos iniciativas de conservación existentes con la estrategia propuesta de Cinturón Verde. Su establecimiento requiere acuerdos entre Xalapa y los municipios aledaños. La estrategia propuesta requiere reunir a los gobiernos locales y ciudadanos para preservar la vegetación remanente y así promover el bienestar de los habitantes locales.French AbstractLes ceintures vertes sont fréquemment proposées comme une alternative pour limiter l’expansion urbaine désordonnée, restaurer les processus écologiques, récupérer la connectivité et maintenir la multifonctionnalité que les villes requièrent. Cet article analyse une proposition de ceinture verte pour Xalapa dans l’état du Veracruz au Mexique. Celle-ci est examinée et élaborée en particulier à partir du concept de cité-jardin, formée par une trame qui entoure la ville et son analyse a été élaborée par un Système d’information géographique (SIG). Les conditions existantes sont également discutées. Deux initiatives de conservation qui suivent la stratégie de la ceinture verte sont comparées. Leur mise en oeuvre implique des accords entre Xalapa et les municipes des alentours. La stratégie proposée impose la réunion des gouvernements locaux et des citoyens pour préserver la végétation restante et faciliter la promotion du bien-être des habitants.

Abstract Introduction: Chimeric antigen receptor (CAR) T-cells redirected against CD19 have demonstrated remarkable clinical activity in children and adults with relapsed/refractory (r/r) B-cell malignancies. The risk of lineage switch (LS) following CD19-directed therapies has been well documented but has been primarily limited to case reports. Additionally, the risk of subsequent malignant neoplasms (SMN) following CAR T-cells has not yet been described. Distinguishing LS (B-ALL to myeloid malignancy) from a therapy-related myeloid neoplasm is both clinically and biologically relevant. The former emerges from a highly refractory leukemic clone, likely resistant to salvage therapy, whereas the latter represents a new malignancy that can be associated with long-term survival. Methods: We conducted a multicenter, retrospective review of children and young adults with r/r B-acute lymphoblastic leukemia (B-ALL) who received either commercial tisagenlecleucel or 1 of 3 investigational murine-based CD19-CAR constructs on clinical trials at 7 US centers between 2012-2019. Patients diagnosed with B-ALL before age 25 years were included and patients who had received any prior CAR product were excluded. Results: Of 420 CAR-treated patients, with a median follow-up of 30.1 months, 12 (2.9%) experienced LS and 6 (1.4%) developed a SMN (Table). The median time to diagnosis of LS following CAR T-cell infusion was significantly shorter compared to diagnosis of SMN (65.5 days vs. 883.5 days; p=0.005). Eleven of 12 patients (91.7%) with LS converted to acute myeloid leukemia (AML). One patient converted to mixed phenotype acute leukemia, B/myeloid type. The leukemia of 10 of 12 patients with LS harbored cytogenetics similar to those at initial diagnosis. For the remaining 2 patients with LS, cytogenetics were unavailable, but the leukemias were considered LS by the treating institution. KMT2Ar rearrangement (KMT2Ar) was a predominant cytogenetic abnormality seen in patients with LS. Overall, 38 of 420 patients (9%) had a KMT2Ar. KMT2Ar was present in 9 of 12 (75%) patients with LS compared to 20 of 408 (7.1%) non-LS patients (p<0.001). Patients with LS were younger at initial diagnosis compared to the remaining cohort (median age, 1.6 years vs. 7.7 years; p=0.001), reflecting the inherent association between KMT2Ar and infant ALL. Otherwise, there were no significant differences in gender, prior hematopoietic stem cell transplant (HSCT), prior blinatumomab exposure, or CAR response. Within the KMT2Ar cohort, 31 (81.6%) patients achieved a complete remission post-CAR. Eight of these patients received a consolidative HSCT (representing 4 first and 4 second HSCTs). No KMT2Ar patient experienced a post-HSCT LS and 3 are alive with a median follow-up of 1164 days post-CAR. In contrast, of the 23 KTM2Ar patients who did not receive HSCT post-CAR, 7 developed LS and 14 are alive with a median follow-up of 864 days post-CAR. Relative contraindications to post-CAR HSCT included a prior HSCT (n=11) or early LS (n=5). Of the 7 CAR non-responding patients with KMT2Ar, 2 (28.6%) had rapid emergence of LS by the first restaging timepoint. There are no long-term survivors following LS, regardless of KMT2A status, dying a median of 123 days (range, 36-594 days) after diagnosis of LS. The 6 SMNs were cholangiocarcinoma, synovial sarcoma, malignant melanoma and 3 therapy-related myeloid neoplasms (MDS/AML), distinguished from LS based on loss of original cytogenetics. Notably, 4/6 (67%) patients that developed a SMN had received an allogeneic HSCT prior to development of SMN. Four patients (67%) remain alive and in remission with a median follow-up of 304 days after diagnosis of SMN, including 2 patients with MDS/AML. Conclusions: In the largest series of pediatric patients treated with CAR T-cell therapy, we show that LS occurs in 2.9% of children. The presence of a KMT2Ar was the biggest risk factor, with 23.7% of these patients experiencing LS. We found that LS can occur very early in a patient's post CAR T-cell course, and despite a variety of treatment approaches, the outcomes for these patients are dismal. Given the predisposition to LS, the role for consolidative HSCT in KMT2Ar patients warrants further study. Limited by a short follow-up period, we saw SMNs in only 1.4% of our patients. Causality is unknown and likely unrelated to CAR-T, but this further supports the long-term safety of CAR T-cells in children with B-ALL. Figure 1 Figure 1. Disclosures Borowitz: Amgen, Blueprint Medicines: Honoraria. Lee: Harpoon Therapeutics: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Other: trial funding; Gilead: Other: trial funding. Grupp: Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards; Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy; Novartis, Kite, Vertex, and Servier: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding. Verneris: jazz: Other: advisory board; Novartis: Other: advisory board; Fate Therapeutics: Consultancy. Gore: Mirati: Current equity holder in publicly-traded company; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Honoraria; Clovis: Current equity holder in publicly-traded company; Celgene: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Sanofi Paris: Current equity holder in publicly-traded company; Anchiano: Current equity holder in publicly-traded company; Blueprint Medicines: Current equity holder in publicly-traded company. Brown: Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees; KIte: Membership on an entity's Board of Directors or advisory committees. Pulsipher: Equillium: Membership on an entity's Board of Directors or advisory committees; Adaptive: Research Funding; Jasper Therapeutics: Honoraria. Rheingold: Pfizer: Research Funding; Optinose: Other: Spouse's current employment. Gardner: BMS: Patents & Royalties; Novartis: Consultancy.

Background: Venetoclax (VEN), a B-cell lymphoma 2 inhibitor, is an oral agent with demonstrated efficacy in patients (pts) with chronic lymphocytic leukemia (CLL). VEN treatment induces rapid tumor reduction, posing a risk for tumor lysis syndrome (TLS), particularly in pts with high tumor burden, and may require inpatient monitoring at the initiation of therapy. Agents such as obinutuzumab (G), ibrutinib, and bendamustine (B) have been used in clinical studies to debulk tumors prior to treatment with VEN. However, the benefits of these debulking regimens could not be established conclusively, as disease restaging was rarely performed. In the present study, disease restaging was performed every 2 cycles to evaluate the efficacy and safety of G, with or without B, as a debulking therapy in untreated pts with CLL, prior to VEN treatment in an outpatient community setting. Methods: This open-label, phase 3b trial (NCT03406156) enrolled adult pts with previously untreated CLL/small lymphocytic lymphoma (excluding those with 17p deletion) who had Eastern Cooperative Oncology Group performance status of ≤1 and medium (any lymph node [LN] 5 to <10 cm or absolute lymphocyte count [ALC] ≥25 × 109/L) or high (any LN ≥10 cm or ALC ≥25 × 109/L and any LN ≥5 cm) tumor burden. Pts received at least 2 cycles of debulking therapy (G±B), which could be repeated for a maximum of six 28-day cycles until low tumor burden (ALC <25 × 109/L and all LN <5 cm) was achieved. B was administered at investigator discretion, with protocol recommendation for pts with LN >10 cm or with del(11q) and LN >5 cm. Restaging data were obtained after every 2 cycles of debulking therapy. When low tumor burden was achieved, VEN was administered (5-week ramp-up schedule) as combination therapy with G (VEN+G) for 5 months, and then as monotherapy (VEN mono) for a total of 1 year. Response assessments were scheduled at week 38 and week 65 post-VEN initiation. Adverse events (AEs) were monitored throughout the study. Primary endpoints were the reduction in tumor burden after debulking therapy and the complete remission (CR)/CR with incomplete marrow recovery (CRi) rates of pts subsequently treated with VEN. We report the results of a planned interim analysis when 50 pts had completed their week 38 disease assessment. Results: As of 3 Feb 2020, 117 pts were treated with study drug(s): 80 (68%) received G and 37 (32%) received G+B for debulking; 113 pts were active in study (7 in the debulking phase; 106 completed debulking therapy and initiated VEN, including 26 in posttreatment follow-up). Four pts discontinued study due to withdrawal by pt (n=2; 1 at debulking and 1 at VEN treatment phase) and physician decision (n=1; at VEN treatment phase) and other (n=1; at debulking). At baseline, 85% of pts had ALC ≥25 × 109/L, 9% had LN ≥10 cm, 23% had LN 5-10 cm; 74%/26% had medium/high TLS risk, respectively, per investigator assessment (1 pt with low TLS risk was enrolled and subsequently discontinued). After 2 cycles of debulking therapy, low tumor burden was achieved in 85% (89/105) of evaluable pts: 86% (63/73) with G and 81% (26/32) with G+B. Reductions by pt subgroups and genetic features are presented in Figure. For pts debulked with G, similar debulking efficacy was observed among the subgroups being explored (Figure). Of the 50 pts with a week 38 disease assessment, 17 pts had an initial response of partial remission and await confirmation per IWCLL criteria. Objective response rate was 96% (48/50) overall, with 95% (37/39) for those debulked with G and 100% (11/11) for those debulked with G+B. The rate of CR or CRi was 52% (26/50) overall, with 54% (21/39) achieving CR/CRi for those debulked with G and 45% (5/11) for those debulked with G+B (Figure). More grade ≥3 AEs were observed in pts receiving G+B than those receiving G: debulking, 62% vs 40%; VEN+G, 43% vs 34%; VEN mono, 41% vs 28%. Conclusions: Most pts (85%) achieved low tumor burden after 2 cycles of G±B. Similar debulking efficacy was observed across subgroups in pts debulked with G. In this early efficacy analysis, CR/CRi at week 38 was observed in 52% of pts treated with VEN after the debulking phase. Preliminary efficacy results from this study are consistent with other VEN studies in treatment-naive pts. Current study highlights the efficacy of the debulking strategy prior to treatment with VEN; this may allow more pts to have VEN ramp-up in outpatient setting. Figure Disclosures Flinn: Calithera Biosciences: Research Funding; Forma Therapeutics: Research Funding; F. Hoffmann-La Roche: Research Funding; Celgene: Research Funding; Merck: Research Funding; Curio Science: Consultancy; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Novartis: Research Funding; MorphoSys: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Constellation Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Teva: Research Funding; BeiGene: Consultancy, Research Funding; Curis: Research Funding; Nurix Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Forty Seven: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Takeda: Consultancy, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; Agios: Research Funding; ArQule: Research Funding; Kite Pharma: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; IGM Biosciences: Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Great Point Partners: Consultancy; Loxo: Research Funding; Genentech, Inc.: Research Funding. Andorsky:AstraZeneca: Research Funding; Celgene: Research Funding; AbbVie: Honoraria. Melear:Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau. Manda:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials. Anz:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials. Kolibaba:Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Verastem: Honoraria; Cell Therapeutics: Research Funding; Celgene: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Atara Biotech: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Acerta: Research Funding; Compass Oncology: Ended employment in the past 24 months; McKesson Life Sciences: Consultancy; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: travel, accommodations, expenses, . Yimer:Sanofi: Speakers Bureau; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; TG Therapeutics: Consultancy; Celgene, a Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; BeiGene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Texas Oncology: Current Employment; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Epizyme: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; Karyopharm: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau. Burke:Adaptive: Consultancy; Kura: Consultancy; Morphosys: Consultancy; Celgene: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Gilead: Consultancy; Seattle Genetics: Speakers Bureau; Roche: Consultancy; Bristol Myers Squibb: Consultancy; Verastem: Consultancy; Astra Zeneca: Consultancy; Epizyme: Consultancy; Adaptive Biotechnologies: Consultancy. Fanning:TG Therapeautics: Consultancy; Abbvie: Consultancy; Prisma Health: Current Employment; Sanofi Aventis: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Courtright:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. Islas-Ohlmayer:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. Kambhampati:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. Jiang:AbbVie: Current Employment, Other: may hold stock or options. Pesko:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Vizkelety:AbbVie: Current Employment, Other: may hold stock or stock options.. Sharmokh:AbbVie: Current Employment, Current equity holder in publicly-traded company. Sharman:AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; BeiGene: Research Funding; Acerta: Consultancy, Research Funding; Roche: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding.

Background: Thrombopoietin receptor agonists (TPO-RAs) (e.g., romiplostim, eltrombopag, avatrombopag) are used to stimulate platelet production in patients with primary immune thrombocytopenia (ITP). While it was previously thought that patients would need to remain on a TPO-RA indefinitely, case reports and cohort studies have shown that some patients have discontinued TPO-RAs while maintaining a hemostatic platelet count. We convened a panel of experts to develop clinical recommendations on when it is appropriate to consider tapering and how to taper TPO-RAs in children and adults with persistent or chronic primary ITP. Methods: Using a RAND/UCLA modified Delphi panel, we convened 9 hematologists with an average of 25 years of experience and 1 patient representative. Experts were provided with a summary of evidence from 12 case reports, 11 cohort studies, and 2 clinical trial analyses on sustained remission in patients with ITP treated with TPO-RAs. Experts collaboratively developed and then rated (on a 1 to 9 scale) how appropriate it would be to recommend tapering (with the aim of discontinuing) TPO-RA monotherapy in 432 patient scenarios. Each scenario was a simplified patient history which varied by current platelet count, history of bleeding, intensification of treatment, trauma risk, use of anticoagulants or platelet inhibitors, duration of ITP, months on TPO-RA monotherapy, and early platelet response to TPO-RA (Table 1). In addition, the rating form included different ways to taper patients off therapy, how to monitor patients after discontinuation, and how to restart therapy. Ratings were completed independently by each expert before a full-day meeting. Median ratings were grouped into 3 categories (1-3, 4-6, 7-9) and disagreement was defined as ≥2 ratings of 1-3 and ≥2 ratings of 7-9 for a given scenario. During the meeting, discordant ratings were discussed. At the conclusion, experts completed ratings again (final round). Chi-square tests were conducted to determine if each patient characteristic significantly impacted ratings. Final ratings were used to describe the circumstances when it is inappropriate or appropriate to consider tapering TPO-RA monotherapy, how to taper TPO-RAs, how to monitor patients after discontinuation, and how to restart therapy. The panel was double-blinded while work was ongoing: the sponsor did not know the identity of the experts and the experts did not know the identity of the sponsor. The sponsor did not provide input on study design, methods, results, or interpretation of findings. Results: The proportion of items with disagreement decreased from 20% to 10% following the meeting. In the final round, 5 patient characteristics were found to significantly impact ratings and thus the appropriateness of tapering TPO-RA treatment: platelet count (p<0.001), history of bleeding (p=0.001), intensification of treatment (p<0.001), trauma risk (p<0.001), use of anticoagulants or platelet inhibitors (p<0.001). These characteristics were used to describe when it is inappropriate or appropriate to consider tapering TPO-RA monotherapy (Table 1). Experts agreed that it is inappropriate to consider tapering TPO-RA monotherapy in responding patients with low platelet counts, in patients with less than normal but still adequate platelet counts who have a history of major bleeding, or in patients who have a high risk of trauma and are using anticoagulants or platelet inhibitors (regardless of platelet count). It is appropriate to consider tapering TPO-RA monotherapy in patients with normal/above normal platelet counts, no history of major bleeding, and who have not required an intensification of treatment in the past 6 months. Recommendations on how to taper patients off therapy, how to monitor patients after discontinuation, and how to restart therapy were also developed. Conclusion: A validated methodology was used to assist an expert panel in developing clinical recommendations on when it is inappropriate or appropriate to consider tapering TPO-RA monotherapy and how to safely taper patients off therapy. The guidance reflects areas of greatest agreement based on clinical experience and currently available limited evidence. These recommendations could serve as a guide to clinical care and inform the development and design of clinical trials that prospectively test the safety of tapering TPO-RA monotherapy in patients with ITP. Disclosures Cuker: Pfizer: Research Funding; Novartis: Research Funding; Novo Nordisk: Research Funding; Sanofi: Research Funding; Spark: Research Funding; Takeda: Research Funding; Alexion: Research Funding; Bayer: Research Funding; Synergy CRO: Consultancy. Despotovic:Dova: Consultancy; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Grace:Novartis: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; Pfizer: Research Funding. Kruse:UCB: Other: Grant and consultancy fee, all paid to PDSA; Rigel: Other: Grant paid to PDSA; Principia: Other: Grant paid to PDSA; Pfizer: Other: Grant and consultancy fee, all paid to PDSA; Argenx: Other: Grant paid to PDSA; Amgen: Other: Grant and honorarium, all paid to PDSA; Novartis: Other: PDSA received payment for recruiting patients to I-WISh and for promoting I-WISh on the globalitp.org website. Grant and consultancy fee, all paid to PDSA outside the submitted work; CSL Behring: Other: Grant paid to PDSA. Lambert:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Platelet Disorder Support Association (PDSA): Consultancy; ClinGen: Honoraria; Principia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenix: Consultancy; Bayer: Consultancy; ITP Australia: Consultancy; AstraZeneca: Research Funding; Sysmex: Research Funding; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees; CdLS Foundation: Consultancy; RDMD ITP study: Consultancy; 22qSociety: Consultancy; Octapharma: Consultancy, Research Funding; Educational Concepts in Medicine: Consultancy; Shionogi: Consultancy. Liebman:Janssen: Consultancy; Amgen: Research Funding; Novartis: Honoraria, Research Funding; Kezar: Research Funding; Argenix: Research Funding; Alexion: Other; Genzyme: Consultancy; BMS: Consultancy; Rigel: Consultancy, Research Funding; Portola: Consultancy; Principia Biopharma: Consultancy. Lyons:Novartis: Honoraria; Texas Oncology/US Oncology: Current Employment. McCrae:Dova: Consultancy; Rigel: Consultancy; Momenta Pharmaceuticals: Consultancy; Novartis: Honoraria. Pullarkat:Dova: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wasser:Amgen: Consultancy; Biogen: Current equity holder in publicly-traded company, Other: He and his wife have equity ownership; Eli Lilly: Current equity holder in publicly-traded company, Other: He and his wife have equity ownership; Novartis: Honoraria, Speakers Bureau; Pfizer: Current equity holder in publicly-traded company, Other: He and his wife have equity ownership, Research Funding; Incyte: Research Funding; Merck: Current equity holder in publicly-traded company, Other: He and his wife have equity ownership, Research Funding. Beenhouwer:Dr. Beenhouwer reports other from Novartis during the conduct of the study; other from AbbVie, other from Akcea, other from ASPC, other from Amgen, other from AstraZeneca, other from BMS, other from Boston Scientific Corporation, other from Celgene, other: Other: Dr. Beenhouwer reports other from Novartis during the conduct of the study; other from AbbVie, other from Akcea, other from ASPC, other from Amgen, other from AstraZeneca, other from BMS, other from Boston Scientific Corporation, other from Celgene, other. Gibbs:Ms. Gibbs reports other from Novartis during the conduct of the study; other from AbbVie, other from Akcea, other from ASPC, other from Amgen, other from AstraZeneca, other from BMS, other from Boston Scientific Corporation, other from Celgene, other from: Other: SN Gibbs is an employee of the Partnership for Health Analytic Research (PHAR), LLC, which was paid by Novartis to conduct this research.. Yermilov:Dr. Yermilov reports other from Novartis during the conduct of the study; other from AbbVie, other from Akcea, other from ASPC, other from Amgen, other from AstraZeneca, other from BMS, other from Boston Scientific Corporation, other from Celgene, other f: Other: Dr. Yermilov reports other from Novartis during the conduct of the study; other from AbbVie, other from Akcea, other from ASPC, other from Amgen, other from AstraZeneca, other from BMS, other from Boston Scientific Corporation, other from Celgene, other f. Broder:Dr. Broder reports other from Novartis during the conduct of the study; other from AbbVie, other from Akcea, other from ASPC, other from Amgen, other from AstraZeneca, other from BMS, other from Boston Scientific Corporation, other from Celgene, other fro: Other: MS Broder is an employee of the Partnership for Health Analytic Research (PHAR), LLC, which was paid by Novartis to conduct this research..

Abstract BACKGROUND: Current treatment guidelines recommend tyrosine kinase inhibitors (TKIs) as first-line and second-line treatment options for patients with chronic myeloid leukemia (CML). 1,2 However, approximately 20% of CML patients fail to respond to the first- and second-generation TKIs, and evidence-based guidelines for late-line treatment options after failure/intolerance to TKIs are limited. 3,4 Therefore, this study sought to describe the clinical characteristics and real-world treatment patterns of CML patients who received 2 prior lines of TKI therapy. METHODS: A retrospective cohort design was utilized to identify adult CML patients who initiated a new line of therapy (LOT) after 2 prior lines of TKI therapy between 4/2013 and 12/2020 in the Florida Cancer Specialists network's electronic health records (EHR) database. The index LOT date was the start date of a new CML treatment regimen in LOT≥3 after 2 prior lines of TKI therapy. Patients were followed until 1 of the following occurred: death, loss to follow-up (last structured activity in EHR), or end of study period (3/31/2021). Demographic and clinical characteristics were captured during the baseline period starting 3 months prior to the initial CML diagnosis until the index LOT date and included age, gender, race, Eastern Cooperative Oncology Group performance status (ECOG PS) and comorbidity burden. Treatment patterns of all available LOTs from initial CML diagnosis were investigated and the following metrics were captured: regimen details of systemic CML therapies, duration of LOT, treatment-free interval. This study was descriptive in nature and no inferential statistics were computed. RESULTS: A total of 157 patients who initiated a new CML treatment regimen in LOT≥3 after 2 previous lines of TKI therapy were included in this study. The median age of the study sample at initial CML diagnosis was 63.8 years, 57.3% of the sample were male, and 50.3% were White. At index LOT, 46.5% of the sample had an ECOG PS score of 0-1, 5.1% had ECOG PS score of 2-4, and 48.4% had an unknown ECOG PS score. The majority of the sample initiated the index LOT in LOT 3 (n=151; 96.2%) vs in LOT 4 (n=6; 3.8%). The median duration of the index LOT was 6.6 months with median follow-up from index LOT being 23.0 months. After 2 prior lines of TKI therapy, 93.0% of the sample continued on TKIs only, 1.3% initiated a non-TKI CML drug, and 5.7% received a combination of CML drugs. Dasatinib (31.2%) and imatinib (30.6%) were the most commonly used TKIs in the index LOT. There was significant variability in the treatment sequences across LOTs, however, 50.3% of the sample restarted the same TKI in their index LOT which had been used in a prior LOT. A total of 65 patients (41.4%) initiated a new LOT after the index LOT, and the treatment-free interval following the index LOT was 1.8 months, on average. CONCLUSIONS: The majority of the CML patients who received 2 prior lines of TKI therapy continue to cycle through additional LOTs containing TKIs, and half of the patients restart the same TKI used in a prior LOT. The findings of this study highlight the need for better novel therapies that can fill the treatment gap for CML patients who are refractory or intolerant to TKIs. REFERENCES: 1. Deininger MW, Shah NP, Altman JK, et al. Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18(10):1385-1415. 2. Hochhaus A, Saussele S, Rosti G, et al. Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv41-iv51. 3. Perrotti D, Jamieson C, Goldman J, et al. Chronic myeloid leukemia: mechanisms of blastic transformation. J Clin Invest. 2010;120(7):2254-2264. 4. Cortes J, Lang F. Third-line therapy for chronic myeloid leukemia: current status and future directions. J Hematol Oncol. 2021;14(1):44. Disclosures Patel: Novartis Pharmaceuticals Corporation: Research Funding. Raju: Xcenda LLC: Current Employment, Other: Xcenda LLC received research funding from Novartis Pharmaceuticals Corporation. Coutinho: Xcenda LLC: Current Employment, Other: Xcenda LLC received research funding from Novartis Pharmaceuticals Corporation. Maegawa: Novartis Pharmaceuticals Corporation: Current Employment, Current equity holder in publicly-traded company. Lunacsek: Xcenda LLC: Current Employment, Other: Xcenda LLC received research funding from Novartis Pharmaceuticals Corporation. Deyoung: Xcenda LLC: Current Employment, Other: Xcenda LLC received research funding from Novartis Pharmaceuticals Corporation. Iorga: Novartis Pharmaceuticals Corporation: Current Employment, Current equity holder in publicly-traded company. Cao: Novartis Pharmaceuticals Corporation: Current Employment, Current equity holder in publicly-traded company.

Abstract Background: Venetoclax (VEN), an oral B-cell lymphoma 2 inhibitor, is approved for use in adult patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). As a targeted and highly active antitumor agent, VEN induces rapid and profound tumor reduction. Inpatient monitoring for initial doses of VEN is recommended by US Prescribing Information for pts with medium tumor burden and reduced renal function or high tumor burden. Administration of debulking agents, such as obinutuzumab (G), help reduce tumor burden and, consequently, facilitate subsequent administration of VEN in the outpatient setting. However, tumor reduction data are needed to definitively establish the utility of a debulking strategy. This study performed disease restaging after every 2 cycles of debulking to evaluate the safety and efficacy of G ± bendamustine (B) as a debulking regimen before VEN treatment in the outpatient community setting. The safety and efficacy of subsequent VEN+G treatment after debulking was also evaluated. Methods: This open-label, Phase 3b study (NCT03406156) enrolled adult pts with previously untreated CLL/SLL (except those with 17p deletion) who had medium (any lymph node [LN] 5 to <10 cm or absolute lymphocyte count [ALC] ≥25×10 9/L) or high (any LN ≥10 cm or any LN ≥5 cm and ALC ≥25×10 9/L) tumor burden. A maximum of six 28-day cycles of G±B were administered, and disease restaging was performed after every 2 cycles. Once low tumor burden was achieved (all LN <5 cm and ALC <25x10 9/L), VEN+G was administered for 5 cycles followed by VEN monotherapy for a total time on VEN of up to 1 year. Disease assessments were performed at the end of combination therapy (EoCT; 5 mo after last dose of G) and at the end of therapy (EoT; 3 mo after last dose of VEN), and peripheral blood was collected for assessment of minimal residual disease (MRD) using the clonoSEQ assay (Adaptive Biotechnologies). Undetectable MRD was defined as <1 CLL cell/10 4 leukocytes (<10 -4; uMRD4), <10 -5 (uMRD5), or <10 -6 (uMRD6). The primary endpoints were the percentage of pts achieving low tumor burden after 2, 4, and 6 cycles of G±B debulking and complete remission (CR) and CR with incomplete marrow recovery (CRi) rates among pts receiving VEN. Results: Of 120 pts treated, 81 received G for debulking and 39 received G+B. As of 13 May 2021, 2 pts remained on study treatment, 108 were in posttreatment follow-up, and 10 had discontinued the study for reasons including death (n=7), withdrawn consent (n=2), and COVID-19 infection (n=1). At baseline, 82.5% of pts had ALC ≥25x10 9/L, 33.3% had LN ≥5 cm, and 24.2%/75.0%/0.8% had high/medium/low tumor burden, respectively. Low tumor burden was achieved in 91.6% (109/119) of evaluable pts receiving G±B debulking. In the all-treated population (N=120), the objective response rate (ORR) was 90.0% and the CR/CRi rate was 35.8%. Among pts receiving VEN with disease assessment at EoT (N=76), the ORR was 98.7% and the CR/CRi rate was 44.7% (Table). The best uMRD4 rates in peripheral blood were 89.2% (107/120) for all-treated and 98.2% (107/109) for evaluable pts. Among evaluable pts, the uMRD4 rates were 100% (100/100) and 97.1% (68/70) at EoCT and EoT, respectively. Among pts with MRD assessments at both timepoints (N=67), 19.4% had a deepening of their MRD response from EoCT to EoT, and 67.2% maintained the same MRD level (Figure). At a median follow-up of 24.0 mo, 7 deaths (6 related to COVID-19 infection and 1 from cardiac complication after pancreatic mass resection) and no incidences of disease progression were reported; the estimated 18-mo PFS was 94.1%. In pts treated with G vs G+B debulking, respectively, the incidences of Grade ≥3 TEAEs were 71.6% vs 84.6% (most common was neutropenia at 28.4% vs 41.0%) and serious AEs were 23.5% vs 17.9% (most common were pneumonia and COVID-19 pneumonia, each at 3.7% vs 2.6%). Conclusion: In this study, most (91.6%) pts achieved low tumor burden after debulking. The uMRD4 rate was 98.2% among MRD-evaluable pts (89.2% among all pts), with 100% and 97.1% uMRD4 rates at EoCT and EoT, respectively. Overall, these results highlight the utility of G±B as an effective debulking strategy that can facilitate VEN treatment initiation in the outpatient setting. The efficacy and safety results are consistent with other VEN+G trials. Preventive measures for COVID-19 should be continuously emphasized for pts with CLL. Figure 1 Figure 1. Disclosures Flinn: AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Andorsky: AbbVie: Research Funding; Celgene/Bristol Myers Squibb: Consultancy; Celgene/Bristol Myers Squibb: Research Funding; Epizyme: Research Funding; AstraZeneca: Other: served on steering committees; AbbVie: Consultancy. Melear: TG Therapeutics: Speakers Bureau; Astrazeneca: Speakers Bureau; Janssen: Speakers Bureau. Manda: Morphosys: Honoraria; Genmab: Current equity holder in publicly-traded company. Kolibaba: TG Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Atara Biotechm: Consultancy; McKesson Specialty Health: Consultancy; Sunitomo Dainippon Pharma: Consultancy; Tolero Pharma: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Yimer: GSK: Speakers Bureau; Beigene: Speakers Bureau; Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Texas Oncology: Current Employment. Burke: Kura: Consultancy; Epizyme: Consultancy; Kymera: Consultancy; Adaptive Biotechnologies: Consultancy; Roche/Genentech: Consultancy; Beigene: Consultancy, Speakers Bureau; MorphoSys: Consultancy; Verastem: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy; X4 Pharmaceuticals: Consultancy; SeaGen: Consultancy, Speakers Bureau. Fanning: BMS: Speakers Bureau; TG Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genmab: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Speakers Bureau; Takeda: Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees. Islas-Ohlmayer: OHC/USON: Current Employment; AbbVie: Honoraria; Rigel: Honoraria, Speakers Bureau. Vizkelety: AbbVie: Current Employment, Current equity holder in publicly-traded company. Pesko: AbbVie: Current Employment, Current equity holder in publicly-traded company. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Jiang: AbbVie: Current Employment, Current equity holder in publicly-traded company. Sharman: Pharmacyclics LLC, an AbbVie Company: Consultancy; BMS: Consultancy; Lilly: Consultancy; BeiGene: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy.

Neste último número do ano de 2008 em primeiro lugar queremos agradecer a todas aquelas pessoas que contribuiram e contribuem com a edição desta revista eletrônica e desejar que todos tenhamos um ano 2009 pleno de realizações profissionais e pessoais.Os artigos que aqui apresentamos refletem pesquisas em vários temas relacionados ao turismo: ensino, economia, novas tendências de mercado, patrimônio. Todos trazem visões diferentes e até antagônicas, mostrando a complexidade deste fenômeno ou fato social que está, de fato, pleno de contradições.Em relação ao tema ensino, Francisco José da Costa apresenta um estudo sobre o interesse dos alunos dos cursos de turismo da cidade de Fortaleza (CE) em empreender atividades empresariais após a formatura. O autor descobre que o discurso da academia quanto ao empreendedorismo tem um eco relativo e que o empreendedorismo interessa mais aos estudantes que têm propensão natural para ele ou que provêm de famílias empreendedoras. Embora se trate de um estudo com poucos casos, circunscrito a uma capital, portanto não passível de generalização, pode ser indicativo de uma tendência, que deveria alertar para os demais cursos do país, fundamentalmente aqueles que alicerçam seus programas na formação para o empreendedorismo.Enquanto os cursos de turismo continuam tentando estimular novos empresários e formando recursos humanos para o planejamento do turismo, o poder público parece não despertar para a necessidade do mesmo, nem os empresários que têm dinheiro para abrir seus próprios negócios. É o que discute Roque Pinto num estudo de caso em Ilhéus, na BA. Este município que fora extremadamente rico durante o auge da monocultura do cacau, muito conhecido através da literatura e da pessoa de Jorge Amado (1912-2001), passou a ter um crescimento espontâneo do turismo, mas sem planejamento nem público nem privado. O estado não cuida da infra estrutura e o empresariado atua na área de turismo enquanto espera o retorno das benesses do cacau, ou como passatempo enquanto desfruta da aposentadoria numa cidade tranquila perto do mar. Para o autor, o problema principal é que nem estes empresários nem o estado enxergam o turismo como possibilidade econômica.Paradoxalmente, Mónica Lacarrieu que é antropóloga tal qual Roque Pinto, enfatiza, no seu artigo, que o problema do turismo tem sido o contrário: ser visto apenas como um fator econômico. A autora discorre sobre a necessidade de ver a relação entre turismo e política, no que traz uma inovação importante nos estudos realizados não apenas na América do Sul mas também do mundo, desde que são poucos os trabalhos fora os de Linda Richter, que focalizam a tal relação.Apresentando o caso de Buenos Aires, Lacarrieu analisa a utilização turística de estereótipos históricos pasteurizados que mascaram os problemas sociais e dos problemas sociais em si mesmos, tais como a pobreza recentemente instalada pelo projeto neoliberal do ex presidente Menem, e o protesto político muitas vezes dirigida a partir outros centros de poder.Como podem duas pessoas com a mesma formação e com o mesmo respaldo teórico oferecem duas explicações antagônicas? Podem, desde que o turismo não têm as mesmas características nem o mesmo desempenho nem obedece aos mesmos fatores em todos os lugares. É, como vimos afirmando há vários anos, um fenômeno rizomático o que tem tornado tão difícil haver um corpo de teorias a alicerçar os estudos, ou, dito de outra forma, a construção de teorias sobre o turismo.Dentro da rubrica produtos e serviços, o artigo de Kushano e Almeida mostra a triste realidade quanto à contradição entre prática e discurso, assim como a limitação de determinados conceitos ou do entendimento dos mesmos. Analisando a adaptação da hotelaria para portadores de necessidades especiais, descobrem que os portadores de deficiência auditiva estão muito pouco ou quase nada contemplados na hotelaria. Embora também se trate de um estudo de caso restrito à cidade de Curitiba (PR) a evidência empírica permite sugerir uma tendência no restante do país e, por que não, do cone sul, problema que também se verifica na área da cultura em geral e da educação.Finalmente, mostrando outro paradoxo do turismo, Berdasco, Afonso e Medeiros, sob orientação de Rejowski, investigam que, na cidade de São Paulo (SP), muitos hotéis se aparelham e muito bem para atender cães e gatos, sozinhos ou com seus donos. As autoras também alertam para o fato de que não é possível fazer generalizações e transparece no texto que tampouco a humanização dos animais é exclusiva do turismo. Os animais de estimação vêm ganhando cada vez mais espaço, no mercado de consumo assim como nos lares, face à crescente solidão em que vivem as pessoas no mundo contemporâneo, questão sobre a qual as autoras conclamam a refletir.A presente edição fecha com a crônica do evento anual da ANPTUR que esta vez aconteceu na cidade de Belo Horizonte, escrita pela presidente da associação, Mirian Rejowski e com a resenha de um livro pouco conhecido ainda no Brasil, The business of Tourism Management, na qual os leitores poderão ter, em oito páginas, um resumo de quase seiscentas, feito com maestria por Alexandre Panosso Netto.Margarita BarrettoSênia Bastos Editoras

O presente trabalho teve como objetivo determinar por espectroscopia de emissão óptica com plasma indutivamente acoplado (ICP OES) o teor dos minerais cobalto, cobre, ferro, fósforo, cálcio, magnésio,manganês, níquel, potássio e zinco, presentes nas folhas e no caule do Hibiscus sabdariffa L (vinagreira).Fez-se a triagem fitoquímica para verificar os compostos fitoquímicos como saponinas, taninos, fenóis, terpenos, esteróides, alcalóides, resinas, e flavonóides) da vinagreira coletada do município de São José de Ribamar-MA, onde os agricultores plantam o H. sabdariffa L) e comercializam para a maioria das feiras dessa região. Para os testes fitoquímicos realizados no caule e nas folhas da planta observaram-se saponinase esteróides moderamente positivo, taninos tanto condensado como hidrolisado fraco positivamente. As resinas foram encontradas moderadamente no caule e ausente na folha do H. sabdariffa L. Para os teste de flavonóides obteve reação forte para o caule e moderada para a folha. Observou-se a ausência de fenóis, terpenos e alcalóides. Em relação ao teor de metais presente no caule e na folha do H. sabdariffa L (vinagreira) verificaram-se respectivamente, uma quantidade significativa de ferro (11,91 e 30,04 mg/l) e cálcio (6,08 e 7,09 mg/l); para os demais minerais, o teor foi menor: magnésio (0,31 mg/l), potássio (0,36 e 0,72 mg/l) manganês (0,14 e 0,02 mg/l) e fósforo somente nas folhas (0,62 mg/l).Palavras-chave: Hibiscus sabdariffa L. Minerais. Espectroscopia. PHYTOCHEMISTRY EVALUATION AND DETERMINATION OF MINERAL SIN SAMPLES Hibiscus Sabdariffa L (vinegar)Abstract: This study aimed to determine by optical emission spectroscopy with inductively coupled plasma (ICP OES), the mineral content of cobalt, copper, iron, phosphorus, calcium, magnesium, manganese, nickel,potassium and zinc, present in the leaves and the stem of Hibiscus sabdariffa L (vinagreira). Became the phytochemical screening to check phytochemicals like saponins, tannins, phenols, terpenes, steroids, alkaloids, resins, and flavonoids) of vinegar collected in São José de Ribamar-MA, where farmers plant H. sabdariffa L ), and trade fairs for most of this region. For the tests performed phytochemicals in stems and leaves of the plant was observed saponins and steroids moderately positive, both condensed tannins hydrolyzateas weak positive. The resins were found moderately in stems and absent in leaf H. sabdariffa L. For the test flavonoids obtained strong reaction to stem and leaf to moderate. We observed the absence of phenols, terpenes and alkaloids. WRegarding the metal content present in the stem and leaf H. sabdariffa L (vinegar) respectively, a significant amount of iron (11,91 and 30,04 mg /l), calcium (6,08 and 7,09 mg/l) for the remaining minerals content was lower: Magnesium (0,31 mg/l), potassium (0,36 and 0,72 mg /l) Mn (0,14 and 0,02 mg/ l) and only on phosphor sheets (0,62 mg/l).Keywords: Hibiscus sabdariffa L. Mmineral. Spectroscopy. EVALUACIÓN FITOQUÍMICA Y DETERMINACIÓN DE MINERALES EN MUESTRA SEN MUESTRAS Hibiscus SabdariffaL (vinagre)Resumen: Este estudio tuvo como objetivo determinar por espectroscopia de emisión óptica con plasma acoplado inductivamente (ICP OES), la concentración de minerales de cobalto, cobre, hierro, fósforo, calcio,magnesio, manganeso, níquel, potasio y zinc, presentes en las hojas y el tallo de Hibiscus sabdariffa L (vinagrera). Se realizaron los ensayos generales para comprobar la presencia de fitoquímicos como saponinas,taninos, fenoles, terpenos, esteroides, alcaloides, resinas y flavonoides) en la vinagrera recogida en São José de Ribamar-MA, donde los agricultores siembran H. sabdariffa L, y la comercializan en las ferias de la mayor parte de esta región. En las pruebas realizadas para la detección de fitoquímicos en los tallos y hojas de la planta se observó saponinas y esteroides moderadamente positivos, taninos tanto condensados como hidrolizados dando positivo débil. Las resinas se encuentran moderadamente en los tallos y ausentes en las hojas de H. sabdariffa L. En los ensayos para flavonoides se obtuvo fuerte reacción en los tallos y moderada en las hojas. Se observó la ausencia de fenoles, terpenos y alcaloides. En cuanto al contenido de metales presentes en el tallo y en las hojas de H. sabdariffa L (vinagrera), respectivamente había una cantidad significativa de hierro (11,91 y 30,04 mg / l), y calcio (6,08 y 7 09 mg / l) para el restante de los minerales el contenido fue menor: de magnesio (0,31 mg / l), potasio (0,36 y 0,72 mg / l) Mn (0,14 y 0,02 mg / l ) y fósforo sólo en las hojas (0,62 mg/l).Palabras clave: Hibiscus sabdariffa L. Minerals. Espectroscopia.

Abstract Background: BCL2, a key regulator of apoptosis, is aberrantly expressed in many hematologic malignancies, which can lead to pathologic cancer cell survival. BCL2 inhibitors have been shown to be safe and effective, resulting in their approval for the treatment of pts with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and acute myeloid leukemia. Treatment with the currently approved BCL2 inhibitor, venetoclax, can be limited by common gastrointestinal toxicities, neutropenia, and the emergence of specific BCL2 mutations around the BH3-binding groove causing resistance. BGB-11417 was developed as a potent and highly selective inhibitor of BCL2. It has shown antitumor activity superior to venetoclax in human acute lymphoblastic leukemia, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL) xenograft models (Hu, AACR 3077). BGB-11417 also has a favorable pharmacokinetic profile with excellent bioavailability and selectivity for BCL2 at concentration <1nM. Toxicology studies have shown a broad therapeutic index and tolerable safety profile. The combination of a BCL2 inhibitor and a BTK inhibitor is tolerable with synergistic activity in CLL and MCL pts (Hillmen, J Clin Oncol 2019;37(30):2722-9; Jain, N Engl J Med 2019;30;380(22):2095-103; Siddiqi, ASH 2020 S158; Tam, N Engl J Med 2018; 378:1211-23). Zanubrutinib is a next-generation BTK inhibitor that has shown excellent activity and favorable toxicity in pts with CLL/SLL (Hillmen, EHA 2021 LB1900) and MCL (Tam, Blood Adv 2021;5(12):2577-85); with approval for treatment in MCL. Here we report preliminary results of the BGB-11417-101 trial (NCT04277637) in pts with non-Hodgkin lymphoma (NHL) or CLL/SLL treated with BGB-11417 monotherapy or in combination with zanubrutinib. Methods: BGB-11417-101 is a phase 1, open label, multicenter, dose-escalation and expansion study. Pts with NHL or CLL/SLL are treated with BGB-11417 as monotherapy or in combination with zanubrutinib. For dose escalation, pts with R/R B-cell malignancies are enrolled in 1 of 5 potential dose levels of BGB-11417 (40, 80, 160, 320, or 640 mg once daily). All pts utilize a ramp-up to intended target dose that varies by disease type. Pts in the combination therapy arm receive zanubrutinib 320 mg daily beginning 8-12 weeks before BGB-11417 is introduced. Adverse events (AEs) are reported per Common Terminology Criteria for AEs v5.0. Dose-limiting toxicity (DLT; assessed from ramp-up through day 21 at intended daily dose), evaluated by Bayesian logistic regression model, will be used to determine the maximum tolerated dose (MTD). Results: As of 24 May 2021 (data cutoff) 19 pts had been treated; 14 pts with monotherapy (NHL: n=11; CLL/SLL: n=3) and 5 pts with combination (all CLL; 3 pts were still on zanubrutinib pretreatment; 2 had started combination treatment). Median age was 72 y (range, 50-86); median follow-up was 1.9 mo (range, 0.7-12.4); all pts were R/R with a median of 2 prior regimens (range, 1-4). No DLTs were observed in pts with NHL receiving BGB-11417 monotherapy (n=11) up to the 160 mg dose level. AEs across all dose levels occurring in ≥2 pts (monotherapy) or ≥1 pt (combination) are listed in Table 1. A total of 5 pts discontinued treatment (all NHL) due to disease progression (n=4; 2 at 40 mg, 2 at 80 mg) or lack of efficacy (n=1 at 40 mg). No pt discontinued due to AEs. Laboratory tumor lysis syndrome was observed in 1 pt with CLL and high tumor burden (resolved with no sequelae). Initial efficacy after 3-month restaging in pts with CLL/SLL demonstrated 1 partial response (monotherapy arm) at the first dose level tested. All pts with CLL/SLL who have completed ramp-up (n=2, both monotherapy) normalized absolute lymphocyte count (ALC). Marked decreases in ALC were observed in pts with CLL at doses as low as 1 mg (Figure 1). Conclusion: Preliminary results suggest that BGB-11417 monotherapy is tolerable in pts with R/R NHL at the tested dose levels. Further assessment of safety and efficacy of BGB-11417 +/- zanubrutinib in CLL/SLL and NHL will be presented at the meeting, and evaluation in patients with treatment naïve CLL/SLL, R/R MCL, and R/R WM is planned. Figure 1 Figure 1. Disclosures Tam: AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Loxo: Consultancy; Novartis: Honoraria; Pharmacyclics: Honoraria. Verner: Janssen-Cilag Pty Ltd: Research Funding. Lasica: Celgene: Other: Travel, Accommodations, Expenses; Janssen: Other: Education. Arbelaez: Amgen: Other: Travel, Accommodations, Expenses. Browett: AbbVie: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Soumerai: BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Consultancy; GlaxoSmithKline: Research Funding; BostonGene: Research Funding; BMS: Consultancy; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy, Research Funding. Hilger: BeiGene: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Fang: BeiGene (Shanghai) Co, Ltd.: Current Employment, Current equity holder in publicly-traded company. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Simpson: Janssen: Research Funding; GSK: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; MSD: Research Funding; Roche: Research Funding; Celgene: Research Funding; Amgen: Research Funding; AbbVie: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; BeiGene: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Opat: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GIlead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Monash Health: Current Employment; BeiGene: Research Funding; Sandoz: Research Funding. Cheah: Ascentage Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not been approved for NHL or CLL/SLL in the US

Restarts are an important technique to make search more robust. This paper is concerned with how to maintain and propagate nogoods recorded from restarts efficiently. It builds on reduced nld-nogoods introduced for restarts and increasing nogoods introduced for symmetry breaking. The paper shows that reduced nld-nogoods extracted from a single restart are in fact increasing, which can thus benefit from the efficient propagation algorithm of the incNGs global constraint. We present a lighter weight filtering algorithm for incNGs in the context of restart-based search using dynamic event sets (dynamic subscriptions). We show formally that the lightweight version enforces GAC on each nogood while reducing the number of subscribed decisions. The paper also introduces an efficient approximation to nogood minimization such that all shortened reduced nld-nogoods from the same restart are also increasing and can be propagated with the new filtering algorithm. Experimental results confirm that our lightweight filtering algorithm and approximated nogood minimization successfully trade a slight loss in pruning for considerably better efficiency, and hence compare favorably against existing state-of-the-art techniques.

Abstract The March 2011 nuclear accident (3.11) shook Japan’s nuclear energy policy to its core. In 2012, the Liberal Democratic Party (LDP) returned to government with a pro-nuclear policy and the intention to swiftly restart nuclear power plants. In 2020, however, only six nuclear reactors were in operation. Why has the progress of nuclear restarts been so slow despite apparent political support? This article investigates the process of restarting nuclear power plants. The key finding is that the ‘nuclear village’, centered on the LDP, Ministry of Economy Trade and Industry, and the nuclear industry, which previously controlled both nuclear policy goal-setting and implementation, remained in charge of policy decision making, i.e. goal-setting, but lost policy implementation power to an extended conflict over nuclear reactor restarts. The main factors that changed the politics of nuclear reactor restarts are Japan’s new nuclear safety agency, the Nuclear Regulation Authority (NRA), and a substantial increase in the number of citizens’ class-action lawsuits against nuclear reactors. These findings highlight the importance of assessing both decision making and implementation in assessments of policy change.

Alors que de nombreux animaux fréquentent l’espace aérien, les activités humaines occupent également sensiblement cette strate. Dans cet article nous prenons l’exemple de quatre types d’obstacles – les aéronefs, le bâti, les éoliennes et les lignes électriques – afin d’illustrer leurs impacts sur trois groupes d’espèces volantes en particulier, les Oiseaux, les Chauves-souris et les Insectes. Nous montrons que, d’après la littérature existante, ces obstacles aériens sont clairement une source de mortalité par collision, électrocution ou barotraumatisme, en plus de générer des nuisances, une perte et une fragmentation des habitats. Cependant, la quantification de ces problèmes reste très variable en fonction des obstacles et des espèces et en France elle est globalement mal connue (à l’exception des aéronefs et, dans une moindre mesure, des éoliennes). Nous présentons ensuite différentes mesures de gestion qui sont d’ores et déjà mises en œuvre ou testées pour diminuer ces impacts. Mais il ressort aussi que leur déploiement est très variable selon les obstacles (par exemple, la gestion du risque aviaire sur les aéroports bénéficie de plusieurs décennies d’expériences alors que l’impact du bâti n’est quasiment pas pris en compte) et que la plupart du temps ces mesures sont sectorielles et plus ou moins efficaces à ce jour (certaines restant au stade de la recherche et du développement). Nous soulignons alors l’intérêt d’une démarche globale, via l’approche par trames, afin d’approfondir ces problématiques, et proposons plusieurs pistes pour mettre en œuvre cette « Trame aérienne ».

AbstractAn epidemic multi-group model formed by interconnected SEIR-like structures is formulated and used for data fitting to gain insight into the COVID-19 dynamics and into the role of non-pharmaceutical control actions implemented to limit the infection spread since its outbreak in Italy. The single submodels provide a rather accurate description of the COVID-19 evolution in each subpopulation by an extended SEIR model including the class of asymptomatic infectives, which is recognized as a determinant for disease diffusion. The multi-group structure is specifically designed to investigate the effects of the inter-regional mobility restored at the end of the first strong lockdown in Italy (June 3, 2020). In its time-invariant version, the model is shown to enjoy some analytical stability properties which provide significant insights on the efficacy of the implemented control measurements. In order to highlight the impact of human mobility on the disease evolution in Italy between the first and second wave onset, the model is applied to fit real epidemiological data of three geographical macro-areas in the period March–October 2020, including the mass departure for summer holidays. The simulation results are in good agreement with the data, so that the model can represent a useful tool for predicting the effects of the combination of containment measures in triggering future pandemic scenarios. Particularly, the simulation shows that, although the unrestricted mobility alone appears to be insufficient to trigger the second wave, the human transfers were crucial to make uniform the spatial distribution of the infection throughout the country and, combined with the restart of the production, trade, and education activities, determined a time advance of the contagion increase since September 2020.

All tumors have DNA mutations, and a predictive understanding of those mutations could inform clinical treatments. However, 40% of the mutations are variants of unknown significance (VUS), with the challenge being to objectively predict whether a VUS is pathogenic and supports the tumor or whether it is benign. To objectively decode VUS, we mapped cancer sequence data and evolutionary trace (ET) scores onto crystallography and cryo-electron microscopy structures with variant impacts quantitated by evolutionary action (EA) measures. As tumors depend on helicases and nucleases to deal with transcription/replication stress, we targeted helicase–nuclease–RPA complexes: (1) XPB-XPD (within TFIIH), XPF-ERCC1, XPG, and RPA for transcription and nucleotide excision repair pathways and (2) BLM, EXO5, and RPA plus DNA2 for stalled replication fork restart. As validation, EA scoring predicts severe effects for most disease mutations, but disease mutants with low ET scores not only are likely destabilizing but also disrupt sophisticated allosteric mechanisms. For sites of disease mutations and VUS predicted to be severe, we found strong co-localization to ordered regions. Rare discrepancies highlighted the different survival requirements between disease and tumor mutations, as well as the value of examining proteins within complexes. In a genome-wide analysis of 33 cancer types, we found correlation between the number of mutations in each tumor and which pathways or functional processes in which the mutations occur, revealing different mutagenic routes to tumorigenesis. We also found upregulation of ancient genes including BLM, which supports a non-random and concerted cancer process: reversion to a unicellular, proliferation-uncontrolled, status by breaking multicellular constraints on cell division. Together, these genes and global analyses challenge the binary “driver” and “passenger” mutation paradigm, support a gradient impact as revealed by EA scoring from moderate to severe at a single gene level, and indicate reduced regulation as well as activity. The objective quantitative assessment of VUS scoring and gene overexpression in the context of functional interactions and pathways provides insights for biology, oncology, and precision medicine.

Abstract This research note unveils new archival evidence from Amnesty International's first twenty-five years (1961–1986) to shed light on the realization of international human rights as Amnesty balanced “nonpolitical politics” through multifaceted government relations. The research draws from minutes and reports of eighty meetings of Amnesty's executive leadership and interviews from the 1983 to 1985 Amnesty Oral History project, all collected from the International Institute of Social History. The records show that during this time Amnesty relied on government and foundation funding to exit a severe financial crisis. Amnesty also cultivated a private diplomatic network with governments for access and advocacy and conducted side bargains with closed countries for access and reforms. In one sense, the new evidence complicates the conventional wisdom that Amnesty was only financed from small, individual donors and stayed away from private government dealings. In another sense, the new data extend existing insights about INGO strategic action by revealing Amnesty's pragmatic trade-offs when maintaining arms–length relations with governments to better appreciate the organization's early challenges and accomplishments. The note ultimately contributes to scholarship on the strategic choices of INGOs and provides new data for future research on the agency of nonstate actors in global governance navigating complex government relations. Esta nota de investigación presenta nueva evidencia documental de los primeros 25 años de Amnistía Internacional (Amnesty International), de 1961 a 1986, para arrojar luz sobre el cumplimiento de las normas internacionales de derechos humanos mientras Amnistía balanceaba la “política no política” mediante relaciones gubernamentales polifacéticas. La investigación incorpora actas e informes de 80 reuniones del liderazgo ejecutivo de Amnistía y entrevistas de 1983 a 1985 del proyecto Historia Oral de Amnistía (Amnesty Oral History), recopiladas del Instituto Internacional de Historia Social. Los documentos muestran que, en ese momento, Amnistía necesitó financiación gubernamental y de fundaciones para salir de una crisis financiera grave. Amnistía también cultivó una red diplomática privada con gobiernos a cambio de acceso y defensa, y tuvo negocios paralelos con países cerrados a cambio de acceso y reformas. En un sentido, la nueva evidencia complica la sabiduría convencional de que Amnistía solo tuvo financiamiento de donantes pequeños e individuos y se mantuvo lejos de los negocios privados con gobiernos. En contraste, los nuevos datos amplían las percepciones existentes sobre la acción estratégica de organizaciones no gubernamentales internacionales (ONGI), revelando las concesiones pragmáticas de Amnistía al mantener relaciones independientes con gobiernos, y permiten apreciar mejor los desafíos y logros iniciales de la organización. La nota, fundamentalmente, contribuye a la investigación sobre las decisiones estratégicas de las ONGI y brinda nuevos datos para futuras investigaciones sobre la autonomía de los actores no estatales que navegan relaciones gubernamentales complejas en la gobernanza global. Cet exposé de recherche dévoile de nouvelles preuves issues des 25 premières années d'archives d'Amnesty International (1961–1986) pour apporter un éclairage sur l'application des droits de l'Homme tandis qu'Amnesty équilibrait la « politique apolitique » par le biais de relations gouvernementales à plusieurs facettes. Cette recherche s'appuie sur des minutes et rapports de 80 réunions de la haute direction d'Amnesty, ainsi que sur des entretiens qui ont eu lieu entre 1983 et 1985 dans le cadre du projet Oral History (Histoire orale) d'Amnesty. Ces données ont toutes été recueillies auprès de l'Institut International d'Histoire Sociale. Les archives montrent que durant cette période, Amnesty a dû compter sur le financement de gouvernements et de fondations pour sortir d'une grave crise financière. Amnesty a également cultivé un réseau diplomatique privé avec des gouvernements pour faciliter son accès et son plaidoyer dans le pays concerné tout en menant des négociations parallèles avec les pays fermés pour y favoriser son accès et les réformes. En un sens, les nouvelles preuves compliquent les idées reçues selon lesquelles Amnesty ne serait financée que par de petits donateurs individuels et resterait à l’écart des affaires gouvernementales privées. Mais en un autre sens, ces nouvelles données enrichissent les renseignements existants sur l'action stratégique des organisations non gouvernementales internationales en révélant qu'Amnesty s’était livrée à des compromis pragmatiques en entretenant des relations avec les gouvernements tout en restant à distance. Ces renseignements nous permettent donc de mieux apprécier les premiers défis et accomplissements de l'organisation. En définitive, cet exposé contribue aux études sur les choix stratégiques des organisations non gouvernementales internationales et fournit de nouvelles données pour les recherches futures sur l'intervention des acteurs non étatiques dans la gouvernance mondiale tandis qu'ils naviguent dans des relations gouvernementales complexes.

I love memory. It reminds me of who I am and how to get home, whether there's bread in the freezer and if I've already seen a movie. It's less helpful on whether I've already met someone and utterly useless in reminding me if I owe money. Overall, though, I'd rather have it than not. Psychologists and philosophers tell us that memory is one of the ways in which we maintain the integrity of the self. I've never met anyone who's lost his memory, but we've all seen movies in which it happens. First, you lose your memory, then you're accused of a crime you can't remember committing. I forget how it turns out but I did once see a documentary about a man who'd lost his memory. It was horrible. It was driving him insane. He could remember his wife, but couldn't remember when he'd last seen her. He thought it was years ago although it had only been 5 minutes. Every time she entered the room, he traversed paroxysms of agony as though seeing her again after an eternity of waiting. The experience was overwhelming for both of them. Of course, psychoanalysts are unequivocal about the importance of memory: repressed memories are the very stuff of the unconscious and analysis helps us remember. When memories are repressed, bad things happen. As Breuer and Freud stated in 1893, "hysterics suffer mainly from reminiscences". History has also long been concerned to discover a true memory, or at least an official one. And history has become one of the main cultural battlegrounds over the right way to remember. But lately, memory has become big business. Entire industries are devoted to selling it back to us. Not private memories, but the likely memories of a group. For example, my newsagent carries at least 3 "nostalgia" magazines, replete with loving photographs of old toys, reprints of old ads, interviews with old personalities, and so on. Fortunately, they're all just a bit too old and the absence of my personal nostalgia reassures me that I'm not quite as decrepit as Generation Xers claim. Nonetheless, amongst my 200-odd TV channels, there is one devoted exclusively to old shows, TVLand. It broadcasts nothing later than 1981 and, though its policies are clearly guided by contractual availability and cost, specialises in TV of the mid-1960s. Now that is getting dangerously close to home. And I confess that, after 30 years, re-viewing episodes of Julia or Petticoat Junction or The Mod Squad ("one's white, one's black, one's blond") is an experience both compelling and embarrassing. And again, this summer, as for the past 15 years, movie screens were awash in retro-films. Not films with old-fashioned plots or deliberately nostalgic styles -- such as Raiders of the Lost Ark -- but films based on cultural artefacts of the near past: The Avengers, Lost in Space, Sergeant Bilko, McHale's Navy, another Batman, The Mask of Zorro, etc. Indeed, now that we've lived through roughly six Star Treks, Mission Impossible, The Flintstones, The Twilight Zone, The Beverly Hillbillies, The Jetsons, and in view of the fact that even now -- even as I write these very lines -- locations are being scouted for Gilligan's Island: The Movie, it seems appropriate to ask if there is a single TV show of the 1960s which will NOT become a major Hollywood movie? That's not all. I have access to approximately 10 "golden oldies" music stations, some specialising solely in "PowerHits of the '70s" or "Yesterday's Country" or "Hits of the Big Band Era". In fact, I think Big Band is making a comeback on the pop charts. Maybe everything old is new again. On the other hand, memory has also become highly political. Much more that I ever remembered. All over the world, governments and institutions are rushing to remember the wrongs of the past and issue sincere apologies. President Clinton apologised to Japanese Americans, some Australian state and local governments to Aborigines, Canada to the displaced Inuit, Tony Blair to the Irish, Swiss banks to the victims of Nazi gold. The return of the repressed is apparently highly therapeutic and certainly very virtuous. Strangely, though, the institutional process of memory recovery is happening at precisely the time that the same recovered memory theory is under attack in the courts. After having been a potent argument in the 1980s, especially in cases involving a sexual component, recovered memory is now widely discredited. Indeed, even movies-of-the-week which at one time preached recovered memory as unassailable truth now regularly use it as the cover of false accusations and gross miscarriages of justice. Even the Canadian Minister of Justice is under pressure to review the cases of all persons jailed as a result of its use. It would seem that after having been private for so many years, memory has gone public. It's a political tool, a legal argument, a business. The opposite of hysteria: we suffer from too much memory. Which leads me to my problem. I can't remember Princess Diana. This is no doubt because I avoided all mention of her when she was alive. And when she died, I was away. Not far away but conceptually away. Away from the media. I didn't follow the news till days later, when it was all over and TV had moved on to something else. Her exit, of course, was rather nasty. Not the sort of thing I'd want to witness, but certainly the sort of thing I'd like to know about. And it didn't exactly happen away from the public eye. There was, it is said, a crush of paparazzi in hot pursuit. And there are allegedly tons of photographs. So how come we haven't seen any? How have the authorities managed to control all those pictures? Supremely concerned with her image in life, Diana is fortunate that others are concerned with it in death. At least the absence of photographs allows us to preserve an unblemished memory of Diana, beautiful, beneficent, almost a people's princess. It does seem though that her memory, like her fame, is largely a by-product of media exposure. If you're in it, everyone knows about you. You're everywhere, inescapable. Your smiling face beams down on millions, your every thought reported. And it's not just the excessive, tabloid press, the fake news programmes, and the tawdry scandal sheets that indulge in this oversaturation -- although they do indulge quite a bit -- but all media. Obviously, competitive pressures are to blame. And probably also a cultivated appetite for the sordid and the scandalous. The upside of so much attention, of course, is that, once you're gone, there will be lots of images and sound bites to remember you by. These will be recycled again and again and again. Today's fragments of time are tomorrow's memories. Consequently, if you must be a public figure, try to have a good exit. Consider perhaps James Dean's advice to "live fast, die young, and leave a good looking corpse." Especially a good looking corpse. Of course, if you're out of it -- out of the media system, that is -- then, you're just out of it. Nobody will remember you anyway. This is why Elvis will never die and John Kennedy will never stop dying. Except perhaps for his heavy Las Vegas phase, virtually all of the images of the King show him as magnetic, powerful, and exciting. Colonel Parker was careful about that. Elvis constantly exudes energy, an all-too-palpable physicality, forever re-energised and re-distributed by the film images of him. And the posters, and the sound of his voice, and the myth of his wildness. Fortunately, though, Elvis had the good grace to expire privately, beyond the public eye. In this, he resembled Marilyn, Rock Hudson, and Walt Disney. Of that event, he left no record. Indeed, the absence of such a record has allowed the remaining images to fuel a new myth. Endlessly re-circulated in a media sub-system, the images prove that Elvis lives! Consequently, people -- usually those first contacted by aliens -- keep spotting him at 7-Elevens, supermarket checkouts, and isolated gas stations. Apparently, he just wanted to live life normally. The fame had become too intrusive. And who could begrudge him that? So he faked his death, left no trace, and wandered off into the wilderness. To this extent, Elvis shares the fate of Hitler and the Romanovs whose deaths were deliberately obscured. As a result, Hitler lives on, at times on a desert island, sometimes in a bunker deep beneath the earth. And wasn't that Alexis, the tsarevitch? And over there, Anastasia? Aren't they having lunch with Amelia Earhardt? Kennedy, though, left a bad image, the queasy head shot. Too public, too visible, too shocking. It wasn't what James Dean meant. And that one image has absorbed all the others. This is ironic because Kennedy was the first president to look and behave like an actor whereas it would be years before an actor could look and behave like the president. Kennedy loved the camera and the camera, as they say, loved him. He had a permanent staff photographer who generated thousands of shots. He embraced television as no president had before, dominating the televised debates, holding live press conferences, opening the White House to TV tours. He invited Robert Drew to film his 1959 nomination campaign in Primary, giving him, as is always said in these cases, "unprecedented access". But the only pictures we remember come from Dallas. Gloria Steinem called it "the day the future died". Then, if we think really hard, we remember the funeral. But we can hardly remember anything else. Pictures of Jack campaigning, playing with the kids, receiving Marilyn's birthday greetings, are almost surprising. They're so fresh, as though we'd never seen them before. Kennedy should have died like Elvis, he would have lived longer in the imagination. As it is, he only ever dies and the very publicness of his death seems to have authorised its endless restaging. Has any film ever been more publicly scrutinised, examined, and re-created than the Zapruder film? The incident has littered the culture with such stock phrases as 'lone gunman' and 'grassy knoll'. It's also the birthplace of every crazy conspiracy theory. And everyone from the Warren Commission to Oliver Stone and Jerry Seinfeld has used the phrase "Back, and to the left". It's not surprising that our memory of public events should be bound up with images of those events. Most of us, most of the time, have no other access to them. This knowledge, combined with the pervasiveness of the media system, has led clever marketers of all sorts, to attempt to stage what Daniel Boorstin in 1961 called "pseudo-events". Events which exist for the benefit of the camera, with no real substance of their own. Their purpose is precisely to create an image, a feeling, a mood. Of course, every propagandist of any skill understood these facts long before Boorstin. How many photographs were doctored on Stalin's orders? How often was the mole on Mao's chin repainted? How often was Lenin's face itself repainted with embalming fluid? And didn't Adolf Hitler surround himself with the most exquisite filmmakers, photographers, and image-makers available? You just can't dictate without a firm grasp of your image. And that's the other side of modern times. Increasingly, we all have a firm grasp of image. We are no longer the media dupes which moralists frequently presume. The media have made us all rather sophisticated in the ways of the media. Everyone understands that politicians manage their images and stage events. Everyone knows that advertising is only creatively truthful. No one believes that what happens in a film really happens. We all realise that most of what's seen on TV is spin doctoring. We're hardened. And this is no doubt why the creamy sincerity of the eager tears which now attend public disclosures, the touchy-feely goodness of anyone who can "feel our pain" are so much in demand. No matter how fake, how contrived, how manipulative, they at least look like the real thing. At one time, popular culture merely suggested shock and violence. It did not show them directly. The Kennedy assassination marked the end of that time as people turned away from the screen in horror, asking "Did they have to show us that?" We're now in a time when popular culture suggests nothing and shows everything, in as much detail as possible. This is the moment of Diana's death and we turn to our screens demanding to see more, shouting "We have a right to know!" But a slippage may be happening. We know so much about media operations -- or believe that we do -- that the media may be losing their ability to define events and construct memory. This appears to be one of the lessons of the Diana coverage: the paparazzi in particular, and the media in general, were at fault. Public anger was directed not at her driver, her companions or her lifestyle, but at the media. That the behaviour of the paparazzi remains to be fully elucidated, and that Diana had the weight of accumulated prestige and exposure on her side, make meaningful commentary more difficult, but there is a clear sense in which the public sided with perceived sincerity and genuineness and against perceived exploitation. Clearly, these matters are always open to revision, but the anger directed against the media in this affair spoke of pent-up rage, of long nursed grudges, of a generalised judgment that the media have done more harm than good. Something similar is happening in the Clinton-Lewinsky affair. The US media are apparently obsessed with this event and greatly agitated by the necessity of further coverage. Public opinion, however, has indicated just as firmly that it doesn't care and wants the whole thing to go away. There's a split between the definitional power of the media and public opinion, a drifting apart that wasn't supposed to happen. Media commentators of both the left and the right, both those who believe in media effects and those who decry the concentration of ownership, have long agreed on one thing: the media have too much power to tell us what to think. And yet, in this case, it's not happening. Indeed, 10 years from now, what will we remember? That Bill Clinton and Monica Lewinsky had an affair or that the media were very agitated about it? The way in which media images are linked to popular memory may be changing. We are less concerned with whether the media got the event right than with how they approached it at all. Already, concern over the Gulf War centres as much on the manner of coverage as on the legitimacy of the war's objectives. And the old complaint that the media cover elections as strategic horse races, thereby ignoring substantive issues, presumes the naivety of the audience. Everyone can tell exactly what the media are doing. So what will we remember? How will we feel in 40 years examining old footage of today's newscasts? Memory fades and images are about emotion. Will we experience the diffuse grimness of the WWII veteran watching Saving Private Ryan, identifying less with specific acts than with the general feeling of the moment? Probably. But perhaps we'll also carry with us a second layer of meaning, an equally diffuse recognition that the moment was constructed. I was watching a documentary last night about Hitler's last days. I'm sure everyone's seen it or something like it. The very fact I can be sure of this is the measure of the media's ability to shape popular memory. Hitler, visibly ailing, emerges from his bunker to acknowledge his last line of defence, a string of soldiers who are really only children. He stops as though to speak to one and pats the boy on the cheek. It's a profoundly creepy moment. One feels discomfort and distaste at being so close, one is acutely aware of the distance between the image's intention and the reality of which we have knowledge. Then, suddenly and imperceptibly, the camera shifts angles and follows Hitler down the line of soldiers, a standard travelling shot. It's invisible because that's the way military reviews are always shown. It works because we want a good view. It's compelling because it draws us into the scene. It looks so real and is plainly read that way, as historical actuality footage. But it's also plainly constructed. And that's increasingly what we see nowadays. We see the way in which images intend to connect to emotions. Maybe it's the future of all memory, to be disjointed and creepy. To acknowledge simultaneously the reality of the event and its fakeness. Rather like the performance of Hollywood actors or US presidents or publicly proffered sentiment. Clearly, we won't be dealing with the return of the repressed as we'll remember everything. We'll just have too much memory. Citation reference for this article MLA style: Paul Attallah. "Too Much Memory." M/C: A Journal of Media and Culture 1.2 (1998). [your date of access] <http://www.uq.edu.au/mc/9808/memory.php>. Chicago style: Paul Attallah, "Too Much Memory," M/C: A Journal of Media and Culture 1, no. 2 (1998), <http://www.uq.edu.au/mc/9808/memory.php> ([your date of access]). APA style: Paul Attallah. (1998) Too much memory. M/C: A Journal of Media and Culture 1(2). <http://www.uq.edu.au/mc/9808/memory.php> ([your date of access]).

This paper will discuss the way in which the creative component of my thesis Hannah’s Place uses a style of neo-historical fiction to find ‘good’ narratives in (once) ‘bad’ women, keeping with the theme, here paraphrased as: The work of any researcher in the humanities is to…challenge what is simply thought of as bad or good, to complicate essentialist categories and question passively accepted thinking. As a way of expanding this statement, I would like to begin by considering the following quote from Barthes on the nature of research. I believe he identifies the type of research that I have been involved with as a PhD candidate producing a ‘creative’ thesis in the field of Communications. What is a piece of research? To find out, we would need to have some idea of what a ‘result’ is. What is it that one finds? What is it one wants to find? What is missing? In what axiomatic field will the fact isolated, the meaning brought out, the statistical discovery be placed? No doubt it depends each time on the particular science approached, but from the moment a piece of research concerns the text (and the text extends very much further than the literary work) the research itself becomes text, production: to it, any ‘result’ is literally im-pertinent. Research is then the name which prudently, under the constraint of certain social conditions, we give to the activity of writing: research here moves on the side of writing, is an adventure of the signifier. (Barthes 198) My thesis sits within the theoretical framework of postmodern literature as a new form of the genre that has been termed ‘historical fiction’. Although the novel breaks away from and challenges the concept of the traditional ‘saga’ style of narrative, or ‘grand narrative’ within historical fiction, it is no less concerned with events of the past and the idea of past experience. It departs from traditional historical fiction in that it foregrounds not only an imagined fictional past world created when the novel is read, but also the actual archival documents, the pieces of text from the past from which traditional history is made, and which here have been used to create that world–‘sparking points’ for the fictional narrative. These archival documents are used within the work as intertextual elements that frame, and, in turn, are framed by the transworld characters’ homodiegetic narrations. The term ‘transworld character’ has been attributed to Umberto Eco and refers to any real world personages found within a fictional text. Eco defines it as the ‘identity of a given individual through worlds (transworld identity)…where the possible world is a possible state of affairs expressed by a set of relevant propositions [either true or untrue which] outlines a set of possible individuals along with their properties’ (219). Umberto Eco also considers that a problem of transworld identity is ‘to single out something as persistent through alternative states of affairs’ (230). In Postmodernist Fiction, Brian McHale also puts forward a number of definitions for ‘transworld identity’. For my purposes, I take it to mean both that defined by Eco but also the literary device, as defined by McHale, of ‘borrowing a character from another text’ (57). It is McHale who elaborates on the concept as it relates to historical fiction when he states: All historical novels, even the most traditional, typically involve some violation of ontological boundaries. For instance they often claim ‘transworld identity’ between characters in their projected worlds and real-world historical figures (16-17). Interestingly for the type of fiction that I am attempting to write, McHale also takes the idea into another area when he discusses the ontological levels of the historical dimension that transworld identities may undergo. Entities can change their ontological status in the course of history, in effect migrating from one ontological realm or level to another. For instance, real world entities and happenings can undergo ‘mythification’, moving from the profane realm to the realm of the sacred (36). For transworld identities, such as those within my novel, this may mean a change in status between the past, where they were stereotyped and categorised as ‘bad’ in contemporary newspapers (my intertext elements), to something in the present approaching ‘good’, or at least a more rounded female identity within a fictional world. The introduced textual elements which I foreground in my novel are those things most often hidden from view within the mimetic and hermeneutic worlds of traditional historical fiction. The sources re-textualised within my novel are both ‘real’ items from our past, and representations and interpretations of past events. The female transworld characters’ stories in this novel are imaginative re-interpretations. Therefore, both the fictional stories, as well as their sources, are textual interpretations of prior events. In this way, the novel plays with the idea of historical ‘fact’ and historical ‘fiction’. It blurs their boundaries. It gives textual equality to each in order to bring a form of textual agency to those marginalised groups defined by PF Bradley as the ‘host of jarring witnesses, [of history] a chaos of disjoined and discrepant narrations’ (Bradley in Holton 11): In the past in Australia these were lower class women, Aboriginals, the Irish, the illiterate, and poor agricultural immigrants whose labour was excess to Britain’s needs. Hannah’s Place – A Brief Synopsis Six individual women’s stories, embedded in or ‘framed’ by a fictional topographic artist’s journal, recount ‘real’ events from Australia’s colonial past. The journal is set in 1845; a few years after convict transportation to Australia’s eastern states ceased, and the year of the first art exhibition held in the colony. That same year, Leichhardt’s expedition arrived at Port Essington in Australia’s far north, after 12 months inland exploration, while in the far south the immigrant ship Cataraqui was wrecked one day short of arrival at Melbourne’s Port Phillip with the drowning of all but one of the 369 immigrants and 38 of the 46 sailors on board. Each chapter title takes the form of the title of a topographic sketch as a way of placing the text ‘visually’ within the artist’s journal narrative. The six women’s stories are: New South Wales at Last (Woman on a Boat): A woman arrives with a sick toddler to tent accommodation for poor immigrants in Sydney, after a three month sea voyage and the shipboard birth, death, and burial at sea of her baby daughter. Yarramundi Homestead, as Seen from the East: An ill-treated Irish servant girl on a squatter’s run awaits the arrival of her fiancée, travelling on board the immigrant ship Cataraqui. In the Vale of Hartley: In the Blue Mountains, an emancipist sawyer who previously murdered three people, violently beats to death his lover, Caroline Collitts, the seventeen-year-old sister of Maria, his fifteen-year-old wife. She Being Dead Yet Speaketh: In Goulburn, Annie Brownlow, a pretty 24-year-old mother of three is executed by a convict executioner for the accidental ‘murder’, while drunk, of her adulterous husband. The Eldest Daughter: The isolated wife of a small settler gives birth, assisted by Lottie, her eldest daughter, and Merrung, an Aboriginal midwife. On Wednesday Last, at Mr Ley’s Coach and Horses Hotel: In Bathurst, a vagrant alcoholic, Hannah Simpson, dies on the floor of a dodgy boarding house after a night and a day of falling into fits and ranting about her lifetime of 30 years migration. Historiographic Metafiction Has been defined by Linda Hutcheon as ‘Fiction which keeps distinct its formal auto-representation from its historical context and in so doing problematises the very possibility of historical knowledge… There is no reconciliation, no dialectic…just unresolved contradiction’ (106). Unresolved contradiction is one of the themes that surfaces in my novel because of the juxtaposition of archival documents (past text ‘facts’) alongside fictional narrative. Historiographic metafiction can usefully be employed as a means of challenging prior patriarchal narratives written about marginalised women. It allows the freedom to create a space for a new understanding of silenced women’s lives. My novel seeks to illuminate and problematise the previously ‘seamless’ genre of hical fiction by the use of (narrative) techniques such as: collage and juxtaposition, intertextuality, framing, embedded narrative, linked stories, and footnote intertext of archival material. Juxtaposition of the fiction against elements from prior non-fiction texts, clearly enunciated as being those same actual historical sources upon which the fiction is based, reinforces this novel as a work of fiction. Yet this strategy also reminds us that the historical narrative created is provisional, residing within the fictional text and in the gaps between the fictional text and the non-fictional intertext. At the same time, the clear narrativity, the suspenseful and sensationalised text of the archival non-fiction, brings them into question because of their place alongside the fiction. A reading of the novel questions the truthfulness or degree of reliability of past textual ‘facts’ as accurate records of real women’s life events. It does this by the use of a parallel narrative, which articulates characters whose moments of ‘breaking frame’ challenge those same past texts. Their ‘fiction’ as characters is reinforced by their existence as ‘objects’ of narration within the archival texts. Both the archival texts and the fiction can be seen as ‘unreliable’. The novel uses ex-centric transworld characters and embedded intertextual ‘fragments’ to create a covert self-reflexivity. It also confuses and disrupts narrative temporality and linearity of plot in two ways. It juxtaposes ‘real’ (intertextual element) dates alongside conflicting or unknown periods of time from the fictional narrative; and, within the artist’s journal, it has a minimal use of expected temporal ‘signposts’. These ‘signposts’ of year dates, months, or days of the week are those things that would be most expected in an authentic travel narrative. In this way, the women’s stories subvert the idea, inherent in previous forms of ‘historical’ fiction, of a single point of view or ‘take’ on history that one or two main characters may hold. The use of intertext results in a continued restating of multiple, conflicting (gender, race, and class) points of view. Ultimately no one ‘correct’ reading of the past gains in supremacy over any other. This narrative construct rearticulates the idea that the past, as does the present, comprises different points of view, not all of which conform to the ‘correct’ view created by the political, social and economic ‘factors’ dominant at the time those events happen. For colonial Australia, this single point of view gave us the myth of heroic (white male) pioneers and positioned women such as some of those within my fiction as ‘bad’. The fictional text challenges that of the male ‘gaze’, which constructed these women as ‘objects’. Examples of this from the newspaper articles are: A younger sister of Caroline Collit, married John Walsh, the convict at present under sentence of death in Bathurst gaol, and, it appears, continued to live with him up till the time of her sister’s murder; but she, as well as her sister Caroline, since the trial, have been ascertained to have borne very loose characters, which is fully established by the fact, that both before and after Walsh had married the younger sister, Caroline cohabited with him and had in fact been for a considerable time living with him, under the same roof with her sister, and in a state of separation from her own husband (Collit). Sydney Morning Herald, April 27, 1842, The Mount Victoria Murder. About twelve months after her marriage, her mother who was a notorious drunkard hanged herself in her own house… Sydney Morning Herald, April 27, 1842, The Mount Victoria Murder. And when we further reflect that the perpetrator of that deed of blood was a woman our horror is, if possible, much augmented. Yes! A woman and one who ought to have been in as much as the means were assuredly in the power of her family-an ornament to her sex and station. She has been cut off in the midst of her days by the hands of the common executioner. And to add to our distress at this sad event she to whose tragic end I am referring was a wife and a mother. It was her hand which struck the blow that rendered her children orphans and brought her to an ignominious end… The Goulburn Herald, October 20, 1855, Funeral sermon on Mary Ann Brownlow. His wife had been drinking and created an altercation on account of his having sold [her] lease; she asked him to drink, but he refused, when she replied “You can go and drink with your fancywoman”. She came after him as he was going away and stabbed him…..she did it from jealousy, although he had never given her any cause for jealousy. The Goulburn Herald, Saturday, September 15, 1855, Tuesday, September 11, Wilful Murder. She was always most obedient and quiet in her conduct, and her melancholy winning manners soon procured her the sympathy of all who came in contact with her. She became deeply impressed with the sinfulness of her previous life… The Goulburn Herald, October 13, 1855, Execution of Mary Ann Brownlow. [Police] had known the deceased who was a confirmed drunkard and an abandoned woman without any home or place of abode; did not believe she had any proper means of support…The Bathurst Times, November 1871. It is the oppositional and strong narrative ‘voice’ that elicits sympathies for and with the women’s situations. The fictional narratives were written to challenge unsympathetic pre-existing narratives found within the archival intertexts. This male ‘voice’ was one that narrated and positioned women such that they adhered to pre-existing notions of morality; what it meant to be a ‘good’ woman (like Mary Ann Brownlow, reformed in gaol but still sentenced to death) or a ‘bad’ woman (Mary Ann again as the murdering drunken vengeful wife, stabbing her husband in a jealous rage). ‘Reading between the lines’ of history in this way, creating fictional stories and juxtaposing them against the non-fiction prior articulations of those same events, is an opportunity to make use of narrative structure in order to destabilise established constructs of our colonial past. For example, the trope of Australia’s colonial settler women as exampled in the notion of Anne Summers of colonial women as either God’s police or damned whores. ‘A Particularly rigid dualistic notion of women’s function in colonial society was embodied in two stereotypes….that women are either good [God’s police] or evil [Damned whores]’ (67). With this dualism in mind, it is also useful here to consider the assumption made by Veeser in laying the ground work for New Historicism, that ‘no discourse imaginative or archival, gives access to unchanging truths or expresses unalterable human nature’ (2). In a discussion of the ideas of Brian McHale, Middleton and Woods acknowledge McHale’s point of view that readers do recognise the degree to which all knowledge of the past is a construction. They make the claim that ‘the postmodern novelist answers that sense of dislocation and loss…by wrapping ruins of earlier textualities around the narrative’ (66). This to my mind is a call for the type of intertextuality that I have attempted in my thesis. The senses of dislocation and loss found when we attempt to narrativise history are embodied in the structure of the creative component of my thesis. Yet it could also be argued that the cultural complexity of colonial Australia, with women as the subjugated ‘other’ of a disempowered voice has only been constructed by and from within the present. The ‘real’ women from whose lives these stories are imagined could not have perceived their lives within the frames (class, gender, post coloniality) that we now understand in the same way that we as educated westerners cannot totally perceive a tribal culture’s view of the cosmos as a real ‘fact’. However, a fictional re-articulation of historical ‘facts’, using a framework of postmodern neo-historical fiction, allows archival documents to be understood as the traces of women to whom those documented facts once referred. The archival record becomes once again a thing that describes a world of women. It is within these archival micro-histories of illiterate lower-class women that we find shards of our hidden past. By fictionally imagining a possible narrative of their lives we, as the author/reader nexus which creates the image of who these transworld characters were, allow for things that existed in the past as possibility. The fictionalised stories, based on fragments of ‘facts’ from the past, are a way of invoking what could have once existed. In this way the stories partake of the Bernstein and Morson concept of ‘sideshadowing’. Sideshadowing admits, in addition to actualities and impossibilities, a middle realm of real possibilities that could have happened even if they did not. Things could have been different from the way they were, there are real alternatives to the present we know, and the future admits of various possibilities… sideshadowing deepens our sense of the openness of time. It has profound implications for our understanding of history and of our own lives (Morson 6). The possibilities that sideshadowing their lives invokes in these stories ‘alters the way that we think about earlier events and the narrative models used to describe them’ (Morson 7). We alter our view of the women, as initially described in the archival record, because we now perceive the narrative through which these events and therefore ‘lives’ of the women were written, as merely ‘one possibility’ of many that may have occurred. Sideshadowing alternate possibilities gives us a way out of that patriarchal hegemony into a more multi-dimensional and non-linear view of female lives in 19th Century Australia. Sideshadowing allows for the ‘non-closure’ within female narratives that these fragments of women’s lives represent. It is this which is at the core of the novel—an historiographic metafictional challenging by the fictional ‘voices’ of female transworld characters. In this work, they narrate from a female perspective the might-have-been alternative of that previously considered as an historical, legitimate account of the past. Barthes and Bakhtin Readers of this type of historiographic metafiction have the freedom to recreate an historical fictional world. By virtue of the use of self-reflexivity and intertext they participate in a fictional world constructed by themselves from the author(s) of the text(s) and the intertext, and the original women’s voices used as quotations by the intertext’s (male) author. This world is based upon their construction of a past created from the author’s research, the author’s subjectivity (from within and by disciplinary discourse), by the author(s) choice of ‘signifiers’ and the meanings that these choices create within the reader’s subjectivity (itself formed out of their individual cultural and social milieu). This idea echoes Barthes concept of the ‘death of the author’, such that: As soon as a fact is narrated no longer with a view to acting directly on reality but intransitively, that is to say, finally outside of any function other than that of the very practice of the symbol itself; this disconnection occurs, the voice loses its origin, the author enters into his own death, writing begins. (142) When entering into the world created by this style of historical fiction the reader also enters into a world of previous ‘texts’ (or intertexts) and the multitude of voices inherent in them. This is the Bakhtinian concept of heteroglossia, that ‘every utterance contains within it the trace of other utterances, both in the past and in the future’ (263). The narrative formed thus becomes one of multiple ‘truths’ and therefore multiple histories. Once written as ‘bad’, the women are now perceived as ‘good’ characters and the ‘bad’ events that occurred around them and to them make up ‘good’ elements of plot, structure, characterisation and voice for a fictionalised version of a past possibility. Bad women make good reading. Conclusion This type of narrative structure allows for the limits of the silenced ‘voice’ of the past, and therefore an understanding of marginalised groups within hegemonic grand narratives, to be approached. It seems to me no surprise that neo-historical fiction is used more when the subjects written about are members of marginalised groups. Silenced voices need to be heard. Because these women left no written account of their experiences, and because we can never experience the society within which their identities were formed, we will never know their ‘identity’ as they experienced it. Fictional self-narrated stories of transworld characters allows for a transformation of the women away from an identity created by the moralising, stereotyped descriptions in the newspapers towards a more fully developed sense of female identity. Third-hand male accounts written for the (then) newspaper readers consumption (and for us as occupiers of the ‘future’) are a construct of one possible identity only. They do not reflect the women’s reality. Adding another fictional ‘identity’ through an imagined self-narrated account deconstructs that limited ‘identity’ formed through the male ‘gaze’. It does so because of the ability of fiction to allow the reader to create a fictional world which can be experienced imaginatively and from within their own subjectivity. Rather than something passively recorded, literature offers history as a permanent reactivation of the past in a critique of the present, and at the level of content offers a textual anamnesis for the hitherto ignored, unacknowledged or repressed pasts marginalised by the dominant histories. (Middleton and Woods 77) References Bakhtin, Mikhail. The Dialogic Imagination: Four Essays. Trans. Michael Holquist. Ed. Caryl Emerson. Austin: U of Texas P, 1981. Barthes, Roland, and Stephen Heath, eds. Image, Music, Text. New York: Hill and Wang, 1977. Eco, Umberto. The Role of the Reader: Explorations in the Semiotics of Texts. Bloomington and London: Indiana UP, 1979. Holton, Robert. Jarring Witnesses: Modern Fiction and the Representation of History. New York: Harvester Wheatsheaf, 1994. Hutcheon, Linda. A Poetics of Postmodernism: History, Theory, Fiction. New York: Routledge, 1988. McHale, Brian. Postmodernist Fiction. New York and London: Methuen, 1987. Middleton, Peter, and Tim Woods. Literatures of Memory: History, Time and Space in Postwar Writing. Manchester and New York: Manchester UP, 2000. Morson, Gary Saul. Narrative and Freedom: The Shadows of Time. New Haven: Yale UP, 1994. Summers, Anne. Damned Whores and God’s Police. Ringwood Vic: Penguin Books, 1994. Veeser, H. Aram. The New Historicism. London: Routledge, 1989. Citation reference for this article MLA Style Lowes, Elanna Herbert. "Transgressive Women, Transworld Women: The Once ‘Bad’ Can Make ‘Good’ Narratives." M/C Journal 8.1 (2005). echo date('d M. Y'); ?> <http://journal.media-culture.org.au/0502/04-herbertlowes.php>. APA Style Lowes, E. (Feb. 2005) "Transgressive Women, Transworld Women: The Once ‘Bad’ Can Make ‘Good’ Narratives," M/C Journal, 8(1). Retrieved echo date('d M. Y'); ?> from <http://journal.media-culture.org.au/0502/04-herbertlowes.php>.